Ethical and regulatory requirements for conducting researcher-driven large-scale multinational genetic haematological studies: the INHERENT experience

Abstract

Background

The International Hemoglobinopathy Research Network (INHERENT) focuses on studying genetic modifiers through large, multi-ethnic genome-wide association studies involving paediatric and adult patients with haemoglobinopathies. The growing integration of genetics and genomics into global healthcare has highlighted the need for standardized policies on biospecimen and data handling. This study describes the necessary ethical and regulatory framework for conducting multinational, researcher-driven genetic studies on humans.

Methods

Key areas related to the INHERENT study were identified through collaborative research. A review of the grey literature was performed, consulting official sources. An online survey was conducted to identify the local rules.

Results

Despite the availability of 33 international documents applicable to the three key areas of our investigation, i.e. personal data processing, clinical research and biospecimen management, there is no unique reference for genetic studies without investigational drugs, i.e. outside the scope of good clinical practice. Specific laws and guidelines/recommendations governing the processing of personal data and privacy have been released in most of the 32 surveyed countries. As an example, discordances were found regarding the requirement to get approval from the ethics committees.

Conclusions

Such heterogeneity challenges the scientific community in conducting these genetic studies. This study calls for further efforts to harmonize international standards for genetic research.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12961-025-01375-z.

Background

Within the field of rare haematological diseases, multinational collaborations are key to advancing scientific discovery and improving treatments [1]. The International Hemoglobinopathy Research Network (INHERENT) was formed in 2020 to study the role of genetic modifiers in hemoglobinopathies through large, multi-ethnic genome-wide association studies (GWAS)[2–4]. For this purpose, a global, multicentre clinical study involving both paediatric and adult patients affected by hemoglobinopathies is ongoing (NCT05799118) [5]. In this framework, an ad hoc multinational working group with researchers and experts in regulatory, ethical, legal and societal issues has been established (Ethics Working Group) to guide on compliance with the applicable ethical and regulatory requirements.

The implementation of genetics/genomics into the global healthcare sector has advanced the need for standardized policy regarding all aspects of biospecimens handling and data processing, including data collection, storage, sharing and dissemination of the results. The successful implementation of these policies strongly enhances the ability of researchers to collect biospecimens and biomedical data that are geographically distributed to adequately reflect the genetic diversity of the human population [6–11].

Health data represent a special category of personal data. They can be collected both from clinical practice and clinical research through (electronic) health records, claims and prescription data or within patient registries. Notably, the crucial need for sharing and reusing internationally sensitive health data, such as genetic data, and biospecimens, raises ethical and legal issues, especially in the field of rare disease research [11, 12]. They include privacy and discrimination, the right to access research findings and informed consent [13, 14], the risk of data breach that can lead to participants stigmatization, and the risk of incidental findings and of providing information about participants’ family members [10].

The globalization of biomedical research requires strict compliance with both international and local standards for the protection of human subjects. The Declaration of Helsinki [15] established the framework for human research ethics worldwide and set ethical principles such as the privacy right, the oversight of an independent ethics committee (EC), informed consent, as well as publicly accessible research results.

However, the disparate national settings that determine ethical and regulatory rulings further affect the conduct of multinational clinical studies [16–18]. It is estimated that there are over 1000 laws, regulations, and guidelines in 133 countries worldwide on the conduct of human research [19]. It has been shown that in African, Latin, and North American countries, the ethical and regulatory frameworks are heterogeneous and challenging, as demonstrated in the field of genomic and biobanking research [17, 20–22]. In the European Union (EU), the regulation in this field is changing too, showing differences among countries [17, 23]. Recently, the EU has issued EU-wide regulations on clinical trials [24] and data protection [25].

Complying with the existing data-sharing policies, especially the harmonization across sites, has been considered one of the major ethical and administrative challenges [26]. Each site has its own study protocol and consent forms, and the institutional review board at each site requests conditions on the basis of institutional policy and local procedures [16].

Within the scientific community, different practical concerns have also been raised pertaining to sharing data and biological samples, the use of healthcare data for scientific research purposes, the rights of data subjects and further processing of health-related data [11, 27].

This lack of uniformity demands the creation of overarching regulatory frameworks and the facilitation of international collaborations, as well as the development of a more complete understanding of regional laws [28]. Ethical and regulatory discrepancies result in a greater effort to guarantee an ethical standard among trial sites in the case of a multinational study. For instance, the written and oral information should be guaranteed in the same way in all centres and customized according to the cultural, political and social settings [17]. Furthermore, these matters might directly or indirectly impact patient engagement, participation rates and ultimately, multinational study outcomes, because they make the preparatory and authorization phase slower, and subsequently the study start-up and conduct.

Harmonization is one of the main objectives of supra-national initiatives, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) [29] and the Council for International Organizations of Medical Sciences (CIOMS) [30].

Additional efforts have been made by the Global Alliance for Genomics and Health (GA4GH) [31], established in 2013, which aims to accelerate progress in genomic research and human health by implementing a common framework of standards and consistent approaches for genomic and health-related data sharing. Two key documents have been released by this not-for-profit non-governmental alliance, one on the “Framework for Responsible Sharing of Genomic and Health-Related Data” [32] and one on “Privacy and Security Policy” [33].

Currently, an international ethical and scientific standard is available only for interventional clinical trials testing medicines, i.e. ICH E6 (R2) and Good Clinical Practice (GCP) guidelines [34]. Therefore, for other types of clinical studies where GCP is not applicable, a unique internationally approved standard establishing roles, requirements and procedures is lacking.

This work aims to describe the applicable ethics and regulatory framework needed to conduct a researcher-driven multinational genetic study involving human subjects. We focused our attention on the general principles, procedures and laws in this field considered applicable in the countries involved in this study. This helped to facilitate compliance with both the international and local rules within the INHERENT network focused on hemoglobinopathies.

Methods

Identification of the key topics

Through a collaborative research approach among experts in regulatory, ethical, legal and societal issues and researchers participating in INHERENT [35], the Ethics Working Group (WG) identified the key research topics related to the implementation of a genetic study involving human subjects.

Grey literature analysis of the relevant international standards

We collected the most recent version of official documents (recommendations, guidelines, considerations, concept papers, standards, among others) provided by international organizations engaged in the health and research field without any commercial interest, and currently applicable to clinical research with genetic analyses [29, 30, 36–40]. We also analysed whether they included provisions on genetic research.

We also explored the European [41–43] and American [44–48] frameworks, given their widespread influence on international regulatory practices, while acknowledging the importance and diversity of other regional approaches. All the documents were then classified according to the identified key topics (Supplementary Material: Supplementary Table S1).

Identification of the applicable local rules

A separate analysis was performed to retrieve the country-specific rules, including laws, acts, guidelines and recommendations, applicable to the conduct of genetic studies involving humans.

To this aim, an online questionnaire was run from July 2021 to March 2022 via LimeSurvey^® tool [49]. It was built by the INHERENT Ethics WG on the basis of the identified key topics (Supplementary Material).

For each topic, the aspects related to genetic analyses were specifically considered and included in the questionnaire.

Local experts who were engaged in biomedical research, ethics and legal matters were identified within the INHERENT network and invited to participate in the survey; at least one reference person was detected per country. Participants were allowed to answer on the basis of their own experience and knowledge; therefore, the possibility to choose the “I do not know” option was offered. Remote technical and content assistance was provided as well.

A total of 100 invitations were sent out, covering 43 countries, as shown in the Supplementary Material: Supplementary Fig. S1.

Data analysis

Data collected from the survey was extracted for each country. In cases of multiple responses from the same country, agreement between answers was sought; in case of inconsistencies, reference people were re-contacted.

For each topic, the following variables were analysed:

• Applicable provisions

• Informed consent for data processing and research conduct

• Approval of the EC/competent authority (CA) for clinical research and data processing for research purposes

• Provisions for data and sample collection, storage, transfer and destruction

• Secondary use of samples and data

• Specific provisions for children and vulnerable populations

• Specific provisions for genetic tests

The “I don’t know” answers were considered as not available data and were not included in the percentage calculation; therefore, the percentages were based on acquired responses (denominator).

On the basis of the identified topics and the geographical distribution of the responses, a descriptive analysis was performed to describe all variables. A cluster analysis was conducted to identify groups behaving similarly. Percentages across four continents were calculated: Africa, the Americas (North and South), Asia and Europe.

Results

Key topics

Three key human subjects’ genetic research topics were identified:

• Processing of personal data, as defined by the General Data Protection Regulation (GDPR) [25];1

• Clinical research, as defined by the Clinical Research Roundtable [50], including genetic research;2

• Management of biospecimens, as defined by the National Heart, Lung and Blood Institute (NHI) – Biologic Specimen and Data Repository Information Coordinating Center Glossary [51]3.

The first topic covers rules on handling sensitive personal data, such as health and genetic information, the transfer of personal data and the secondary use of them.

The second topic focuses on genetic research involving adults and children, including rules for informed consent, assent and the approval process by EC and relevant authorities.

The third topic outlines provisions for collecting, storing, transferring and disposing of samples, including those from children and vulnerable groups.

International standards

After consulting the official sources, 33 documents were identified and included in our analysis [14, 15, 25, 52–81] (Supplementary Material: Supplementary Table S1). Among them, 13 (39.4%) cover issues related to genetic research.

As shown in Fig. 1, 26 of the identified documents (78.8%) deal with clinical research, 24 (75.8%) with data protection and 15 (45.5%) with biospecimens management. To note, 24 documents cover more than one topic; therefore, they were counted more than once.

Fig. 1.

Number of international documents identified by consulting the official sources by topics

The selected documents included two declarations from the World Medical Association (WMA) [15, 76], six ICH guidelines [34, 58–61, 80] and two CIOMS guidelines [62, 63]. Two of the ICH guidelines [60, 61] specifically refer to genomic research.

In addition, other documents in the European and American frameworks were considered. With regards to the EU framework, the Oviedo Convention [64], further complemented by an additional protocol [65] that defines the fundamental rights of participants in biomedical research, and two European recommendations, one on research on biological materials [66] and one on paediatric studies [81], were identified. In this context, Convention 108+ of the Council of Europe [57] should also be highlighted, as it provides a comprehensive legal framework for data protection, including the processing of health-related data in biomedical research, thus reinforcing the protection of participants’ rights and privacy.

With regard to the United States framework, several provisions were found:

• The International Compilation of Human Research Standards [67], regularly updated since 2005 and divided into nine categories, five of them specifically relevant to our research: Drugs and Devices, Clinical Trial Registries, Privacy/Data Protection, Human Biological Materials and Genetic;

• The six provisions from the National Institutes of Health (NIH) [68–71, 77, 78], three of them specifically dealing with genomic research [68, 69, 77];

• Two Office for Human Research Protection (OHRP) guides [72, 73];

• A Food and Drug Administration (FDA) guide [79].

Furthermore, although not mandatory, the Nuremberg Code, Directives for Human Experimentation [52] and the Belmont Report [74] are strongly recommended in the United States.

Applicable national and local rules

Out of 43 countries where the questionnaire was received, 32 completed the survey, as shown in the Supplementary Material: Supplementary Fig. S1. The response rate was 37%, as detailed in Table 1.

Table 1.

Descriptive analysis of variables related to the local frameworks on data protection, clinical research and biospecimens management per continent

Local framework	Variables	Percent of positive answers across continents
		Africa [8] (%)	Americas [4] (%)	Asia [9] (%)	Europe [11] (%)
Data protection	Informed consent required	100%	100%	88.9%	100%
	Secondary use	100%	100%	100%	100%
	Data transfer	100%	100%	88.9%	100%
	EC approval	100%	100%	100%	90.9%
	CA authorization	75%	75%	66.7%	87.5%
Clinical research	Secondary use of samples	100%	100%	100%	88.9%
	EC approval	100%	100%	100%	100%
	CA authorization	80%	66.7%	50%	88.9%
	Informed consent	100%	100%	100%	100%
	Assent	100%	66.7%	90%	90%
	Separate consent for genetic tests	25%	66.7%	62.5%	62.5%
Biospecimens management	Provisions for sample collection and management	75%	100%	50%	80%
	Provisions for storage	100%	100%	71.4%	87.5%
	Provisions for transfer	100%	100%	77.8%	77.8%
	Requirements for genetic tests	60%	50%	66.7%	83.3%
	Measures for paediatric and vulnerable populations	100%	75%	75%	80%
	Measures for sample destruction (consent withdrawal)	75%	100%	71.4%	87.5%

The number of countries is indicated in brackets. The percent values represent the number of positive answers out of the total number of responses collected

For five countries (i.e. Nigeria, Malaysia, Belgium, Germany and Sri Lanka), two completed questionnaires were received; therefore, for these countries, agreement was reached between answers, as detailed in the Methods section.

Data protection

Overall, 88% (22/25; data not available for 7 countries, as detailed in the Supplementary Material, Supplementary Table S2) of respondents confirmed that the processing of personal data is regulated by a national law in their own country.4 The survey respondents declared that no specific law has been issued in Azerbaijan, Bangladesh or Pakistan.

Of note, in Pakistan and in Bangladesh, laws on data protection were not implemented at the time of the survey (2021–2022); in Azerbaijan, Law on Personal Data of 11 May 2010 was already in force at the time the survey was conducted, but it was not reported by the respondents.

In 10 out of these 22 countries (45.5%), guidelines and/or recommendations, policies and templates for the processing of personal data were also adopted, thus complementing the national laws in force. Most of these countries (17/22; 77.3%) also have provisions related to genetic data specifically.

Informed consent is required for data processing in 96.3% of the countries involved (26/27; data not available for 5 countries, as detailed in the Supplementary Material: Supplementary Fig. S2); in Bangladesh, it is not required.

The secondary use of data is definitively allowed in all [23] countries providing data (data not available for nine countries, as detailed in the Supplementary Material).

In most countries (28/29; 96.6.%; data not available for 3 countries, as detailed in the Supplementary Material), approval from an EC is required to process personal data for health research purposes. In addition, 16 of these countries (16/28; 55.2%) declared that authorization from a national CA should be sought. Overall, the CA authorization for such data processing varies and is required in about 50% of countries across all the continents (Supplementary Material: Supplementary Table S2).

Data transfer to third parties is allowed in most countries (23/24; 95.8%; data not available for 8 countries, as detailed in the Supplementary Material), while in Brunei it is not allowed (provided certain conditions are met), as declared by survey respondents. In 4 out of 23 countries (17.4%), i.e. Azerbaijan, Bangladesh, Italy and Malta, a data transfer agreement (DTA) is not mandatory when data sharing is expected (Fig. 2). To note, provisions on transfer/sharing of data can apply differently if the transfer is foreseen between countries that have settled on a framework of mutual recognition of an adequate data protection rule, e.g. EU and United States, or within the EU [25].

Fig. 2.

Data transfer to third parties/other countries. Data transfer is allowed in 23 countries out of 24 (95.8%). Specifically, in the majority of them (19/23), a data transfer agreement (DTA) is mandatory

Ad hoc provisions for children are included in the laws/guidelines of 19 countries (19/22; 86.4%; data not available for 10 countries, as detailed in the Supplementary Material).

Clinical research

Most of the respondents (27/27; 100%; data not available for 5 countries, as detailed in the Supplementary Material) stated that local laws, regulations or guidelines ruling clinical research exist in their own country (Supplementary Material: Supplementary Table S3).

All respondents confirmed that approval from the EC is required to conduct clinical research (Supplementary Material: Supplementary Table S3). In four countries (4/27; 14.8%), a national EC was established, while in most countries (23/27; 85.2%) more than one EC is in place (Fig. 3a).

Fig. 3.

(a) Ethics committees (EC) per country. In most countries (23/27; 85.2%), more than one EC is established. (b) Number of countries requiring ethics approval per type of studies, i.e. interventional clinical trials with/without drugs, non-interventional clinical studies, and clinical studies on genetic data with drugs

The EC approval must be sought for interventional clinical trials with drugs, non-interventional clinical studies, and clinical studies on genetic data with/without drugs in all the countries, except in Denmark, where ethics approval is not requested for non-interventional clinical studies, and in Azerbaijan, for clinical studies on genetic data (Fig. 3b).

Respondents from 18 countries (18/25; 72%; data not available for 7 countries, as detailed in the Supplementary Material) state that authorization from the CA is also required for clinical research, but this is related to a great variability across continents ranging from 50% in European countries to 38% in Asian countries (Supplementary Material: Supplementary Table S3).

Informed consent must be obtained from study participants in all the countries of our sample.

With regards to assent from minors, it is required for participation in research in 26 out of 29 (26/29, 89.7%; data not available for 3 countries, as detailed in the Supplementary Material: Supplementary Table S3). In contrast, in other analysed countries, namely Azerbaijan, Portugal and the United States, assent is not mandatory (Supplementary Material: Supplementary Table S3), although it is encouraged.

The legal age of consent is 18 years of age in most of the countries (28/29; 96.6%); Angola sets the legal age of consent at 15 years, while it is 16 years in Canada (as a general rule, as it may vary across provinces), Cyprus and the United Kingdom. In 14 countries (14/17; 82.4%; data not available for 14 countries), the investigator must ask the minor for confirmation/modification/withdrawal of the parental consent when she/he reaches the legal age of majority. This is not required in Malta, Tanzania, Belgium and Sri Lanka.

A separate informed consent for genetic tests must be obtained in 13 countries (13/24; 54.2%; data not available for 8 countries, as detailed in the Supplementary Material), while in 11 (11/24; 45.8%) a separate consent is not required (Supplementary Material: Supplementary Table S3).

The storage of collected samples for future research use is allowed by law in 25 countries (25/26; 96.2%, data not available for 6 countries, as detailed in the Supplementary Material: Supplementary Table S3). This is not allowed in Malta.

Biospecimens management

Specific laws and/or guidelines/recommendations on biospecimens management are in force in 21 out of 24 countries (65.6%, data not available for 8 countries, as detailed in the Supplementary Material: Supplementary Table S3).

Provisions for storage duration, appropriate data safety and confidentiality conditions, planned de-identification measures, among others, were identified in 18 countries (18/23, 78.3%; data not available for 9 countries, as detailed in the Supplementary Material).

Provisions for the transfer of biospecimens to other countries were identified in 23 countries (23/27; 85.2%; data not available for 5 countries, as detailed in the Supplementary Material), as shown in Fig. 4. Respondents from some countries specifically mentioned the need for special permissions from national CA or EC to transfer samples across boundaries (i.e. Zambia, Pakistan, the Democratic Republic of the Congo, Bangladesh and South Africa).

Fig. 4.

Available provisions for biospecimen transfer across countries. Provisions to transfer biospecimens were identified in 23 countries out of 27 (85.2%)

Table 1 provides a comparative overview by continent of the percentage of positive responses related to key provisions of data protection, clinical research and biospecimen management, highlighting significant heterogeneity of local requirements and practices.

Special measures for handling biological samples for genetic tests are available in fewer countries (10/10, 100%; data not available for 12 countries), as well as measures for handling biospecimens in paediatric and vulnerable populations (e.g. size-/age-appropriate tools, noninvasive procedure, maximum of blood) (11/18; 61.1%; data not available for 14 countries), as detailed in the Supplementary Material.

In 15 countries (15/21; 71.4%; data not available for 11 countries, as detailed in the Supplementary Material: Supplementary Table S4), the existing laws and guidelines include measures for the destruction of the samples, in case of consent withdrawal.

Discussion

Multinational collaboration brings many advantages to clinical research, notably in challenging settings such as paediatrics and rare diseases, where knowledge and expertise are limited, and patients’ populations are often geographically dispersed [12, 82, 83]. However, as mentioned in the Introduction, multinational studies are more complex to carry out, especially because of the diversity of legal frameworks and operational practices. This complexity is particularly evident when these studies are initiated by academia that usually lacks on-site relevant expertise and resources [17, 84]. Hoffmann et al. highlighted that regulatory and legal support is essential for the quality and coordination of investigator-initiated studies [85].

Our study shows that a unique international ethical and regulatory environment is lacking to guide multi-regional genetic studies that fall outside the scope of GCP [17], despite the availability of several guidelines issued by international organizations, such as CIOMS, ICH and WMA, and cover issues related to genetic research with humans.

We also confirmed the heterogeneity of the local regulatory systems [17, 20–22], particularly concerning clinical studies with genetic tests. This is challenging for the scientific community and affects clinical research in general, but also the processing of personal data and the management of biospecimens.

Our analysis of the information collected on these fields highlights both areas of convergence and meaningful differences across the regions involved (Africa, the Americas, Asia and Europe).

In the field of data protection, regions traditionally well-represented in international research, i.e. the Americas and Europe, have similar/aligned regulatory frameworks: key principles, such as the requirement for informed consent, ethics approval, data transfer and secondary use of data allowed, are broadly observed. Asian countries also demonstrate strong adherence to these principles, although with slightly lower percentages in specific areas, such as informed consent (88.9%) and secondary data use (87.5%), potentially reflecting variations in regulatory interpretation or implementation. Notably, the requirement for authorization from CA varies more widely across regions; while this is universally applied in the Americas (100%), it is less reported in Africa (75%) and Asia (66.7%). Europe presents a slightly higher level of implementation (87.5%).

Regarding clinical research, there is a strong and consistent commitment across all regions to fundamental ethical safeguards, including informed consent and ethics approval. However, divergences emerge in relation to more specific regulatory practices. For example, assent for minors is required in Africa (100%) and Europe (90%) but appears less consistently applied in the Americas (50%). Similarly, the use of separate consent for genetic testing is reported less frequently in Africa (25%) and the Americas (50%), while being more commonly adopted in Asia (66.7%) and Europe (62.5%).

CA authorization also reflects variable practice, with values ranging from 50% in the Americas and Europe to 88.9% in Africa, suggesting differing national requirements or administrative procedures.

Biospecimen management reveals further variation across regions. Africa stands out for its comprehensive approach, with all surveyed countries reporting the existence of provisions for collection, management and transfer. In contrast, Europe displays a more fragmented picture, particularly with respect to the existence of formal provisions for sample collection (62.5%) and requirements related to genetic testing (66.7%). Protective measures for vulnerable groups and protocols for sample destruction in the event of consent withdrawal are more frequently reported in Europe (80% and 87.5%, respectively) and Africa (100% and 75%), and appear less consistently implemented in Asia and the Americas.

The need and benefits of sharing health data to advance scientific research and improve disease outcomes have been well documented [12, 86]. Our work underlined that specific laws, as well as guidelines/recommendations ruling the processing of personal data and privacy, have been released in most of the surveyed countries. Most of them deal with genetic data, require informed consent and allow for the secondary use of data. However, only some of those already in force deal specifically with the processing of genetic data for research purposes.

Notably, barriers exist when working with a diverse group of countries. For instance, data transfer is not allowed in some countries; in addition, data transfer is forbidden in many Asian countries; for example, Brunei has no specific laws on data protection.

Further discordances exist across countries concerning the requirement to get approval from EC and/or CA authorization, both for processing personal data for research purposes and for performing clinical studies. It should also be considered that such approval depends on the national laws, as well as the establishment of one or more ECs within the same country. In fact, ethics approval is sought in most countries when processing personal data, and worldwide for clinical studies, as well as informed consent from participants. Conversely, the CA authorization varies in all continents, and it is not always mandatory.

Hence, we confirmed discrepancies across countries when performing clinical research.

Specific provisions for informed consent focused on genetic tests should be kept in mind, especially in the genomics era [87]. Nevertheless, our work showed that separate consent for genetic tests is implemented only in a few countries worldwide.

The involvement of children in the consent process of clinical research, according to age and maturity, is crucial. As highlighted by Lepola P. et al., in Europe [88], the assent process for paediatric clinical studies is not harmonized, e.g. in terms of the legal age of consent or need for informed assent from children involved in clinical studies.

Biospecimen management in clinical research is also a challenge, as the legal context to collect, transfer, store and destroy biospecimens is miscellaneous worldwide. Provisions to collect, transfer, store and destroy them are differently implemented in the countries involved, especially the adoption of specific requirements for genetic studies. Focusing on genetic tests in regard to pediatric and other vulnerable populations is even more relevant. This is consistent with previous data showing that a multinational paediatric study involving EU and non-EU countries should be performed in compliance with a set of different rules. For example, in Egypt, the national law prevents the movement of biological samples beyond the borders, unless special authorization is granted from National Security [17].

Our large network has engaged not only countries that are traditionally well represented in the human research landscape but also those historically underrepresented. This inclusive approach has enabled us to capture practice-based insights into the realities of each participating country and to identify both commonalities and differences across national regulatory contexts.

Among underrepresented countries, e.g. Angola, Bangladesh and Côte d’Ivoire, regulatory gaps, especially regarding informed consent, secondary use of data and pediatric protection, were revealed both in terms of lack of specific legislation and in terms of knowledge, considering frequent lack of responses or information.

Even among well-represented countries, certain gaps persist; for instance, the United States and India often lack documented authorization from CAs. In contrast, the domestic regulatory frameworks in Europe appear comprehensive and more harmonized (Supplementary Material: Supplementary Tables S2–S4). These findings highlight the need to strengthen regulatory frameworks in less regulated contexts to promote equity and participant protection in research.

Our work highlighted that additional efforts should be considered to further promote an international harmonization process of the ethical and legal requirements for genetic multinational studies in the non-industry setting.

A stricter collaboration between research networks, such as INHERENT, and existing initiatives (GA4GH, CIOMS, among others) could strengthen international harmonization efforts. In addition, international multi-stakeholder forums might facilitate discussions and implementation of a common practice guiding this kind of research, as already initiated by the Organisation for Economic Co-operation and Development (OECD) Global Science Forum [89]. Ad hoc international standards on the content of the submission package for EC approval and/or CA authorization, the informed consent and assent process, samples and data sharing procedures and requirements for genetic tests should be developed in close collaboration with all the involved stakeholders from different geographical regions.

By mapping the applicable ethics and regulatory frameworks to conduct a multicentre multinational researcher-driven genetic clinical study, this work helped the INHERENT network to comply with both the international and local rules while setting up and implementing its first pilot multinational study, and to address the regulatory variability. In detail, a unique clinical study protocol was prepared for all sites, and the templates for consent, assent, DSA and MTA were designed, all aligned with the applicable requirements. Interactions with the EC were facilitated as well. Overall, the research activities conducted or planned within the network are guided by this approach. This approach was consistent with previous experiences [17, 90]. To build on these insights and address the identified gaps, considering INHERENT as an expanding network, we plan to further extend this work to cover as many countries as possible within other initiatives and surveys.

To this end, the survey will be kept open to anyone interested in participating that can contact the corresponding author for further details.

We deem that this work can lay the groundwork towards implementing more awareness and standardization for genetic multinational, large-scale researcher-driven studies with the final aim to balance research advancements with patients’ interests and ethical principles.

Our work represents the first analysis of the global ethical and regulatory framework for multi-regional genetic studies applied to hempglobinopathies and in general, can be referenced in relation to other human research applications. In fact, we described both the available international standards and the local rules applicable to human genetic research, covering 32 countries worldwide (all continents except Oceania). Therefore, we provide a regulatory tool to guide clinical research activities not only within the INHERENT network but also in genetic studies in other disease areas.

Nevertheless, our study has some limitations. Even if the information was provided by the ethics/regulatory/legal reference persons of the INHERENT network, we got a significant proportion of “I don’t know” responses.

Moreover, often, an official English version of the national documents was not available.

It should also be considered that the applicable regulatory landscape continuously evolves. Therefore, regular revisions should be performed. A comprehensive and in-depth review of all responses could be performed with other national ethical, legal and societal experts, regulators, academia, industry, and patient representatives. The limits of this work might be also overcome in future studies (e.g. multilingual surveys, and training modules for respondents). These efforts would allow us to address the research objectives while respecting all the research participants, including children and patients suffering from rare diseases.

Conclusions

Our work represents the first analysis of the global ethical and regulatory framework for multi-regional genetic studies applied to haemoglobinopathies and in general, can be referenced in relation to other human research applications. In fact, we described both the available international standards and the local rules applicable to human genetic research, covering 32 countries worldwide (all continents except Oceania). Therefore, we provide a regulatory tool to guide clinical research activities.

Nevertheless, our study has some limitations. The information was provided by the representatives of clinical centres on the basis of their knowledge/expertise. It should also be considered that the applicable regulatory landscape continuously evolves. Therefore, regular revisions should be performed.

Overall, this experience emphasizes the need for harmonizing human research out of the scope of good clinical practice (GCP) [29].

Abbreviations

INHERENT

International Hemoglobinopathy Research Network

GWAS

Genome-wide association studies

WG

Working group

EU

European Union

ICH

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

CIOMS

Council for International Organizations of Medical Sciences

GA4GH

Global Alliance for Genomics and Health

GCP

Good clinical practice

EC

Ethics committee

CA

Competent authority

DTA

Data transfer agreement

GDPR

General Data Protection Regulation

NHI

National Heart, Lung and Blood Institute

WMA

World Medical Association

NIH

National Institutes of Health

OHRP

Office for Human Research Protection

FDA

Food and Drug Administration

OECD

Organisation for Economic Co-operation and Development

DSA

Data Sharing Agreement

MTA

Material Transfer Agreement

Author contributions

Conceptualization, design of the work and main manuscript writing: A.D. and V.G.; acquisition and analysis: A.D., E.G. and S.S.; interpretation of data: A.D., V.G., P.K. and S.S.; review: V.G., N.A., E.G., E.P., P.K., F.B. and S.S.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.