Risk–Benefit and Participant Protection

Research involving human participants may be conducted only when its scientific and social value justifies the reasonably foreseeable risks and burdens and when appropriate measures are in place to protect participants throughout the research.

The rights, safety, dignity, and well-being of participants must remain central to study design, ethical review, recruitment, conduct, monitoring, and reporting.

Under the World Medical Association Declaration of Helsinki (2024), medical research involving human participants may proceed only when the importance of the research objective outweighs the risks and burdens to participants. Predictable risks and burdens must be assessed against foreseeable benefits before the research begins, measures to minimize them must be implemented, and risks and burdens must be continuously monitored, assessed, and documented.

Risk–Benefit Assessment

Before research begins, investigators must identify and assess the reasonably foreseeable risks, burdens, and potential benefits of participation.

The assessment should take account of the nature and probability of potential harm, its severity and duration, the characteristics of the participant population, and the scientific and social value of the research.

Relevant risks may include, as applicable:

• physical harm, pain, or discomfort;
• psychological or emotional distress;
• social or reputational harm;
• privacy or confidentiality breaches;
• risks associated with genetic or familial information;
• burdens related to repeated procedures, appointments, travel, or time;
• risks associated with withholding, delaying, or modifying standard care;
• other study-specific risks reasonably foreseeable from the protocol.

Benefits should not be overstated. A distinction should be maintained between direct benefit to the participant, possible benefit to the participant group or community, and the broader scientific or social value of the knowledge expected from the research.

Minimization of Risk and Burden

Researchers must take reasonable steps to minimize avoidable risks and burdens without compromising the scientific integrity necessary to answer the research question.

Risk minimization may include, where appropriate:

• using the least invasive scientifically adequate procedure;
• avoiding unnecessary tests, samples, or repeated interventions;
• coordinating research procedures with clinical care where ethically appropriate;
• limiting the volume and frequency of biological sampling;
• using qualified personnel and appropriate facilities;
• providing suitable pain, distress, or anxiety management;
• minimizing collection of identifiable information;
• implementing appropriate infection-control and safety procedures;
• establishing clear criteria for modifying or stopping study procedures.

The Declaration of Helsinki requires measures to minimize risks and burdens and requires researchers to monitor, assess, and document them throughout the research.

Continuous Safety Assessment

Risk–benefit assessment is not limited to the initial ethics review.

Researchers must continue to evaluate participant safety as the study progresses and consider:

• adverse events and serious adverse events;
• unexpected harms or new risks;
• emerging evidence about the intervention;
• protocol deviations that may affect safety;
• changes in participant condition;
• new scientific information that alters the anticipated benefit;
• cumulative burden from continued participation.

Where applicable, safety information must be communicated to the responsible ethics committee, sponsor, regulatory authority, or independent safety-monitoring body in accordance with the approved protocol and applicable requirements.

Modification or Termination of Research

Research must not continue unchanged when emerging information shows that the original risk–benefit assessment is no longer acceptable.

The protocol should provide appropriate mechanisms for modifying, suspending, or stopping the study when participant protection requires it.

The 2024 Declaration of Helsinki states that when risks and burdens are found to outweigh potential benefits, or when definitive outcomes have been established, researchers must assess whether the research should continue, be modified, or be stopped immediately.

Recruitment targets, publication objectives, financial considerations, sponsor interests, or study timelines must never justify exposing participants to unjustified risk.

Pediatric Risk–Benefit Assessment

Research involving newborns, infants, children, and adolescents requires particularly careful assessment of risks and burdens.

Pediatric participants may experience research procedures differently from adults. Assessment should therefore consider:

• age and developmental stage;
• body size and physiological maturity;
• clinical condition and prognosis;
• ability to understand and anticipate procedures;
• pain, fear, anxiety, and psychological distress;
• frequency and invasiveness of procedures;
• blood volume or other biological sampling;
• interference with sleep, feeding, schooling, family life, or normal development;
• cumulative burden of repeated study procedures;
• long-term and future privacy implications.

A procedure that represents a relatively minor burden for an adult may constitute a more substantial burden for a young child.

The study design should therefore be specifically appropriate for the pediatric population rather than simply adapting adult procedures without adequate justification.

Children Without Prospect of Direct Benefit

Research involving children or other persons unable to provide independent informed consent requires additional safeguards.

The 2024 Declaration of Helsinki provides that persons unable to give free and informed consent may be included only where the research is likely to provide them with personal benefit or where it entails only minimal risk and minimal burden, in addition to the protections required for persons in situations of particular vulnerability.

The inclusion of such participants must be scientifically necessary and ethically justified.

Detailed requirements concerning children and decision-making are provided in Children and Vulnerable Participants and Parental Permission and Child Assent.

Protection of Participants in Clinical Care

Where research participants are also patients receiving medical care, the distinction between research and treatment must remain clear.

Participation in research must not unjustifiably compromise access to appropriate clinical care.

Physicians who combine research with medical care should involve their patients only where participation is justified by potential preventive, diagnostic, or therapeutic value and where there is good reason to believe that participation will not adversely affect the patient’s health.

A research intervention should not be represented to participants as proven treatment when its benefits and risks remain investigational.

Safety Monitoring

The level of safety monitoring should be proportionate to the study’s risk profile.

Depending on study design, this may include:

• regular clinical monitoring;
• predefined adverse-event assessment;
• laboratory or diagnostic monitoring;
• stopping rules;
• interim analyses;
• independent safety oversight;
• a Data and Safety Monitoring Board or equivalent mechanism where appropriate;
• procedures for emergency clinical management.

High-risk research generally requires more intensive and independent monitoring than minimal-risk research.

The monitoring arrangements should be described in the protocol and approved by the responsible ethics committee where applicable.

Research-Related Harm

Participants who experience harm related to research must receive appropriate attention consistent with applicable ethical, legal, institutional, and regulatory requirements.

The 2024 Declaration of Helsinki states that appropriate treatment and compensation for participants harmed as a consequence of research participation must be ensured.

Where relevant, information about arrangements for treatment or compensation for research-related harm should be included in the protocol and explained during the informed-consent process. The Declaration also requires such provisions to be addressed in the research protocol and participant information.

The journal does not prescribe a universal compensation scheme because applicable legal and institutional requirements differ across jurisdictions.

Independent Ethical Oversight

The responsible ethics committee must be provided with sufficient information to evaluate the anticipated risks, burdens, benefits, safety measures, and participant protections.

Where required, the committee or an appropriate safety-monitoring body should receive relevant information about serious adverse events and other developments affecting participant safety.

The 2024 Declaration of Helsinki gives research ethics committees authority to monitor ongoing research, recommend changes, suspend research, or withdraw approval.

Ethics approval does not remove the investigators’ continuing responsibility to protect participants.

Vulnerability and Fair Protection

Risk–benefit assessment should consider whether particular participants or groups may face greater risk because of age, illness, dependency, impaired decision-making capacity, social circumstances, or other vulnerabilities.

Additional safeguards should correspond to the actual source and degree of vulnerability.

At the same time, protection should not result in unjustified exclusion from research that is relevant to the health needs of the population.

The 2024 revision of the Declaration of Helsinki places increased emphasis on participant-centered protection, vulnerability, and fair distribution of research benefits, risks, and burdens.

Post-Trial Protection

For clinical trials, participant protection may extend beyond completion of the intervention period.

Where participants continue to need an intervention that has been identified in the trial as beneficial and reasonably safe, appropriate post-trial arrangements should be considered and established in accordance with the Declaration of Helsinki and applicable requirements.

The 2024 Declaration requires post-trial provisions to be arranged in advance for participants who continue to need such an intervention, subject to ethics-committee-approved exceptions, and requires relevant information to be provided during informed consent.

Detailed requirements may also be addressed in the journal’s Clinical Trials Policy.

Reporting in the Manuscript

Authors should provide sufficient information to permit assessment of participant protection where this is relevant to the interpretation of the study.

Depending on the study, manuscripts should describe:

• important anticipated risks and burdens;
• measures used to minimize them;
• relevant safety-monitoring procedures;
• adverse events or harms;
• reasons for early modification or termination of a study;
• protection of vulnerable participants;
• arrangements relevant to research-related harm;
• other safeguards necessary to understand the ethical conduct of the research.

Safety outcomes must be reported accurately and should not be selectively omitted because they are unfavorable to the intervention or study hypothesis.

Journal Assessment

The journal may request additional information when the risk–benefit balance or participant protection is unclear, including relevant protocol sections, ethics committee documentation, safety-monitoring arrangements, adverse-event information, or explanations of study modifications.

ICMJE requires human research to accord with the 2024 Declaration of Helsinki and confirms that ethics committee approval does not prevent editors from independently judging whether the research was conducted appropriately.

The journal may reject a manuscript where participants were exposed to unjustified or inadequately managed risks, required safeguards were absent, or serious ethical concerns cannot be satisfactorily resolved.

For published work, serious participant-protection concerns may be addressed under the journal’s Research Misconduct, Editorial Actions, and Corrections and Retractions policies.