Comparative analysis of regulatory framework on biobanking to inform policymakers in Central America and the Dominican Republic [version 1; peer review: 2 approved with reservations]

Background.  The clinical and scientific importance of biobanks has been highlighted.  Ethical governance and regulatory oversight for biobanks should be in place to preserve and promote ethical and responsible conduct of research. Methods. This is an analytical documentary study of the regulatory scope concerning biobanks in Central America and the Dominican Republic. From the International Compilation of Human Research Standards 2020 edition of the Office of Human Research Protection Department of Health and Human Services of the United States of America identified the existing guidelines applicable to human research in each of the eight SICA member countries. Regulatory aspects searched for and the analysis was based on the recommendations set forth in Guideline 11 on the collection, storage, and use of biological materials and related data in the International Ethical Guidelines for Research Related to Human Health. Results. There is a lack of specific guidelines for the collection, use, and storage of human biological materials for research purposes, and the creation of biobanks in the countries been studied. No country in Central America and the Dominican Republic region has specific regulations for the creation of biobanks for research purposes. The term "biobank" was not found in the revised regulations. However, there are good examples of ethical governance of research in general in the region been Costa Rica, Panamá, and Guatemala examples of advances towards this direction. Conclusions. There is a need to move forward the governance and regulatory framework of biobanks in Central America and the Open Peer Review


Introduction
Health research involving the use of human biological materials and related data is subject to widely recognised ethical considerations. National and institutional policymakers should adopt international ethical standards to ensure respectful and responsible collection, storage, and use of biospecimens to be used in research 1,2 . The creation and use of biorepositories and biobanks for research purposes is a growing practice around the world. Biorepositories and biobanks offer many advantages to scientific activity, such as resource efficiency, access to biological materials, and the ability to reference related data that enables research that would otherwise not be possible. These advantages, as well as necessities, justify the increasing creation and use of these resource centres. As a result, the number of publications on biobanks has grown steadily over the past two decades. Additionally, the demands of the COVID-19 pandemic has underscored the importance of biobanks 3 .
A biobank is defined as a non-profit-making establishment that collects, processes, stores, and distributes biological samples of human origin and their associated data for research purposes 4 . There are international regulations and specific technical standards for creating and managing biobanks 2, [4][5][6][7][8][9] . Biobanks have been seen as a significant opportunity to advance biomedical research because it optimises the use of resources by avoiding collecting biological samples for each of the thousands of studies carried out in the world. It is a way to take advantage of scarce resources by reusing biological samples and associated data 10 to increase the efficiency of research resources.
Conducting secondary analyses minimises unnecessary duplication of sample and data collection and avoids additional risks on participants 11 . Furthermore, research quality can be improved when various researchers can review and verify the data, thus increasing reliability, reproducibility, and transparency 12,13 . The donor and the family can also benefit, eventually, with the communication of clinically relevant incidental findings. There are relevant advantages of biobanks for the patients, including earlier and cheaper diagnosis, forecast system, new therapeutic targets, and personalised medicine. Biobanks may be useful at the population level in several instances, such as identifying risk factors, a diagnostic tool for prevention, improvement of public health policies, and equity in health.
There are many ethical challenges regarding the establishment of biobanks. Conversely, despite the benefits stated, ethical concerns are diverse [14][15][16] , starting with doubts about getting informed consent (IC). Obtaining the IC is an essential ethical requirement before sharing with third parties the data or material collected. However, IC models require careful consideration before use in biobanks [17][18][19] . The IC may be specific or broad. Specific IC is bound to a particular investigation, while broad IC refers to a donated sample in the context of a study yet to be applied to other unspecified research in the future [20][21][22] . For the biobanks, the recommendation is that IC should be broad to fulfil the functions and purposes of this kind of biorepository.
Another ethical concern is the loss of privacy and confidentiality, which can occur when individual data associated with biological samples are shared 23,24 . For analytical purposes, biobanks may require identifiers from the samples to which they have access. Removing case identifiers (de-identification) is a procedure used to protect individual data. However, there is still a risk of re-identification depending on anonymisation standards. Anonymisation refers to a process of hiding sensitive information to protect confidentiality. The lack of consistency in anonymisation is an ongoing problem 25 , and there is even concern that this is not a sufficient procedure to avoid identifying the donor of the samples.
The challenge of promoting equity is the risk of exploitation. We must explore to what extent biobanks' creation can be useful in promoting justice, building capacity, and sharing benefits. There are fears and distrust given the prevailing view of the harmful results of collaborative research in the past, and there is a perception of protecting local scientists and populations 22 . Another issue related to justice is the inclusion of populations traditionally underrepresented but who do not benefit from the research results and the technologies resulting from them. Involving the community in the different stages of the research project means making them partners in the discussions where the research problem and the method are selected and during the analysis. Utilising community engagement strategies allow research participants and communities to be active entities, not a mere recipient of research outputs. Likewise, it is meaningful to involve them in conversations that seek to implement responsible, efficient, and fair governance frameworks to support the best ethical practices in biobanks and data exchange with cross-border harmonisation. The ethical governance of scientific research occurs within the framework of a broader system 26,27 since it involves the various interest groups recognising their knowledge, attitudes, and perceptions regarding biobanks. Also, it should consider various mechanisms to meet the ethical requirements of this scientific activity 28 . Governance itself has become an object of study 29 , and its been used as a framework in the analysis of the ethics of data sharing and biobanking in health research 30 .
Health research in the member states of the Central American Integration System (SICA) The Central American Integration System (SICA) is the institutional framework for Central American Regional Integration made up of eight countries, including Guatemala, El Salvador, Panama, Honduras, Costa Rica, Nicaragua, Belize, and the Dominican Republic. According to Economic Commission for Latin America and the Caribbean (ECLAC) data (2016), this subregion has more than 57 million inhabitants with an average life expectancy at birth of 75.1 years. It has 63 indigenous peoples. In political terms, the SICA states have had 30 years of peace, democracy, and political stability 31 . While this is true, the last few years have seen reversing trends in the political spheres, and there is a climate of crisis in several SICA countries. In economic terms, Belize's Gross Domestic Product is the lowest (3.22), and the Dominican Republic is the highest in the region (173). The region's unemployment rate ranges from 2.3 to 9%. There are marked differences in health indicators such as infant mortality rate (range 7. 8 -23.3), the maternal mortality rate , and health expenditure (6.1-7.8) (Table 1).
Clinical trials conducted in the SICA Member States during the entire data registration period of 2020 are available on the clinicaltrials.gov website (www.clinicaltrials.gov). A total of 1,119 are reported for SICA Member States; of those 13 in Nicaragua and 308 in Guatemala are reported ( Table 2). As most countries in the region do not have the requirement to register all clinical trials, the number of clinical trials conducted in this region may be higher. In Central America and the Caribbean, there is currently no information regarding the status of normative (laws, guidelines, or recommendations) regulation of the creation of biobanks for research purposes. The problem is that, in the absence of a framework that  The 2018 Global Forum on Bioethics in Research (GFBR) had the theme "data sharing and biobanks." The discussion focused on the main challenges around ensuring participants' rights and the need to increase efficiency in scientific efforts. Key governance issues were identified as a result of discussions among 95 participants from 35 countries 33 . The status of biobank regulations in Central America and the Dominican Republic is currently unknown. The following study aims to analyse the current regulatory framework by identifying deficiencies and gaps in biobanking governance.

Design
This study is an analytical documentary study of the regulatory scope concerning biobanks in SICA member States. Table 3 presents regulatory aspects set out in the guideline Table 3. Regulatory aspects of the collection, use and storage of human biological materials and research-related data as set out in CIOMS Guideline 11.

Regulatory element
Legal status of the biological sample. It is a regime analogous to the donation of organs and tissues of the human body (res extracommercium) Samples as a medium for personal information Data from sample analysis (protection of genetic data)

Biobank definition
Scope of application. The standard refers to cases in which the collection of biological samples of human origin and associated data is applicable for research purposes or when these materials are collected for other purposes but there are expectations of a possible use in research Origin of biological samples. Declaration of origin of samples, collected for the specific purpose of research or for another purpose.
A remnant remains with the expectation of future use in research.
Conditions of consent. Specific IC: specific informed consent for a particular use, broad IC: for an unspecified future use, Children and adolescents: they are asked to consent once they are adults, Results and unsolicited findings, Decisions on aspects not foreseen in the IC, Historical collections of biological samples.

of the International Ethical Guidelines for Health-related
Research Involving Humans applicable to the collection, use, and storage of human biological samples and the creation of biobanks, including topics such as a) the protection of human beings (b) the technical aspects of the organisation, operation, sustainability, closing of biobanks); and (c) the forms and conditions for sharing data, results, and dissemination shared benefits and the involvement of the community and interest groups in research.

Data sources
The International Compilation of Human Research Standards 2020 edition of the Office of Human Research Protection Department of Health and Human Services of the United States of America was used to identify existing guidelines applicable to human research in each of the eight SICA member countries (Table 4). Of the eight countries located in Central America and the Dominican Republic, only Belize have no reported regulations. Nicaragua, which was previously absent at the beginning of this study in 2018, was included in 2020.
Procedures for identifying data The regulatory aspects in Table 3 were used, as a checklist, to review the presence or absence of the regulatory in each country. To facilitate the identification of relevant data, in each regulatory document we conduct a search utilizing the following keywords: "biological material", "biological sample", "biorepository", and "biobank". Also, the content was reviewed thoroughly to make sure that no relevant data was excluded or not identified.

Analysis plan
The analysis plan presents a synthesis of the information found in the review of the regulatory documents in each country. We will focus on Guideline 11 on the collection, storage, and use of biological materials and related data of the International Ethical Guidelines for Research Related to Human Health 34 , in addition to Guideline 7 on community involvement.

Results
The study's first finding was a pervasive lack of specific guidelines for the collection, use and storage of human biological materials for research purposes, and the creation of biobanks in the countries studied. No country in SICA has specific regulations for the creation of biobanks for research purposes. The term "biobank" was not found in the revised regulations. The Costa Rican regulation appropriately covers various protection elements for participants and minimal requirements for laboratories participating in clinical research. Guatemala and Panama also consider several fundamental aspects of the regulation of research involving human beings. However, the necessary provisions for the proper governance and monitoring of the collection and use and storage of human biological materials are meagre.
It is important to note that the current regulatory framework in Central  The following is a summary of the findings for each of the countries with identified regulations (see also Table 4). The following citation appears in this document: "For research already initiated with molecules, invasive clinical procedures, management of blood samples or collection of biological tissues for genetic analysis, which have not received an initial audit, the CNEIS shall indicate an audit of studies already initiated." Additionally, Procedure 3 on "Determining the Type of Project Evaluation" stipulates that expedited evaluation as a possible mechanism for evaluating studies involving materials already collected, which may be data or samples. In El Salvador, there are no specific regulations in this area of biobanking.

Honduras
In Honduras, the Health Code (GACETA NO.26509 DEL 06/08/1991) issued by Decree No. 65-91 of 28/05/1991, in Title III on health professionals in Article 0175 provides the following instruction: "All scientific research involving human subjects must be carried out by professionals specialised in the field and establishments with the appropriate facilities, equipment and materials for each case, following special regulations approved by the Ministry Furthermore, Article 0176 states: "No one may be subjected to the investigations indicated in the previous article, without being previously informed of the risks to which he will be subjected to and without obtaining his written consent or that of his representative in case of incapacity." In this case, the Honduran regulation on organ transplantation alludes to biological samples in educational and research practices.

Dominican Republic
The General Health Law refers to research activity as an essential function of public health. It mentions certain considerations for establishing research priorities, such as the socio-sanitary reality, the causes and mechanisms that determine the modes and means of preventive and curative intervention and the evaluation rigorous of the effectiveness and efficiency of the interventions. Specifically, paragraph 11 refers that the Ministry of Health will prepare the regulations that are required for the application of the listed actions and that investigations should adhere to scientific principles and nationally and internationally approved bioethics.
There is no specific regulation in research, and no content is provided for the collection of biological samples and associated data or biobanks in the revised documents.

Nicaragua
The General Health Law 423 states the role of the Ministry of Health to regulate and promote scientific research in health and biomedical and development and transfer of technology within the Health Sector, also promote the education and training of health researchers. No specific element exists referring to the collection, storage and use of biological materials, and related data and analysis regarding the creation of biobanks for research purposes. Also, in the Ministry of Health there will open a Program and a Committee National Research Council in charge of promoting and prioritizing, issues that contribute to improving the health of the population. The Research must refer to scientific and ethical principles internationally approved. For the application of the indicated actions, will develop a regulation.

Discussion
The present study aimed to analyse the guidelines for collection, storage and use of biological materials, and related data and analysis regarding the creation of biobanks for research purposes in the Member States of the Central American Integration System and the Dominican Republic (SICA).
We have sought to identify gaps in existing regulations that hinder proper governance and adequate protection for people who donate biological material with this analysis. The findings indicate that SICA states have not developed technical, legal, and ethical guidelines or regulations on biobanks. Costa Rica is the only country in the SICA region that displays guidelines for collecting, storing, and using biological materials and related data for research purposes. The Guatemalan regulation has taken steps in that direction but these are not currently sufficient for biobank use.
In other countries, regulatory ethics provisions are much smaller and practically non-existent. Even the fundamental elements concerning the legal status of the biological sample, samples as a medium of personal information, data obtained from the analysis of samples (protection of genetic data), and the collection and use of living donor biological samples, or the use of tissues or body parts have not been addressed from a research point of view. The provisions on organ donation in these countries are not necessarily sufficient or applicable to the research context.
At the same time, the lack of definition creates legal loopholes: what a biobank consists of, its scope of application, the origin of biological samples, standard operating procedures, human resources, infrastructure and operation, distribution of samples and data in transfer agreements, destination of specimens or data, sustainability plan and closure of activities. The existence of national regulations governing biobanks for research purposes in African, Asian, and South American countries indicates a global movement to adopt norms at the local level.
In times of COVID-19, it is relevant to mention the lack of collaboration and the waste of limited resources 34,35 . Many countries have conducted international clinical trials involving the storage of genetic material often shipping those materials outside the country to other facilities and laboratories with the capacity to analyse those samples, without an agreement to transfer biological material. We have found that there are still countries in the Central American region that have not yet established comprehensive and adequate normative frameworks for research involving human beings. This systemic problem must be addressed in a comprehensive way to cover more specific issues such as biobanks, collection, and storage and use of human biological samples.
The current regulations are limited to a subset of ethical matters and leave out important issues. The assertion that in low and middle-income countries, there are no appropriate regulations or governance mechanisms in biobanks is confirmed 36,37 . For example, as De Vries et al. observed in regulations on genetic research in Africa, these are virtually non-existent, outdated, conservative, inefficient or difficult to navigate 23 .
As a document review, this analysis has a limitation: it cannot identify the practices regarding the application of international ethical standards in the collection, storage and use of biological materials, and related data. In this sense, the lack of knowledge of actual practices can only be observed in another type of research design. The deficiency of regulations and their supervision may lead to practices that increase the vulnerability of people who donate biological material and fail to uphold their fundamental rights and human dignity. This study does not capture this incidence. Additionally, in order to provide a full picture of all relevant regulatory aspects concerning collection, storage and use of human biological material it would be necessary to review regulations applicable to the general use of samples, personal data protection laws, human genome (anti-discrimination), and donation of human tissue for research purposes which were not revised in this study.

Conclusions
This review of the regulatory framework of biobanks of the states that make up the SICA region shows the absence of national regulations in this area. The legislation in place is based on fundamental principles of research ethics with human beings and does not incorporate elements contained in current international ethical norms. It is essential to note the interest of SICA authorities in building scientific exchanges in the region, according to a recent call to form research and scientific exchange networks. It is hoped that such initiatives will impact the Central American and the Dominican Republic region. However, under a poorly developed regulatory framework, these initiatives may face many problems accomplishing their goals and meeting international ethical standards when collecting, storing and using human biological samples.
It is highly recommended to launch an initiative based on regional scientific exchange mechanisms and, simultaneously, within the framework of the Council of Ministers of Health of Central America (COMISCA), to advance in the development of a framework of ethical governance in health research relevant to the collection, storage and use of biological materials, and related data covering the creation of biobanks for research purposes as well. Small biorepositories maintained by individual researchers or in research centres may benefit from this kind of regulation. They may scale their biorepositories to a formal biobank as a national and regional biobank that may significantly impact their work. Following this direction avoids the duplication of efforts, the lack of collaboration and formalisation of research that still is a weakness in Latin America 38 . In the midst of difficult times, it is also an opportunity to work together towards a regional mechanism that advance collaboration through international cooperation such as those recently implemented by SICA Executive Secretariat to advance research networks within the region. A similar effort to advance research ethics governance and regulation in biobanking and research, in general, is urgently needed and forthcoming.

Data availability
Underlying data Data pertaining to the regulations discussed in this work are available in Table 4.
11. Tindana P, de Vries J: Broad Consent for Genomic Research and Biobanking:

Introduction
Paragraph 4: The sentence ……conversely, despite the benefits stated, ethical concerns are diverse, starting with doubts about getting informed consent…. may need to be explained further for clarity. I do not think there has been any/much doubt about getting informed consent for sample storage. The main issue seems to be the type of consent (specific, broad, etc.) that may be more appropriate.
In the last paragraph of the introduction, there is an underlying assumption that biobanks are often set up between local and international collaborators and that local sites often do not have the capacity to establish, maintain and use the biobanks. This is not always true. Many countries have set up national and institutional biobanks without international collaborators. If the author is specifically referring to the case in SICA, then this needs to be made clear in the introduction, and information on biobanks in the region should be provided, including why issues of justice, capacity building and benefit sharing should be a major concern. Another example provided by the author on justice-related issues relates to the inclusion of populations traditionally underrepresented but who do not benefit from the research results and the technologies resulting from the use of biobanks. However, a potential reader is left with little information on the nature and types of biobanks in the study region, and if some populations are currently underrepresented or if there are concerns around the exploitation of populations. The paragraph (and the introduction) as a whole needs to provide context to the biobanking situation in the study region Based on the above, I also suggest that the author considers trimming the information on clinical trials, GDP and health indicators and rather include more information about biobanking activities in SICA, including how they compare to each other and why it was necessary to undertake the analysis of national guidelines.

Methods
The manuscript includes information on the CIOMS guidelines (Table 3) and it is stated that the CIOMS guidelines were used as a checklist, to review the presence or absence of specific biobanking regulation in countries in SICA. More information is needed in the methods section on why the CIOMS guidelines selected as a standard for mapping the content of the different national guidelines, and not for example other international guidelines like the Declaration of Helsinki or the OECD guidelines on Human Biobanks and Genetic Research Databases.

Results
The results should also include information on how each country's guidelines compare to the CIOMS e.g. country X met 50% of the CIOMS requirements etc. This is important as it will give the reader an idea of how each country is fairing with respect to the CIOMS. The author may consider including a table that shows each CIOM guideline on biobanking and whether not it is covered in the respective SICA countries.
The title of the paper suggests that this was a comparative analysis of the regulatory framework on biobanking to inform policymakers in Central America and the Dominican Republic. However, in presenting the results, the author gives a narrative description of the guidelines in each country and no major comparison is made. I will suggest that the author considers either 1) revising the title or 2) include a table or text on how the guidelines compare to each other. If the author agrees with the suggestion above, then the table could address this concern.
Minor comments: Page 1: Please provide a reference for the statement on ethical considerations as your potential readers may not be familiar with the range of ethical issues.
The statement "As a result, the number of publications on biobanks has grown steadily over the past two decades" also needs to be referenced.
Introduction could be shortened-some text repeated in paragraphs one and three on the uses/importance of a biobank.
Paragraph 4-First sentence can be dropped-it is repetitive.

Is the study design appropriate and is the work technically sound? Yes
Are sufficient details of methods and analysis provided to allow replication by others?
biomedical and genomic data, is global. Just an example: BGI, a Chinese genome-sequencing company, is receiving information from most than 50 laboratories worldwide to create China's national library of genomic data. ( see https://www.foreignaffairs.com/articles/united-states/2021-02-10/technology-innovation-wars) ( https://en.genomics.cn/) In sum: I think that this article offers a valuable opportunity for analyzing the current shortcomings existent in Central American and Caribbean biobanking regulations and, as such, it deserves to be published. However, the article would gain interest if the author would elaborate a little more on the laws on the use of personal information related to biomedical research considering the novel aspects generated by globalization, the use of Big Data, and existing biotechnological advances.

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate? Not applicable