Attention to impeccable ethical standards is mandatory for all clinical research, especially research involving human individuals. The ethical landscape associated with clinical trials can be particularly nuanced and complicated. As such, researchers have a fundamental duty to safeguard the welfare of study participants and conduct research with risks that are proportional to the expected benefits.

The scientific question of interest must justify the risk or need for a clinical trial. Equipoise is the concept that a clinical trial is needed due to the collective uncertainty about the superiority of one treatment vs an alternative.¹ While equipoise may not be present at the individual practitioner level, equipoise to justify a clinical trial must exist at the collective level among experts in the medical community with respect to the treatments being compared. The clinician should always be aware of their potential role as a double agent—that is, both researcher and treating health care professional. At times there may be a conflict between patient care and the needs of the trial. In all instances, the needs and care of the patient or trial participant must predominate. All human individuals in clinical trials have certain rights, including the ability to discontinue the clinical trial and continue with standard of care treatment, privacy and confidentiality, and informed consent. Informed consent must include not only the patient’s permission, but also assurances that the individual understands all the risks and benefits. Informed consent should include disclosure (ie, discussion of relevant and germane information such as risks and benefits), confirmation of patient understanding (ie, a probative question-and-answer period to ensure the patient has achieved thorough understanding), and patient decision-making (ie, patient analysis of the information and discussion of goals, potential outcomes, and ultimately the choice to participate or not).² From a practical perspective, information required in a consent document should include the nature of the research, its purpose, and alternatives to participation in the study. To verify that consent is given voluntarily, the conditions under which it is obtained should be free of undue influence.¹ As such, the person obtaining consent should not be the patient’s treating physician; rather, an objective third party who is knowledgeable and involved with the trial is generally best to discuss the trial and obtain consent. Deferred consent—whereby patients are enrolled first and then asked to provide informed consent later—may be allowed under specific conditions. Specifically, deferral of consent to participation in a study is permitted to avoid delaying emergency interventions; however, in such cases, proxy consent is preferred and should be sought. Children younger than 18 years are generally not permitted to give consent for medical procedures and treatments. Rather, parents are typically the primary decision-makers for their children. Children who are old enough to understand medical discussions should be asked to give assent for care. Assent means that the child is agreeing to the treatment or procedure. Children being asked to participate in a clinical trial should have the research and treatment as well as risks and potential benefits explained to them and their parents.

The importance of informed consent emanates from several historical events and established principles. Following the heinous criminal and unscientific behavior of physicians in Nazi Germany, the Nuremberg trials helped to define international standards for the ethics of experimentation with human participants.¹ In addition to voluntary consent, the Nuremberg Code established other principles: trials must have a basis in biological knowledge and preclinical experimentation, procedures should avoid unnecessary risk and injury, risks should be proportional to the importance of potential findings, participants can stop participation, and studies must be conducted by qualified scientists. The Helsinki Declaration, another formal code of ethics for physicians engaged in clinical research, was initially proposed in 1964 and has subsequently been revised multiple times.³

In 1974, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research created the mandatory requirement for institutional review boards (IRBs) for all human research funded by the national government. Today, pursuant to the common rule and federal regulations, specific criteria must be met for an IRB to approve a protocol for the involvement of human participants.⁴ In particular, IRBs serve to review clinical trial protocols to determine whether the proposed study and participant population have been determined to ensure the lowest risks possible. Selection of the study population is important to ensure that a suitable patient population is included in the clinical trial.⁵ In particular, special considerations need to be given to protect vulnerable populations (eg, due to age, physical or emotional maturity, mental incompetent, comorbidities, economic or social status, education level, and incarceration status), as well as to ensure an equitable and diverse study population.⁶ The clinical trial protocol should clearly delineate whether the research provides potential benefits directly to participants or society such that the IRB can determine whether the risks to participants are justified by the potential benefits and thus whether the research can be approved. To that end, the proposed interventions or procedures and selection of specific participant populations need to be performed in such a manner to mitigate or eliminate risk and discomfort to participants. In preparing an IRB application for a clinical trial, researchers should define what interventions or procedures are to be performed as part of standard clinical care vs solely for research purposes, as well as how participation in the research study differs from treatment the patient would otherwise receive if not in the study.⁴ In addition, the existing evidence for the proposed study intervention needs to be delineated. The protocol needs to clearly ensure that procedures and policies are in place such that research personnel do not inadvertently increase risks to participants. To this end, all personnel engaged in human subjects research need to undergo training in ethical principles and regulations governing such research. All individuals conducting a given trial should also have the appropriate requisite technical training to carry out any study procedure.

Clinical trials will also generally require a data monitoring plan as well as the establishment of an independent data and safety monitoring board (DSMB).⁷ The members of the DSMB serve to periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and efficacy; in addition, the DSMB may make recommendations about the continuation, modification, or termination of the trial.⁷ Clinical trial investigators need to clearly define how adverse events and unanticipated problems will be reported to the IRB, DSMB, and study sponsor, as well as outline how these problems or adverse events will be handled to ensure timely reporting and participant safety and the ongoing validity and privacy of the data. Routine monitoring of data from clinical trials is important because preliminary data may signal the need to change the research design, change the information presented to participants that may affect their willingness to continue participation, or terminate the project before the scheduled end date.¹ While the IRB’s primary role is not to review scientific or methodological rigor, good science is ethical science. In turn, rigorous well-conducted clinical trials that lead to reliable evidence regarding therapeutic efficacy are foundational to ethical human subjects research.

Investigators involved with clinical trials need to be familiar with ethical considerations related to trial design and implementation as well as analysis and reporting. Human subjects research demands the highest ethical standards to safeguard society and the individual.

It is essential that researchers be familiar with ethical considerations related to trial design and implementation and ensure rigorous statistical analysis and data reporting (eg, power calculation and intent-to-treat reporting). Research protocol and relevant actors should respect human participants based on principles of nonmaleficence (ie, avoid harm), beneficence (ie, the scientific question will potentially benefit society and future patients), autonomy (ie, informed consent), and justice (ie, vulnerable populations should be protected and diverse and representative cohorts should be recruited) (Box).

Box Section Ref ID

Corresponding Author: Timothy M. Pawlik, MD, PhD, MTS, MPH, MBA, Department of Surgery, The Ohio State University Wexner Medical Center, 395 W 12th Ave, Ste 670, Columbus, OH 43210 (tim.pawlik@osumc.edu).

Published Online: October 26, 2022. doi:10.1001/jamasurg.2022.4895

Conflict of Interest Disclosures: None reported.