Identifying serious and complex ethics issues in
EU-funded research

05 July 2021

Disclaimer:This document has been drafted by a panel of experts at the request of the European Commission (DG Research and Innovation) andaims at raising awareness in the scientific community, and in particular with beneficiaries of EU research and innovation projects. It
does not constitute official EU guidance. Neither the European Commission nor any person acting on their behalf can be made responsible
for the use made of it.
Legal notice: This Guidance Note does not create any new obligations on the European Commission, Executive Agencies or researchers
completing their Ethics Self-Assessment.
Acknowledgements:
This document was prepared by the Research Ethics and Integrity Sector, Directorate Research & Innovation, the European Commission
with a collaboration with ethics experts under the supervision of Albena KUYUMDZHIEVA (DG R&I, currently EISMEA) and Ben HAYES.
The main contributors were experts: Ioannis BENEKOS, Vedran KATAVIĆ and Marjo RAUHALA and Siobhán O' SULLIVAN and the staff
members of the Research Ethics and Integrity Sector, DG R&I: Lisa DIEPENDAELE, Yves DUMONT, Francesco DURANTI (currently HADEA)
and Edyta SIKORSKA.
The document was consulted with the following ethics experts: Jacques DE KEYSER, Edward Stellwagen DOVE IV, Jan-Hendrik HEINRICHS,James A HOUGHTON, Vasiliki MOLLAKI and Doris SCHROEDER.
The Research Ethics and Integrity Sector, DG R&I would like to thank all those concerned.
European Commission
DG Research & Innovation
RTD.03.001- Research Ethics and Integrity Sector
E-mail: RTD-ETHICS-REVIEW-HELPDESK@ec.europa.eu
ORBN
B-1049 Brussels/Belgium

21. Introduction
EU-funded research must comply with ethical principles and relevant European, national and international legislation,
including the EU’s Charter of Fundamental Rights and the European Convention on Human Rights and its Supplementary
Protocols.1
All research activities must respect:
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the principle of proportionality
the right to privacy
the right to the protection of personal data
the right to physical and mental integrity of all persons
the right to equality and non-discriminationhigh levels of protection of the environment and human health.2

All proposals, which successfully pass the scientific evaluation and are likely to be funded, shall be systematically screened
to identify those activities raising complex or serious ethics issues. Such proposals shall be submitted to an ethics
assessment by an independent ethics panel, pursuant to established procedures for Horizon Europe funded research.3
This Guidance note aims to guide those independent ethics experts with responsibility for screening proposals andidentifying whether serious and complex ethics issues are likely to arise in the execution of those projects. This
document is also designed to help applicants identify any such issues while preparing their proposals (and understand why
their proposal may have been selected for an ethics assessment).
The seriousness and complexity of the ethics issues are assessed on a proposal-by-proposal basis. It is quiteplausible that research proposals on very similar topics or involving similar techniques are assessed differently in terms of“seriousness” and/or “complexity”, if they have different approaches, methodologies or potential outcomes.
Established fields of scientific research, such as medicine and clinical practice, are subject to legal regulation and wellestablished norms and principles through which serious and complex ethics issues can be identified and addressed, while
this may not be the case with new technologies and applications, which may raise novel and challenging ethical concerns.
If the activities are standard practices, with a clear legal/ethics framework, the related ethics issues should
not in the meaning of Horizon Europe be considered as serious or complex as they should be addressed by at
local, regional and national level, should receive appropriate ethics approval/s and should not undergo an
ethics assessment. In such cases of standard practices, there should be no need of ethics advisors or advisoryboards.
Please note that this Guidance Note should be read in conjunction with wider European Commission (EC) Ethics
rules and guidance notes. For more information, please consult:
How to complete your ethics self-assessment
Online Manual on Funding & Tender Opportunities Portal
Ethics and Data Protection
Ethics in Social Science and Humanities
Other useful links are also available under the Ethics section of the Horizon Europe Program Guide
For research involving human embryos (hE) or human embryonic stem cells (hESC), an ethics assessment is always
mandatory.4 For all other projects, independent ethics experts will be determining which projects constitute serious and/or
complex ethics issues and should be sent for ethics assessment.

1 See Article 19 of the Horizon Europe Framework Programme and Rules for Participation Regulation (EU) 2021/695 (OJ L 170, 12.5.2021)
2 Ibid.
3 Ibid.
4 See Article 19(3) of the Horizon Europe Framework Programme and Rules for Participation Regulation (EU) 2021/695 (OJ L 170, 12.5.2021)

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2. Serious and/or complex ethics issues– general approach
Generally, ethics issues arise whenever research involves:humans participants, and/or their cells/tissues
personal dataanimalsmethods, materials or experiments that could harm the environment, research staff or participants.

Or when research is conducted:
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in locations where the safety and security of researchers and participants may be jeopardised
outside the EU, especially in countries that lack adequate regulation and/or have a limited capacity to enforce therelevant ethical standards and guidelines. Ethics issue may arise, for example, due to the situation in a particulararea or due to the specificities of the local cultural context.

Ethics issues can also take the form of concerns about the potential misuse of new technologies, innovations, applications
or research findings – even where research projects have benign intentions.
To determine whether specific ethics issues are “serious” or “complex” (or both), we use the general indicators andcriteria, as set out below. Specific indicators and criteria that may assist in determining whether specific ethics issues may
be deemed “serious” or “complex” (or both) follow in the subsequent sections.
Generally, ethics issues raised by research activities may be considered as “serious” when the proposed research,
method(s), or outcome(s):have the potential to violate fundamental rights or freedoms set out in the EU Charter of Fundamental
Rights and European Convention on Human Rights, or undermine fundamental EU values such as human dignity,
freedom, democracy, equality and the rule of law; orhave the potential to result in significant harm to researchers, research participants, the public, animals or
the environment; orin light of the European Code of Conduct for Research Integrity, fundamentally call into question the integrity ofthe data and information included in the proposal or the integrity of the practices of the researchers;orEthics issues raised by research activities may be considered as “complex” when the proposed research, method(s) or
outcome(s):involve the development or application of particularly complicated methods or technologies that have notbeen sufficiently tested and give rise to uncertainty as regards to the safety of participants and/or the
impact of the expected results or outcomes on fundamental rights or research integrity; orraise significant ethics issues ‘at scale’ – for example, due to the number of research participants,
controversial methods, high-risk technologies or jurisdictions involved; orraise multiple or ‘intersectional’ ethics issues – meaning that the ethics issues may compound one anotherto exacerbate the potential impact on a particular group (e.g. research into marginalised or vulnerable groups that
exposes them to the risk of stigmatisation, exclusion, reprisals or increased marginalisation).

The ethics issues pertaining to a particular research proposal may also be considered as ‘serious and/or complex’ if:

the area of research is the subject of widespread debate among scientists and ethicists and the specificmethods or techniques involved get to the heart of those debates; orthere are grave doubts about the capacity of the researchers or participating institutions to effectively
mitigate the risks arising from the project’s execution; orthere is a high risk that the research results/findings could be misused, and adequate measures to mitigate orcontain this risk cannot be identified or implemented; orthere is an objective and serious lack of awareness of key ethical issues in the proposal.

43. Specific serious or/and complex cases
This section provides examples of indicators and criteria, that may help you determine whether the ethics issues raised bya particular project could be considered “serious” and/or “complex”.
It is not an exhaustive list. Each research proposal has to be assessed on its own merits – if you identify substantial
ethics concerns that are not covered in this section, you can still recommend a proposal for ethics assessment.
The following research activities are not eligible for funding under Horizon Europe:
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research activities directed at human cloning for reproductive purposes;
research activity intended to modify the genetic make-up of human beings that could make such changes heritable(apart from research relating to cancer treatment of the gonads, which may be financed);research activities intended to create human embryos solely for the purpose of research or stem cell procurement,
including the technique of somatic cell nuclear transfer;5
research that leads to the destruction of human embryos;
research that does not have exclusive focus on civil applications;No funding shall be granted, neither within nor outside the EU, for research activities that are prohibited in all the Member
States. No activity shall be funded in a Member State where such activity is forbidden.6
Research on human stem cells (both adult and embryonic) may be financed, depending both on the content of the scientificproposal and the laws of the Member States involved.

3.1 Human embryonic stem cells (hESCs), human embryos (hEs), human cells and tissues
For all research activities involving human embryos or human embryonic stem cells, an ethics assessment is mandatory,
the provision of Statement by the Commission on ethics/stem cell research – Art. 19 apply, and the funding of hESC or hE
proposals requires and must be approved by the Horizon Europe Programme Committee.7
The ethics issues pertaining to the use in research of other categories of human tissues/cells may be considered “serious
and/or complex” if these are, for example:collected within the project from vulnerable groups (e.g. children, unconscious patients, or patients otherwise
lacking capacity to consent, prison populations) or involve foetal or embryonic tissue (other than hESC) collected
within the project orused in organoid research concerned with neurological conditions or applications; or involving human multiorganoid complexes or related to the development of synthetic/artificial reproductive cells or organs (e.g.
development of ova, in vitro gametogenesis (IVG)), or involving gastruloids or embryoids.

3.2 Humans
Humans must be considered as ‘research participants’ whenever they are recruited, observed, actively engaged, or in any
other way may be influenced, manipulated, or directed by the research. Regardless of the nature, methods, or topic of the
proposed research activities (e.g. collecting biological samples, using personal data, medical interventions, interviews,
observations, tracking etc.), ethical issues may arise in any research involving humans.
These issues may be considered as “serious and/or complex” when the proposed research, for example:

has the potential to result in significant harm to the participants (or researchers), such as significant physicalpain or bodily harm not related to simple routine medical procedures (e.g. taking a blood sample), psychological

5 See Article 18(1) of the Horizon Europe Framework Programme and Rules for Participation Regulation (EU) 2021/695 (OJ L 170, 12.5.2021)
6 See also Article

18(2) of the Horizon Europe Framework Programme and Rules for Participation Regulation (EU) 2021/695 (OJ L 170,
12.5.2021)
7 See Article 11(4) of the Horizon Europe Specific Programme Decision 2021/764 (OJ L 167I)
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harm, personal embarrassment or humiliation, or other harm that may adversely affect the participants in asignificant way; or

employs covert methods or deception that may cause harm to participants (or researchers), or entails
participation in unlawful activities (e.g. following persons making irregular border crossings or supplying illegal
goods or services), or is unnecessary for the realisation of significant scientific, educational, or appliedvalue of the research; orincludes children/minors/people unable to give informed consent, with no clear justification for their
participation or benefit to them; orinvolves highly vulnerable participants, such as people exposed to or affected by multiple or intersecting
vulnerabilities (e.g. refugees or migrants facing extreme poverty, gender-based stigmatisation, or violence), or
methods that have the potential to significantly exacerbate the vulnerability of already vulnerable groups orindividuals; orincludes vulnerable participants in first in-human or early-stage clinical studies for new therapeutics(including new chemical entities, biologics, gene therapies), medical applications and procedures; orinvolves ‘challenge trials’, in which participants are intentionally exposed to an infectious disease that
may result in severe or chronic illness, or when participants have underlying medical conditions that increase
their risks for severe illness; orinvolves clinical studies concerned with end-of-life or emergency care and related clinical decision-making;or

deploys medical devices, particularly implanted devices, that aim to or have the potential to bring about
involuntarily behaviour change or therapeutic ‘adherence’; or

involves potentially traumatising topics (e.g. recounting of personal experiences of war, refugee flight,
violence, assault, abuse, life-threatening illness or injury); oraims to improve human performance by interventions in or on the human body (human enhancement8) – inthe form of implants, drugs, genetic enhancement or machines. This concerns especially interventions that are
irreversible, internal to the body, have long term impacts (physical, psychological, social), have a limited timespanor require updates; or have implications for the privacy of groups and individuals; orinvolves untested forms of human bio-engineering, human-machine integration or human-animal
chimeras; orsuggests the potential coercion of research participants through excessive or inappropriate financial
compensation, or because their relationship to the researchers suggests that their consent may be obtained undersome form of duress or out of a sense of obligation; orimplies the circumvention of EU labour law by ‘crowdsourcing’, ‘micro tasking’ or ‘outsourcing’ the research(e.g. research-related tasks undertaken by remotely located "crowd workers", who may be situated anywhere in theworld, to perform discrete on-demand tasks); or

uses high-risk or inappropriate techniques and methods that may expose participants to unacceptable risk(e.g. insecure online surveys addressing sensitive issues or processing sensitive/special category data, methods
that encourage participation by vulnerable groups without regard to their vulnerability); or

involves studies whose findings carry a high risk of exposure or identification of individuals and/or
stigmatisation of a minority or marginalised group (e.g. on the basis of poverty, ethnicity, religion,
gender/gender identity, disabilities, age, sexuality or perceived involvement in illegal activities); or

8 Human enhancement is a modification aimed at improving human performance and brought about by science-based and/or technology-based

interventions in or on the human body (Sean R. Jensen, Saskia Nagel, Philip Brey, Tanne Ditzel, Rowena Rodrigues, Stearns Broadhead, & David
Wright. (2018). SIENNA D3.1: State-of-the-art Review: Human Enhancement (Version V1.1). Zenodo: https://zenodo.org/record/4066557#.YEo_y2l1pQ)
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involves studies on human sexuality (e.g. research on assisted reproduction, fertility, pregnancy termination,
gender reassignment and transgender issues).

3.3 Incidental or unexpected findings
Incidental or unexpected findings are traditionally associated with clinical research but may occur in human and social
science research as well. Such findings fall outside of the scope of the principal research objectives but necessitate action
on the part of the researchers.
The handling of incidental or unexpected findings may raise ‘serious and/or complex’ ethics issues as such findings can havea significant impact on research participants’ wellbeing, cause psychological distress to researchers, raise safety or
safeguarding issues, or require the researcher to disclose the information to appropriate or designated authorities.
Therefore, the ethics issues in a particular project may be considered as ‘serious and/or complex’ when the proposed researchis likely to yield, for example:
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medical or genetic incidental findings that may have life-changing consequences for research participants
due to their likely impact; orsocial or behavioural unexpected or incidental findings that may require may require interventions tosafeguard the well-being of research participants (e.g. signs of physical abuse, self-harm, or drug
dependency or neglect in minors); or

findings that are subject to positive disclosure obligations under international or EU law, or the national lawsof a country (EU or non-EU) in which the research takes place, requiring researchers to breach the confidence of
research participants. Examples include criminal conduct such as war crimes, child sexual exploitation, humantrafficking or terrorism.

3.4 Safety and security
The safety and security of everybody involved in research – whether as participants, investigators, interlocutors,
communities or third parties impacted by the research – must be a priority in all research proposals.
The ethics issues raised by a particular project may be considered as ‘serious and/or complex’ if the proposed research, forexample:

involves considerable health and safety risks to researchers and/or participants; or

takes place in a situation of international or internal armed conflict, other situations of violence(including domestic violence) or humanitarian crises or emergencies; or

takes place in a political climate that is hostile to the research topic or its objectives and endangers
researchers, research collaborators (including third party collaborators contracted to assist with the research
activities in the relevant location, even if the research staff themselves remain in another location) and/or research
participants; orinvolves the use of potentially harmful substances, processes, technologies, organisms or materials in amanner that raises significant concerns about individual security or safety or the protection of public health.

3.5 Animals and the environment
The EU has signed international conventions and adopted legislation regulating the use of animals in scientific experiments
and protecting the natural environment, its flora, fauna and biodiversity.
In this respect, the ethics issues in a particular project may be deemed ‘serious and/or complex’ if the proposed research,
for example:

has the potential to result in significant and irreversible harm to the environment, flora or fauna; orinvolves experimentation on animals that enjoy particular protection (e.g. non-human primates, animals
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living in the wild, endangered species) without clear benefit to their species or habitat; orinvolves untested forms of animal bio-engineering, animal-machine integration or animal interspecies
chimerism or synthetic biology; or

has the potential to result in significant pain or distress to animals, without a clear justification and/or
sufficient measures to alleviate/prevent such suffering.

3.6 Research in non-EU countries
Conducting research activities, partially or wholly, in a non-EU country can raise numerous ethical issues, particularly inresource-limited settings. Special care must be taken to avoid any ‘double standards in research and support equitable longterm research relationships between partners in lower-income and high-income settings, based on fairness, respect, care andhonesty’.9
In this respect, the ethics issues related to research activities conducted outside of the EU may be considered as ‘serious
and/or complex’ if the proposed research, for example:
appears to take advantage of differences in standards or the absence of legislative protection forresearch participants, local researchers and other local staff, data protection and privacy, animals, the environmentor the public, particularly in lower-income settings; orseeks to exploit scarce or protected local resources, without benefit-sharing community consent (wherepractised and relevant) and/or appropriate permission from relevant local authorities; or

takes place in a setting where the subject matter or research methods are likely to be perceived ashighly controversial by a local community; ordoes not envisage community assent, obtained through recognised local structures and/or local ethics
approval in the country where the research takes place; orinvolves risks of stigmatisation or discrimination, or the possibility of self-incrimination, for either theparticipants, investigators, interlocutors, communities or other stakeholders involved; orinvolves or impacts indigenous people or vulnerable minority groups without sufficiently taking into accountthe local context, vulnerabilities, core beliefs or value systems.

3.7 Data protection
Personal data refers to all information relating to an identified or identifiable natural person. All data controllers andprocessers, including researchers and service providers, must protect personal data in accordance with the EU General Data
Protection Regulation (GDPR) and the respective national and sectorial legal framework.
An identifiable natural person is someone who can be identified, directly or indirectly, in particular by reference to an
identifier such as a name, an identification number, location data, an online identifier or to one or more factors specific to
the physical, physiological, genetic, mental, economic, cultural or social identity of that person.10
Even if service providers and external collaborators are engaged in the research, the obligation to safeguard data
subject’s rights and freedoms rests with the principal researchers (e.g. the beneficiary and partners of a consortium).
This obligation cannot be ‘outsourced’ or delegated (e.g., when surveys are conducted or data is processed or hosted bythird parties or subcontractors). For more details, please consult the ‘Ethics and Data Protection’ guidance note.
The ethics issues related to the processing of personal data in a particular project may be considered as ‘serious and/or
complex’ if the proposed research, for example:

9 Global Code of conduct for research in resource-poor settings
10 Article 2(a) EU General Data Protection Regulation (GDPR).

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envisages the large-scale collection of special category data11 and/or data related to criminal
convictions and offences, if the intended processing poses a significant risk to the rights and freedomsof the research participants; orinvolves the covert observation or deception of research participants, to collect sensitive/special
category data; oruses personal data that was not collected or otherwise provided by the data subjects for research
purposes, and for which the data subjects may have a legitimate objection to (e.g. data collected from‘closed’ or private groups on social media platforms, covert activity trackers or sensors in connected devices, theprocessing of an identifiable individual’s telecommunications traffic or geolocation data); or

carries a significant risk of breaching privacy or confidentiality that is likely to result in threats to data
subjects’ physical safety, loss of business or employment opportunities, humiliation or damage to their reputation
or relationships, or

involves profiling and/or systematic monitoring of individuals or group of individuals, and/or intrusive
methods of data processing (e.g. data-mining, web-crawling, social network analysis, geolocation tracking); or

results in the transfer of special category data to countries with inadequate data protection regimes,12
without the knowledge or explicit consent of the data subjects.

3.8 Development, deployment and use of Artificial Intelligence (AI) and other new and emerging
technologies
Whereas established fields of scientific research, such as medicine and clinical practice, are subject to legal regulation andwell-established norms and principles through which serious and complex ethics issues can be identified and addressed,
this may not be the case with new technologies, which may raise novel and challenging ethical concerns.
The particular ethics issues raised by developing or deploying new technologies will depend on the context, use case or
nature of the application. Specific caution is warranted for technologies that may pose a high risk of harm to people’s healthand safety or fundamental rights and freedom.
Examples of high-risk areas and applications that involve new and emerging technologies include:
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biometric identification systems;
the administration of justice;law enforcement;
migration, asylum and border control;
democratic processes and institutions;the operation of essential critical infrastructure and services;
access to education and vocational training;
employment and worker management;
access to public or private services and social welfare programmes.

When assessing the seriousness and/or complexity of the ethics issues involved in developing or deploying new technologies,
you should take into consideration the type of research being proposed, the technological readiness level, as well as theseverity and likelihood of the potential harm.
The ethics issues related to the use of new technologies in a particular project may be considered as ‘serious and/or complex’
if the proposed research involves the development, deployment or use of, for example:
11 Special categories of personal data (formerly known as ‘sensitive data’) include personal data revealing racial or ethnic origin, political opinions,religious or philosophical beliefs, or trade union membership, and the processing of genetic data or biometric data for the purpose of uniquely identifying
a natural person, data concerning health or data concerning a person's sex life or sexual orientation (Article 9(1) GDPR) EU General Data Protection
Regulation (GDPR).
12 How the EU determines if a non-EU country has an adequate level of data protection: https://ec.europa.eu/info/law/law-topic/dataprotection/international-dimension-data-protection/adequacy-decisions_en
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surveillance technology that is not necessary or proportionate in a democratic society – for example
due to the degree of intrusion, its blanket or indiscriminate effect, or lack of safeguards for affected individuals;or

societal scoring, automated behavioural or psychological profiling, or the use of econometrics or artificial
intelligence, to make probabilistic determinations about individuals and their behaviour, groups or entire
populations that could violate human dignity or lead to stigmatisation, or discrimination against them; orsystems/techniques that have the potential to lead to significant negative social impacts (e.g. on democracy,
media, labour market, freedoms, educational choices, mass surveillance) and/or significant negativeenvironmental impacts – either through intended applications or plausible alternative uses; orsystems/technique aimed at replacing or influencing human decision-making processes in a way likely toadversely impact affected individuals (e.g. issues affecting human life, health, well-being or human rights, or
economic, social or political decisions) or have the potential to circumvent the autonomy of those individuals;orsystems/techniques/technology that can lead to new manipulative, exploitative or social control practices;or

systems/techniques/technology with the potential to have harmful implications for human rights, subordinate,deceive or manipulate people, violate bodily or mental integrity, create attachment or addiction, or hide
the fact that people are interacting with AI.

3.9 Misuse
The findings or outputs from research projects with benign intentions may have the potential to harm humans, animals or
the environment if used for purposes other than those intended. While many research findings have the potential for misuse,
the development or production of certain types of materials, methods, technologies or knowledge may pose a greater riskof unethical use than others may.
The ethics issues related to the potential misuse of findings or outputs or knowledge gained from a particular project may
be considered as ‘serious and/or complex’ if the proposed research, for example, concerns the development of:

surveillance technologies that – if deployed – are likely to have harmful implications for human rights orunduly restrict civil liberties; or

social, behavioural, medical or genetic profiling technologies that could be used to stigmatise, discriminate
against, harass or intimidate people, or to limit their autonomy; ormaterials, methods, technologies or knowledge that could tangibly result in serious harm to humans, publichealth, animals or the environment if they were released, modified or enhanced; orpublicly available tools that could expose exploitable flaws in the cyber- or physical security of criticalsectors (e.g. energy, transport, water, health, communications or finance).

10References and further reading
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How to complete your ethics self-assessment
Online Manual on Funding & Tender Opportunities Portal
Horizon Europe Program Guide
Horizon Europe Framework Programme and Rules for Participation Regulation (EU)
Ethics and Data Protection
Ethics in Social Science and Humanities
European Code of Conduct for Research Integrity
Statement by the Commission on ethics/stem cell research – Art. 19
Commission Recommendation on internal compliance programmes for controls of research involving dual-use items
Potential misuse of research results
Research focusing exclusively on civil applications
Global code of conduct for research in resource-poor settings
SIENNA Ethical guidance for research with a potential for human enhancement
Guidance note on research on refugees, asylum seekers and migrants

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