Regulation of Tissue Engineered Devices in some Latin American Countries: Development and External Influences*

Background : Emergence of new technologies and advances in tissue engineering strategies to treat diseases are shifting the conventional conception of medical devices. Tissue engineered products, manufactured as a combination of biomaterials, cells, and/or bioactive factors, are intended to temporarily restore an organ or tissue function, and induce the generation of newly site-appropriate functional tissue. Regulatory pathways for tissue engineered products require grouping policies controlling each of the components: materials, human cells, and active molecules. Purpose : To review current regulatory policies for medical devices (and within this, tissue engineered products), in a subset of Latin American countries, and to analyze the influence of international organizations and technological world power countries on policies of that subset. Methods : Top-down and horizontal diffusion models were employed to identify how regulatory policies have moved to Brazil, Colombia, Ecuador, Mexico, and Peru. Results : There are differences in technological appropriation to comprehensively define and classify medical devices. None of the countries have a definition of tissue engineered products. A top-down diffusion pattern was found to be associated with the current regulations. A horizontal diffusion is being applied as a regional effort to facilitate commercialization of medical products within Latin America. Conclusion : The concept of tissue engineered products is slowly arriving into the evaluated Latin American countries. Each country has the potential to take advantage of local institutions and regional and inter-regional coalitions to improve current guidelines and prepare the health system to the introduction of tissue engineered products.


INTRODUCTION
With the emergence of tissue engineering applications as an alternative treatment to restore, repair or replace damaged organs in the human body, new medical devices and implantable materials are being produced (1). Research, development, and clinical applications of tissue engineered products have been mostly made in post-industrialized countries like the United States of America, the United Kingdom, some members from the European Union, and Japan. In parallel to product development, these countries have concentrated their efforts in the establishment of new regulatory policies aimed at not only controlling the commercialization of tissue engineered products, but also defining their path from the bench to the bed side, evaluating risks and benefits, and ensuring efficacy of the treatment and security of the patients.
As a result of the high investment and technological resources needed, advances in tissue engineering applications in Latin American countries are lower when compared with developed countries. Even though the clinical applications of tissue engineered products seem to be far from the reality, in part due to elevated costs and lack of coverage by health systems, some initial efforts are being applied for the development of alternative treatments to injuries that otherwise could not be treated by conventional means (2,3). In light of the limitations that emerge from applications that are new in health care systems, it is analyzed here whether the concept of tissue engineering is conceivable within the regulation for research and development of medical and implantable devices in a subgroup of Latin American countries: Brazil, Colombia, Ecuador, Mexico, and Peru.
Additionally, an evaluation of the influence exerted by international public and private organizations upon the existing policies for tissue engineering applications in the studied Latin American countries is included.

TISSUE ENGINEERING: DEFINITION, COMPONENTS, AND FACTORS
The field of tissue engineering has emerged as an interdisciplinary area that combines efforts from biology, medical sciences, and engineering, to design and produce functional substitutes of damaged tissues/organs that due to their extent cannot be repaired by the own biologic system (4).
Tissue engineering applications are of particular interest as an alternative to organ donation strategies, which have been associated with disadvantages in terms of long-life immunosuppression and a limited number of organ donors, among others. Tissue engineered products are intended as temporary substitutes that provide mechanical and functional support while inducing the reparative process within the tissue. For instance, they are ideally composed of a degradable scaffold material to bring the required three-dimensional structure, an adequate source of cells, and bioactive molecules, all of which are employed individually or in combination (1). For this reason, tissue engineering applications can have cell-based approaches, as occur with stem cell injections (5), whereas other applications have scaffold-based approaches, in which an in vivo cell infiltration is expected (6). More complex applications involve the implantation of already cell-seeded scaffold materials (7).
Each constituent of the tissue engineered product has important considerations that should be taken into account and that should be a matter of strict regulation to ensure successful clinical applications. First, scaffold materials which can be produced from synthetic (i.e., polymers), biosynthetic (i.e., polyhydroxyalcanoates), or natural (i.e., xenogeneic or allogeneic extracellular matrix-derived scaffolds) sources, are chemically and structurally different, and therefore could positively or negatively be associated with distinctive responses within the body (8). Factors such as the host response to the implanted scaffold material and the biocompatibility should be evaluated before any intended clinical application (9). The host response in general and in particular the plasticity of macrophages interacting with the scaffold materials, are the determinant factors defining long term outcomes of site appropriate functional tissue remodeling vs. foreign body reaction (10). The term biocompatibility refers to the ability of the implanted scaffold material to perform a tissue-specific function without eliciting a detrimental immune host response, characterized by chronic inflammation and development of a foreign body reaction, which ultimately can influence the failure of the tissue engineered product (10)(11)(12).
Second, it has to be recognized that inclusion of cells within the tissue engineered product increases the complexity of the clinical approaches. When cells are seeded on the scaffold material prior to implantation, an adequate cell source (i.e., autologous vs. heterologous stem cells), the mechanisms for vascularization, and the risks of cell manipulation, are among the factors that should be considered (13). Lastly, addition of bioactive molecules like cytokines, growth factors, or differentiation-stimulating factors, which are needed to promote cell migration, and differentiation, also require a detailed attention. The use of high doses and their release in the circulatory system might have adverse effects in other tissues, raising questions about the safety of the patient receiving the implant (14).
Based on the combinatorial options of tissue engineered components, the required regulatory pathways to commercialize tissue engineered-derived products might vary considerably. Whereas products containing cells require extra controls and highly trained personnel, less complex products (composed solely by the scaffold material) might provide more versatility as they can have a defined and longer shelf life, be shipped, and manipulated without requiring advanced training.

TISSUE ENGINEERED PRODUCTS
The development of a common regulatory framework for assurance of effectiveness and safety of medical devices in a global perspective started in 1992, when a group of medical device regulatory authorities from the European Union, the United States of America, Canada, and Japan formed the Global Harmonization Task Force (GHTF), now identified as the International Medical Device Regulators Forum, IMDRF. The objective of the GHTF was to generate a regulatory consensus for medical devices and practices involving medical devices (15). Likewise, an original aim was to provide assistance in the regulatory process for medical devices in developing countries (16).
The harmonized guidelines include a definition of medical devices as "any instrument, apparatus, implement, machine, appliance, implant, in vitro reagent or calibrator, software, material or other similar or related article: a) Intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the specific purpose(s) of: • Diagnosis, prevention, monitoring, treatment or alleviation of disease… or an injury, investigation, replacement, modification, or support of the anatomy or of a physiological process, supporting or sustaining life, control of conception, disinfection of medical devices, providing information for medical or diagnostic purposes by means of in vitro, examination of specimens derived from the human body; and b) which does not achieve its primary intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its intended function by such means." (17).
Additionally, this guideline provides the final agreement of classification of medical devices based on risk assessment, which means, the probability of that device to generate damage and the evaluation of the severity of the harm produced. The classification system proposes four different risk-based categories (Table 1), and within each one, a comprehensive sub-classification according to invasiveness, bioactivity, and time of contact with the body. The classification and subclassification systems allow for a straightforward searching to determine the risk level of a specific medical device (17).
The harmonization does not explicitly include tissue engineered products, which are the focus of this work; however, they do present options where these products could fit in a regulatory analysis.
Specifically, they would be included into the group D, since they would contain animal-or humanderived cell or tissue components, bioactive components, and degradable materials.

AMERICAN COUNTRIES
The following section will focus on the identification of the tissue engineering term among the regulations for development, manufacturing, and commercialization of medical devices in a subset of Latin American countries: Brazil, Colombia, Ecuador, Mexico, and Peru. The sections will also provide information regarding the mechanisms of classification of medical devices according to the factors identified for tissue engineered products in these countries.

Brazil
In Brazil, the entity in charge of regulating manufacturing, packaging, imports, and commercialization of medical devices is the National Health and Surveillance Agency (ANVISA, Agência Nacional de Vigilância Sanitária). Under the Resolution RDC No. 185 of 2001, ANVISA provides the orientations for registering, validating, and modifying the commercial rights of medical products in the country. According to this entity, a medical product is defined as any equipment, material, or system used to prevent, treat, or rehabilitate patients. Medical products cannot exert their main function through pharmacological, immunological, or metabolic means.
The medical products are classified from I to IV, according to the intrinsic risk that they represent for the patients using them (18). Both risk classification and sub-classification are similar to the guidelines established by the GHTF.
Based on the proposed system of classification and considering the definition of tissue engineered products, those medical devices intended to accomplish functions of tissue repair would belong to class IV devices. The resolution includes the cases of biologic derived materials and combined materials with bioactive molecules (drugs); however, it does not consider regulatory mechanisms of complex tissue engineering applications where the cellular components are included. Devices not intended for connection of an active medical device or connected to a class A device, for a transient use.
Surgically invasive Reusable surgical instruments.

Low-Moderate Risk
Non-invasive Devices connected to a medical device in class B or higher. Devices for storing or channeling blood or other body liquids or for storing organs, parts of organs or body tissues. Devices for filtration, centrifuging or exchanges of gas or of heat of blood, other body liquids or other liquids intended for infusion into the body. Devices that come into contact with injured skin devices principally intended to manage the microenvironment of a wound.
No surgically invasive (used through body orifices) Devices not intended for connection of an active medical device or connected to a class A device, for short term use. Devices that are intended to be connected to an active medical device in class B or a higher class.

Surgically invasive
Devices intended for a transient or short-term use and designed for a single use. Implantable devices, and long-term surgically invasive devices intended to be used in the teeth.

Risk Level Invasiveness
Intended use C

Moderate-High Risk
Non-invasive Non-invasive devices intended for modifying the biological or chemical composition of blood, other body liquids or other liquids intended for infusion into the body. Non-invasive devices which come into contact with injured skin intended to be used principally with wounds which have breached the dermis and can only heal by secondary intent.
No surgically invasive (used through body orifices) Devices not intended for connection of an active medical device or connected to a class A device, for long term use.

Surgically invasive
Transient or short-term devices intended to supply energy as ionizing radiation. Transient devices intended to have a biological effect or be partially/totally absorbed. Short term devices intended to have chemical changes in the body. Transient or short-term devices intended to deliver medicines. Implantable devices, and long-term surgically invasive devices.

D High Risk
Non-invasive or invasive All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, and which is liable to act on the human body with action ancillary to that of the devices. All devices manufactured from or incorporating animal or human cells/tissues/derivatives thereof, whether viable or non-viable Surgically invasive Transient, short term, or long-term devices intended to diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with these parts of the body. Short term or long-term devices intended to have a biological effect or be partially/totally absorbed. Short term devices intended for use in direct contact with the central nervous system. Implantable and long-term devices intended to be life supporting or life sustaining. Implantable and long-term devices intended to administer medicines. Implantable and long-term devices intended to have chemical changes in the body.
Resolution RDC No. 56 of 2010 provides regulations for cell banks working with hematopoietic stem cells derived from bone marrow, peripheral blood, umbilical cord, or placenta, for autologous or allogeneic transplants (19). The use of hematopoietic stem cells is restricted to the correction of defects of the bone marrow or restoration of the hematopoiesis after chemotherapy processes involving damage of the myeloid and lymphoid precursors. The isolation of other cell types (e.g., mesenchymal stem cells) for therapeutic use in tissues other than blood, is not considered within the regulation, and therefore its application in tissue engineered approaches is limited.
In 2010, following an international trend in bio-therapeutic products lead by the World Health Organization (WHO) (20), ANVISA released the Resolution RDC No. 55 to regulate the registration process of biological and biotechnological products in the country for marketing purposes. It includes both products manufactured in Brazil and imported from approved companies to commercialize them in the country. The final goal of the resolution is to guarantee quality and efficacy of biologic medicines, therefore ensuring safety of the patients (21). For instance, the regulation provides mechanisms to control hormones, growth factors, and bioactive molecules that could be used for tissue engineering applications.

Colombia
Colombia has a regulatory system similar to the one described in Brazil. The regulation for licensing for the production, processing, packaging, storage, commercialization, import/export, As seen for the other countries described, the medical devices are defined as articles, instruments, devices, or artifacts, for use in diagnosis, treatment, or prevention, to replace or modify the anatomy or physiological processes in the body. They are classified according to their use (therapeutic or diagnostic), invasiveness (non-invasive or invasive), and risk level (I: very low, II: moderate, III: high, IV: very critical) (28). The regulation, however, does not provide a comprehensive association between the classification criteria (use and invasiveness with risk level).
Additionally for less than 30 days, invasive products for more than 30 days) and safety (defined as "proved" or not in patients) (31). Based on the specific descriptions of the intended use, tissue engineered products will be ranked within class III, since it covers invasive materials that will last more than Under the regulation of CENATRA, Mexico entered in the international efforts to control biologic medicines (32), within the exact same terms used in Brazil, Colombia, and Ecuador. Additional norms are found for the use of human organs and tissues for therapeutic purposes, specifically for transplants (33).
Lastly, the CNTS is in charge of the norms regulating the acquisition and use of hematopoietic stem cells (34) Herein, a medical device is defined as an instrument, machine, material or any other article to be used in the treatment or alleviation of a disease or lesion. It involves also research, replacement, modification, or support of the anatomy or a physiological process (35). Both definitions could include the objective of a tissue engineered product, but the term was not explicitly stated.
Medical devices are classified according to the risk that they represent. Like in the definitions found for the equivalent regulation in other countries, medical devices are ordered as low, moderate, high, or critical risk potential (35). However, as occur with the regulation in Ecuador, the specific parameters that should define the risk levels are not explained in the Law. The same information is found in Decree 016-2011-SA, which regulates Law 29459, and includes the consideration of risk level for medical devices as suggested in the GHTF (36), but the exact descriptions are not provided in the document.
The Decree also has the requirements for commercialization of biologic products. No additional information, compared to those found in other countries' regulations, is present here. Peru relies in the information provided by other countries, which the regulation frames as "countries with high sanitary surveillance", such as France, Holland, United Kingdom, United States, Canada, Japan, Switzerland, Germany, Spain, Italy, Belgium, Sweden, Norway, Australia, Portugal, Denmark, and Korea, to get the certificates to import products for commercialization in the country (36).
On the other hand, the National Organization of Donation and Transplants (ONDT, Organización Nacional de Donación y Trasplantes) was created as the entity in charge of the regulation of human tissue donation for therapy (approved by Law 28,189 of 2004) (37), bone marrow and hematopoietic stem cells transplants (38).

MEDICAL DEVICES IN LATIN AMERICA: WHERE DOES THE REGULATION COME FROM? AND HOW ARE THEY EVOLVING?
From the information above, it can be perceived the similarity of the regulation for medical devices among the studied countries. The information however is more comprehensive in some countries (Brazil, Colombia, and Mexico) than in others (Ecuador and Peru), showing a lack of reflection in the process of policy adaptation.
Regulatory mechanisms being applied in the reviewed Latin American countries have a strong influence from international regulations being applied through global coalitions among the regulatory agencies. It is evident however a less restricted, and lower developed system of evaluation policies for tissue engineered products. These differences provide a window of opportunity for applying clinical research that might not provide the safety and efficacy that should be guaranteed to the patients.