clinical research and ethics

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Nih clinical research trials and you, guiding principles for ethical research.

Pursuing Potential Research Participants Protections

“When people are invited to participate in research, there is a strong belief that it should be their choice based on their understanding of what the study is about, and what the risks and benefits of the study are,” said Dr. Christine Grady, chief of the NIH Clinical Center Department of Bioethics, to Clinical Center Radio in a podcast.

Clinical research advances the understanding of science and promotes human health. However, it is important to remember the individuals who volunteer to participate in research. There are precautions researchers can take – in the planning, implementation and follow-up of studies – to protect these participants in research. Ethical guidelines are established for clinical research to protect patient volunteers and to preserve the integrity of the science.

NIH Clinical Center researchers published seven main principles to guide the conduct of ethical research:

Social and clinical value

Scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent.

• Respect for potential and enrolled subjects

Every research study is designed to answer a specific question. The answer should be important enough to justify asking people to accept some risk or inconvenience for others. In other words, answers to the research question should contribute to scientific understanding of health or improve our ways of preventing, treating, or caring for people with a given disease to justify exposing participants to the risk and burden of research.

A study should be designed in a way that will get an understandable answer to the important research question. This includes considering whether the question asked is answerable, whether the research methods are valid and feasible, and whether the study is designed with accepted principles, clear methods, and reliable practices. Invalid research is unethical because it is a waste of resources and exposes people to risk for no purpose

The primary basis for recruiting participants should be the scientific goals of the study — not vulnerability, privilege, or other unrelated factors. Participants who accept the risks of research should be in a position to enjoy its benefits. Specific groups of participants  (for example, women or children) should not be excluded from the research opportunities without a good scientific reason or a particular susceptibility to risk.

Uncertainty about the degree of risks and benefits associated with a clinical research study is inherent. Research risks may be trivial or serious, transient or long-term. Risks can be physical, psychological, economic, or social. Everything should be done to minimize the risks and inconvenience to research participants to maximize the potential benefits, and to determine that the potential benefits are proportionate to, or outweigh, the risks.

To minimize potential conflicts of interest and make sure a study is ethically acceptable before it starts, an independent review panel should review the proposal and ask important questions, including: Are those conducting the trial sufficiently free of bias? Is the study doing all it can to protect research participants? Has the trial been ethically designed and is the risk–benefit ratio favorable? The panel also monitors a study while it is ongoing.

Potential participants should make their own decision about whether they want to participate or continue participating in research. This is done through a process of informed consent in which individuals (1) are accurately informed of the purpose, methods, risks, benefits, and alternatives to the research, (2) understand this information and how it relates to their own clinical situation or interests, and (3) make a voluntary decision about whether to participate.

Respect for potential and enrolled participants

Individuals should be treated with respect from the time they are approached for possible participation — even if they refuse enrollment in a study — throughout their participation and after their participation ends. This includes:

• respecting their privacy and keeping their private information confidential
• respecting their right to change their mind, to decide that the research does not match their interests, and to withdraw without a penalty
• informing them of new information that might emerge in the course of research, which might change their assessment of the risks and benefits of participating
• monitoring their welfare and, if they experience adverse reactions, unexpected effects, or changes in clinical status, ensuring appropriate treatment and, when necessary, removal from the study
• informing them about what was learned from the research

More information on these seven guiding principles and on bioethics in general

This page last reviewed on March 16, 2016

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Patient Recruitment

Ethics in clinical research, ethical guidelines.

The goal of clinical research is to develop generalizable knowledge that improves human health or increases understanding of human biology. People who participate in clinical research make it possible to secure that knowledge. The path to finding out if a new drug or treatment is safe or effective, for example, is to test it on patient volunteers. But by placing some people at risk of harm for the good of others, clinical research has the potential to exploit patient volunteers. The purpose of ethical guidelines is both to protect patient volunteers and to preserve the integrity of the science.

The ethical guidelines in place today were primarily a response to past abuses, the most notorious of which in America was an experiment in Tuskegee, Alabama, in which treatment was withheld from 400 African American men with syphilis so that scientists could study the course of the disease. Various ethical guidelines were developed in the 20th century in response to such studies. 

Some of the influential codes of ethics and regulations that guide ethical clinical research include:

• Nuremberg Code (1947)
• Declaration of Helsinki (2000)
• Belmont Report  (1979)
• CIOMS (2002)
• U.S. Common Rule (1991)

Using these sources of guidance and others, seven main principles have been described as guiding the conduct of ethical research:

Social and clinical value

Scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, respect for potential and enrolled subjects.

Every research study is designed to answer a specific question. Answering certain questions will have significant value for society or for present or future patients with a particular illness. An answer to the research question should be important or valuable enough to justify asking people to accept some risk or inconvenience for others. In other words, answers to the research question should contribute to scientific understanding of health or improve our ways of preventing, treating, or caring for people with a given disease. Only if society will gain useful knowledge — which requires sharing results, both negative and positive — can exposing human subjects to the risk and burden of research be justified.

A study should be designed in a way that will get an understandable answer to the valuable research question. This includes considering whether the question researchers are asking is answerable, whether the research methods are valid and feasible, and whether the study is designed with a clear scientific objective and using accepted principles, methods, and reliable practices. It is also important that statistical plans be of sufficient power to definitively test the objective, for example, and for data analysis. Invalid research is unethical because it is a waste of resources and exposes people to risk for no purpose

Who does the study need to include, to answer the question it is asking? The primary basis for recruiting and enrolling groups and individuals should be the scientific goals of the study — not vulnerability, privilege, or other factors unrelated to the purposes of the study. Consistent with the scientific purpose, people should be chosen in a way that minimizes risks and enhances benefits to individuals and society. Groups and individuals who accept the risks and burdens of research should be in a position to enjoy its benefits, and those who may benefit should share some of the risks and burdens. Specific groups or individuals (for example, women or children) should not be excluded from the opportunity to participate in research without a good scientific reason or a particular susceptibility to risk.

Uncertainty about the degree of risks and benefits associated with a drug, device, or procedure being tested is inherent in clinical research — otherwise there would be little point to doing the research. And by definition, there is more uncertainty about risks and benefits in early-phase research than in later research. Depending on the particulars of a study, research risks might be trivial or serious, might cause transient discomfort or long-term changes. Risks can be physical (death, disability, infection), psychological (depression, anxiety), economic (job loss), or social (for example, discrimination or stigma from participating in a certain trial). Has everything been done to minimize the risks and inconvenience to research subjects, to maximize the potential benefits, and to determine that the potential benefits to individuals and society are proportionate to, or outweigh, the risks? Research volunteers often receive some health services and benefits in the course of participating, yet the purpose of clinical research is not to provide health services.

To minimize potential conflicts of interest and make sure a study is ethically acceptable before it even starts, an independent review panel with no vested interest in the particular study should review the proposal and ask important questions, including: Are those conducting the trial sufficiently free of bias? Is the study doing all it can to protect research volunteers? Has the trial been ethically designed and is the risk–benefit ratio favorable? In the United States, independent evaluation of research projects is done through granting agencies, local institutional review boards (IRBs), and data and safety monitoring boards. These groups also monitor a study while it is ongoing.

For research to be ethical, most agree that individuals should make their own decision about whether they want to participate or continue participating in research. This is done through a process of informed consent in which individuals (1) are accurately informed of the purpose, methods, risks, benefits, and alternatives to the research, (2) understand this information and how it relates to their own clinical situation or interests, and (3) make a voluntary decision about whether to participate.

There are exceptions to the need for informed consent from the individual — for example, in the case of a child, of an adult with severe Alzheimer’s, of an adult unconscious by head trauma, or of someone with limited mental capacity. Ensuring that the individual’s research participation is consistent with his or her values and interests usually entails empowering a proxy decision maker to decide about participation, usually based on what research decision the subject would have made, if doing so were possible.

Individuals should be treated with respect from the time they are approached for possible participation—even if they refuse enrollment in a study—throughout their participation and after their participation ends. This includes:

• Respecting their privacy and keeping their private information confidential.
• Respecting their right to change their mind, to decide that the research does not match their interests, and to withdraw without penalty.
• Informing them of new information that might emerge in the course of research, which might change their assessment of the risks and benefits of participating.
• Monitoring their welfare and, if they experience adverse reactions, untoward events, or changes in clinical status, ensuring appropriate treatment and, when necessary, removal from the study.
• Informing them about what was learned from the research. Most researchers do a good job of monitoring the volunteers’ welfare and making sure they are okay. They are not always so good about distributing the study results. If they don’t tell you, ask

For more information about what makes clinical research, we refer you to:

Ezekiel J. Emanuel, MD, PhD; David Wendler, PhD, and Christine Grady, PhD. " What Makes Clinical Research Ethical? " Journal of the American Medical Association, Vol. 283, No. 20, May 24, 2000, pp. 2701-2711.

Dr. Grady is acting chief of the Bioethics Department and head of the Section on Human Subjects Research. Dr. Wendler heads the Unit on Vulnerable Populations. Dr. Emanuel was chief of the CC Bioethics Department  1996-2011.

NOTE: PDF documents require the free Adobe Reader .

This page last updated on 10/21/2021

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• Clinical Ethics
• Johns Hopkins Berman Institute of Bioethics
• Research & Outreach

Addressing the the complex set of ethical issues associated with clinical practice

Through our close association with the Johns Hopkins Schools of Medicine and Nursing and the Bloomberg School of Public Health, the Berman Institute is an integral participant in the development of innovations in clinical practice.  Through our interactions with students, we are helping to advance an ethical framework for clinical practice among future health care practitioners and leaders.

Berman Institute faculty members are active in both scholarly and academic roles but also in many other areas such as institutional review boards and operations, as well as many policy making initiatives. We invite you to learn more about our faculty and their contributions.

View Faculty in Clinical Ethics

The Berman Institute leads efforts to create substantive educational experiences in clinical ethics for medical students, nursing students, residents, and other clinicians.

Learn more about our educational experiences for students across Johns Hopkins .

Medical students.

Berman Institute faculty members lead parts of the Johns Hopkins School of Medicine curriculum, which integrate themes of Ethics and Professionalism, Communication, and Cultural Competence throughout the four-year medical school curriculum. These themes are integrated into Selectives and Workshops within preclinical courses, small group sessions that introduce case-based analysis, medical/legal issues when students are transitioning from the classroom to clinical settings, and experiential learning of specific topics within clinical rotations. The Healer’s Art course for first year medical students includes a curriculum to help medical students identify, strengthen, and cultivate the human dimensions of the practice of medicine. Berman faculty also direct a first-year medical student Scholarly Concentrations course and offer a concentration in Ethics and the Art of Medicine.

Nursing Students

All Masters of Nursing students take a core course focused on the philosophical, theoretical, and ethical aspects of advance practice nursing. This course provides students with a foundation of ethical practice in nursing, offers a survey of key ethical issues in clinical practice, and builds foundational elements of ethical competence. The new Masters Entry Program will incorporate this core course as well as integrating ethics content throughout the entire curriculum including new seminars focusing on key clinical ethics topics.

Interns, Residents and Fellows

Berman Institute faculty members are actively involved in ethics education for trainees in the Departments of Medicine at Johns Hopkins Hospital (JHH) and Johns Hopkins Bayview Medical Center (JHBMC), Pediatrics, Surgery, Obstetrics and Gynecology, Neurology, Neurosurgery, Ophthalmology, and Child and Adolescent Psychiatry.  These efforts reach approximately 60% of all residents at Johns Hopkins. The Berman Institute also helps train fellows with interests in clinical ethics through its Hecht-Levi Fellowship Program and the Starkey Fellowship.

Each JHBMC monthly Ethics for Lunch conference session attracts 60–70 attendees drawn from the entire hospital community: physicians, medical students, nurses, social workers, chaplains, etc. They participate in discussion about an important clinical ethics issue. This model will soon be expanded to the JHH. Berman Institute faculty members also lead ethics rounds on selected clinical units.

Bioethics Intensives

The Berman Institute offers non-degree, short-form courses in bioethics each June through the Berman Institute Bioethics Intensives (BI2) program. BI2 courses are open to all and provide an engaging interactive learning opportunity to anyone interested in exploring bioethics. The courses focus on both theoretical and applied aspects of bioethics, including clinical ethics, so they are of practical value to medical, legal, and policy professionals, as well as researchers, scholars, and students.

The Berman Institute produces ground-breaking scholarship on concepts in clinical ethics such as respect, dignity, trust, and compassion. Clinical ethics scholarship and within the Berman Institute addresses issues arising in the world today—from palliative care across the lifespan to obligations to treat patients with Ebola to clinician-patient communication.

Berman Institute faculty members also conduct collaborative empirical research on ethical issues related to clinical practice. The following is a selection of some of the areas of active empirical research:

• Ensuring respect and dignity in the intensive care unit
• Ethical issues in everyday clinical practice
• Palliative and end of life care
• Transplantation
• Ethics in accountable care organizations
• Spirituality and religious beliefs
• Treatment of patients with sickle cell disease and HIV/AIDS
• Decision making among youth with neuromuscular diseases, sickle cell disease
• Moral distress and clinician suffering
• Breast cancer survivorship
• Surrogate and shared decision-making
• Chemotherapy drug shortages in childhood cancer
• Ethical issues involving persons with dementia
• Ethical issues in genetic testing
• Ethical issues and cultural diversity
• Clinical ethics education

Berman Institute faculty members lead the Ethics Committees and Consultation Services at Johns Hopkins Hospital (JHH) and Johns Hopkins Bayview Medical Center (JHBMC). Our faculty also assist with these services in other Johns Hopkins Health System and Affiliate entities. They also serve in related leadership positions in key Hospital, Health System and University Committees and task forces.

Berman Institute faculty play a critical role in the Johns Hopkins Institutional Review Board (IRB) system, by serving as members of all six School of Medicine and both School of Public Health IRBs, with two faculty members in leadership positions on their respective IRBs. Faculty members also serve on key committees and initiatives in their respective Schools of Nursing, Medicine, and Public Health as well as national and international leadership in organizations and initiatives addressing key areas of clinical ethics.

Berman Institute faculty members are involved with national policy initiatives regarding clinical ethics. These include developing standards for clinical ethics consultation, standards for education and training in professionalism, and ethical practice for nurses.

We have assembled the following links to several relevant resources that underscore the Berman Institute’s mission to advance the study and implementation of Clinic Ethics.

• Ethics in Clinical Practice Program (ECPP)
• Johns Hopkins Medicine: Division of General Internal Medicine – Bioethics Research
• Nursing Ethics in the 21st Century: A Blueprint
• Phases – Pregnancy And Hiv/Aids: Seeking Equitable Study
• Center for Bridging Genomics, Infectious Disease, and Society (BRIDGES)
• Vision Of Hope: Integration Of Palliative Care In Chronic Pediatric Disease
• Community Values And The Allocation Of Scarce Medical Resources In Disasters – A Public Engagement Project
• Ethical Challenges in Short-Term Global Health Training
• The Chemotherapy Shortage: Ethical Challenges Facing Pediatric Oncology – Working Group Briefing Website
• User’s Guide to Integrating Patient-Reported Outcomes in Electronic Health Records (PDF)

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The Oxford Textbook of Clinical Research Ethics

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The Oxford Textbook of Clinical Research Ethics is the first systematic and comprehensive reference on clinical research ethics. Under the editorship of experts from the National Institutes of Health of the United States, the book offers a wide-ranging and systematic examination of all aspects of research with human beings. Considering historical triumphs of research as well as tragedies, the textbook provides a framework for analysing the ethical aspects of research studies with human beings. Through both conceptual analysis and systematic reviews of empirical data, the textbook examines issues ranging from scientific validity, fair subject selection, risk benefit ratio, independent review, and informed consent as well as focused consideration of international research ethics, conflicts of interests and other aspects of responsible conduct of research. The editors of The Oxford Textbook of Clinical Research Ethics offer a work that critically assesses and advances scholarship in the field of human subjects research with human beings.

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Code of Ethics

As the primary resource for clinical research professionals in the pharmaceutical, life sciences, biotechnology, and medical device industries, as well as those in hospital, academic medical centers, and physician office settings. ACRP members depend on the association to promote excellence in clinical research and ensure to the best of its ability that clinical research is performed ethically, responsibly, and professionally everywhere in the world.

In line with ACRP’s mission and vision, ACRP has established a code of ethics that:

• Sets standards and defines best practices for the clinical research profession
• Provides a basis to meet compliance requirements for the profession
• Provides a “seal of approval” for professionals to look for when hiring or using ACRP services
• Gives ACRP members a mechanism to file violations of ACRP’s Code of Ethics
• Outlines the role of ACRP’s Ethics Committee and procedures that address violations of the Association’s Code of Ethics
• Documents, according to the Association’s governance, those who have violated the ACRP Code of Ethics

ACRP strongly encourages its members to review and adhere to the Association’s Code of Ethics.

Report a Violation of ACRP’s Code of Ethics >

ACRP Code of Ethics and Professional Conduct

The Association of Clinical Research Professionals (“ACRP”) is a US registered nonprofit, tax-exempt corporation that functions as a global association of clinical research professionals. ACRP’s vision is that clinical research is performed ethically, responsibly, and professionally everywhere in the world. ACRP’s mission is to promote integrity and excellence in clinical research.  The Academy of Clinical Research Professionals (the “Academy”) similarly is a nonprofit, tax-exempt organization that advances and promotes the professional interests of clinical research professionals and provides certification for such professionals.

This Code of Ethics and Professional Conduct (the “Code”) serves as a code of professional conduct for ACRP members and/or Academy Certificants. ACRP members and Academy Certificants are expected to adhere to this Code in all professional activities and relationships with each other, organizations with which they work, research participants and society in general. The core values of Integrity, Courage, Excellence, Dedication and Collaboration are manifest in the ACRP Code.  The Code also applies to individuals who seek membership in and/or certification by ACRP and the Academy.

This Code is a summary of what ACRP, and the Academy define as essential ethical behavior for clinical research professionals. Compliance with the Code is a requirement for initial and continued ACRP membership and/or certification through the Academy.  ACRP members and Academy Certificants affirm their endorsement of the Code and acknowledge their commitment to uphold its principles by joining and subsequently renewing their membership in ACRP and/or by applying for and maintaining certification from the Academy. Violations of the Code may result in sanctions imposed under the Discipline and Complaints Policy (the “Policy”) adopted by ACRP and the Academy. This Policy was adopted to provide clarity of expected behavior and description of due process accorded to ACRP members and Academy Certificants necessary to protect the integrity, and ensure the efficacy, of the Code.

This Code is intended to be used by current and prospective ACRP members and Academy Certificants in conjunction with applicable national and international frameworks that govern the practice of clinical research, such as professional license requirements, ethical principles, guidelines, and laws and regulations applicable to clinical research, including, but not limited to, principles of the Declaration of Helsinki, Belmont Report, ICH GCP, US Codes of Federal Regulations, WHO “Ethical Standards and Procedures for Research with Human Beings,” and UK Research Governance Framework.

The term “Clinical Research Professional” as used herein encompasses many job titles, disciplines and duties within the profession of clinical research. For the purpose of this Code, the term shall include anyone involved in the design, conduct, reporting, review and oversight of clinical research who is an ACRP member or Academy Certificant or applicant for membership or certification, and those who represent ACRP in any elected or volunteer capacity (e.g. Chapter President, Treasurer, etc. or volunteers to serve on a local or national committee, speakers at a conference or event).

Clinical Research Professionals who are current or prospective members of ACRP and/or Academy Certificants (referred to herein as “Members” and “Certificants”) shall abide by and conform to the following ethical standards:

• B ene ficence and Nonmaleficence

Members and Certificants shall:

• Respect and safeguard the rights and welfare of all individuals with whom they interact professionally, including but not limited to research participants.
• Always consider and act in furtherance of the best interests of research participants and society. Where societal and research participants’ interest conflict, best interests of the participants take precedence.
• Ensure that the aims of all clinical research projects are to advance knowledge and promote the health and well-being of research participants.
• When designing, reviewing, or conducting research, ensure that potential risks of the research are reasonable in relation to the anticipated benefits to the participants and the importance of the knowledge to be gained.
• Ensure that potential risks to research participants are minimized to the greatest extent possible and take all necessary steps to protect the participants at all times.

Steps taken to uphold this ethical principle include, but are not limited to:

• Design and conduct studies where a state of clinical equipoise exists, that is, to test hypotheses that have not yet been adequately tested through current or previous reported research results, to avoid unnecessary risks or inconveniences to participants of redundant research and to maximize often scarce research resources.
• Design and conduct research studies with scientific value.
• Ensure clinical research is conducted in accordance with currently accepted ethical guidelines and standards.
• Never use coercion or undue influence when recruiting research participant Seek autonomous informed and appropriately documented consent from participants or, where applicable, their legally authorized representatives prior to the instigation of any research procedure.
• Never coerce, or attempt to coerce or induce individuals, such as staff members, vendors, contractors, investigators, or regulators, to act in an unethical manner in any respect.
• Avoid using substances, such as alcohol or drugs, while performing professional duties that may impair professional judgment or performance.
• Perform only those duties for which one is appropriately qualified and trained to perform.
• Where an individual is a member of a professional organization with its own licensing requirements and/or code of ethical or professional conduct, operate within the scope of practice and professional standards outlined within those professional guidelines, codes or licenses.
• Report any acts that appear to be unethical or illegal to appropriate organizational, institutional or legal authorities, so long as supported by reasonable evidence.

2. Integrity

• Educate themselves, and where applicable, their students and their colleagues, about responsible research practices.
• Apply sound ethical values, scientific principles and judgment in the design, conduct and analysis of clinical studies, and in interpretation of their results.
• Report research findings accurately and avoid misrepresenting, fabricating or falsifying results.
• Conduct research in accordance with an approved research protocol/plan.
• Make all research data available to authorized persons for verification in accordance with established standards of the clinical research profession.
• Ensure the dissemination of scientifically sound information from clinical trials and other investigations, and
• Not withhold information relevant to full evaluation of the safety, efficacy or utility of clinical interventions, agents or devices under investigation for the benefit of medicine, patients, science and society regardless of the research outcome.

3. Conflicts of Interest

It is recognized that real, potential and apparent conflicts of interest naturally occur from time to time. Conflicts of interest arise when personal, professional, business, political and/or financial influences have the potential to significantly impair professional judgment, and hence lead to consequent acts of research or business misconduct.  Additionally, conflicts of interest may occur in relation to other professional and volunteer obligations, whether with ACRP or the broader research community.

It is essential that Members and Certificants:

• Recognize when they may have a conflict of interest, disclose such conflict as soon as the potential conflict is recognized and be transparent in how the conflict will be managed.
• If participation in any research-related activity that poses a potential conflict of interest situation is unavoidable, ensure that steps are taken to appropriately manage any such conflicts to safeguard quality and credibility of their professional judgment from inappropriate influence so that research participants’ rights and safety are fully protected.
• Do not, under any circumstance, unduly exploit any professional or volunteer relationship to further personal, political or business interest at the expense of other individuals or ACRP. This includes both professional and volunteer activities and cases where volunteer activities, as a professional or other body might pose a potential conflict of interest.
• Respect and adhere to Conflict of Interest policies if they are a member of any professional or industry organization, or an employee of an organization that has internal Conflict of Interest policies.

Steps taken to uphold this ethical principle include but are not limited to:

• Publicly disclose relationships and potential conflicts of interest in publications, speaking engagements, Advisory Boards and any other venue or activity, including any ACRP chapter or other meetings in which the Member or Certificant is perceived as providing subject matter expertise or other authority.
• Retain documentation and use factual quantitative measures to conduct one’s own professional duties and procurement of vendor services.
• Avoid dual relationships that could impair professional judgment or increase the risk of harm to others.
• Avoid performing services for direct competitors without the express knowledge and documented consent of each party, either volunteer or professional Direct competitors are individuals or organizations with whom an exchange of services would create a conflict of interest – a situation in which personal, professional, business, political and/or financial influences have the potential to significantly impair professional judgment, and hence lead to consequent acts of research or business misconduct.

4. Privacy and Confidentiality

Privacy refers to the legal rights of individuals to limit public scrutiny; to limit access to their private acts and their personal information; and to limit disclosure of such personal information. Confidentiality refers to the obligation to protect private information about an individual or organization from unauthorized disclosure.  Clinical research professionals have access to confidential information, whether it is intellectual property of a company or personal health information of research participants and have the responsibility to maintain this confidentiality.

Members and Certificants must:

• Maintain the privacy and confidentiality of research participants and of any confidential information received in connection with the Members and Certificants’ research to the extent required by applicable law(s) and/or signed contractual agreements.
• Maintain the privacy and confidentiality of any non-public information, intellectual property of a company or personal health information of research participants, that they may have access to in their roles as clinical research professionals.
• Store written and/or electronic records in secure locations with access provided only to authorized individuals.
• Collect and transmit only the minimum essential information required to accomplish the task at hand.
• Apply standards of confidentiality to retrospective, current and prospective data collection and protected personal information. Treat all confidential data as if it were your own.
• Ensure an understanding of all elements that could be considered confidential information of any kind.
• Ensure that all aspects of the privacy of research participants and their families is respected prior to, during, and following, any clinical research project.

5. Duties to Society and Compliance with the Law

By the very nature of their work, Members and Certificants are engaged in professional endeavors that enhance knowledge, skill, judgment and intellectual development that strives to contribute to improving the human condition. As such, clinical research professionals must be both aware and conscious of their duty to society and the clinical research arena.

ACRP Members and Certificants shall:

• Uphold the profession’s responsibility to society by promoting ethical and professional practice standards, and
• Be willing to be held professionally accountable for upholding those standards.
• Not participate in criminal, fraudulent, or other illegal activities.
• If faced with a conflict between abiding by two conflicting laws or regulations, or between abiding by a law/regulation and following an ethical principle, consult with experienced, respected professional colleagues and seek their guidance whenever possible.
• Not advocate, sanction, participate in, or condone any act that is prohibited by this Code, unless failure to do so would be seriously detrimental to the rights and well-being of others.

6. Duties to Professional Discipline and Beneficiaries of Practice

• Be personally committed to, and encourage others, to engage in safe, sound research practices consistent with the relevant ethical and scientific standards and the requirements of their professional discipline.
• Uphold standards of equality and nondiscrimination in all professional interactions and cooperate with other professionals as appropriate and ethical.
• Assist colleagues entering the profession by sharing knowledge and understanding of the ethics, responsibilities and needed competencies of their chosen area of research and Where Members or Certificants seek to acquire or maintain a medical or other professional license, additional laws and ethical standards of conduct that are not pertinent to clinical research may apply.
• in addition to adhering to this Code of Ethics and Professional Conduct, abide by their respective discipline’s laws and ethical standards of conduct.
• Take affirmative steps to make it clear to research participants and others that there is a distinction between research and standard therapy. Ensure that the roles and responsibilities of physicians and other health care professionals acting as both investigators and care providers remain clear to all concerned.
• Ensure that all contributory information provided to research participants, their legal representatives and other health care providers not involved with the research is fair, balanced, accurate, understandable and sufficiently comprehensive to enable well-informed decisions about the use of pharmaceuticals, medical devices or other clinical services or intervention
• Ensure that when consent is waived, that reasons for waiver of informed consent are valid, that the waiver reasons and process comply with applicable regulations, e.g. regulations in 21 CFR 50 and 56, and that IRB approval for a waiver has been sought, as is generally applicable.
• If a clinical investigation is conducted or supported by HHS and involves an FDA regulated product, the study is subject to both 45 CFR 46 and part 21 CFR 50 and 56. Where the regulations differ, the regulations that offer the greater protection to human subjects should be followed.

7. Duties to ACRP and the Greater Research Community

While there are many professional and personal benefits to volunteering for leadership positions in the community, members and certificants who volunteer for ACRP committee, officer or Board positions at the local chapter and/or international level, have a duty to act in a professional manner and be mindful that they are acting as a representative of ACRP when fulfilling the requirements of their positions, and as such have some greater duties.

In their leadership/volunteer capacities, Members and Certificants shall:

• Ensure that they have the skills and experience to fulfill the requirements of the position they have volunteered for or actively seek training to gain those skills and/or ask for assistance from ACRP staff or other sources to perform necessary functions.
• Commit to understanding, following and upholding the bylaws of the organization in which they are a leader, in addition to the ACRP Code of Ethics.
• Avoid engaging in self-dealing, as well as actual conflicts of interest relating to business affairs. Additionally, they shall use their best efforts to avoid appearance of impropriety, self-dealing or conflict of interest.
• Avoid representing multiple organizations simultaneously in a manner which could potentially be harmful to ACRP or the other organizations.
• Refrain from publicly (including social media) disparaging ACRP, its staff or its membership and/or disseminating false information about ACRP or its affiliates.

8. Grounds for Disciplinary Action

A Member or Certificant shall be subject to disciplinary action if the actions of such Member or Certificant are determined, in accordance with the Discipline and Complaints Policy, to constitute one or more of the following:

• Gross negligence or willful misconduct in the performance of services, or other unethical or unprofessional conduct based upon demonstrable violations of this Code of Ethics and Professional Conduct.
• Conviction of a Member or Certificant of a felony or other crime of moral turpitude under federal or state law, particularly in a matter related to the conduct of the profession.
• Fraud or misrepresentation in the application or maintenance of ACRP membership, Academy certification, or other professional recognition or credential.

Individuals aspiring to become a Member or Certificant shall ensure awareness of and adherence to this Code as an element of eligibility criteria of Membership and/or Certification.  Applicants who knowingly fail to adhere to the Code shall be ineligible for Membership and/or Certification.

9. Complaints

To file a complaint against a Member or Certificant, or applicant Member or Certificant, please email [email protected] . Complaints will be addressed according to the Discipline and Complaints Policy, available here , developed by the ACRP Professional Ethics Committee.

M ONITORING AND REVIEW SCHEDULE

Review every three years by the ACRP Professional Ethics Committee.

DATE REVIEWED BY COMMITTEE December 14, 2015 November 3, 2017 February 7, 2017 November 11, 2019 February 2020

DATE MODIFIED BY COMMITTEE December 14, 2015 November 3, 2017 November 11, 2019 February 2020

DATE APPROVED BY COMMITTEE December 14, 2015 November 3, 2017 November 11, 2019 February 2020

DATE REVIEWED BY BOARD December 17, 2015 December 13, 2017 December 11, 2019 March 17, 2020 June 17, 2020

DATE MODIFIED BY BOARD December 11, 2019 March 20, 2020

DATE APPROVED BY BOARD October 7, 2007 September 2012 December 17, 2015 December 13, 2017 June 17, 2020

Ethical Principles and Laws Governing Clinical Research

• First Online: 03 April 2021

Cite this chapter

• Marcin Karcz 2  

675 Accesses

Clinical research involves the study of human beings in a systematic investigation of health and illness. It is designed to develop or contribute to generalizable knowledge. The goals of clinical research are gathering knowledge through a set of activities that tests hypotheses and permits conclusions useful in understanding human health and illness, and improving medical care. Furthermore, it aims to develop safe and effective interventions to prevent, diagnose, and treat disease. As such, research serves the common good that the individual subject participating in clinical research may or may not benefit from participation. The standard of conduct for scientific researchers is governed by research ethics. The adherence to ethical principles is fundamental to the protection of welfare, rights, and the dignity of research participants. This chapter aims to summarize the history of clinical research ethics, the codes of research ethics, and the seven ethical principles that guide clinical research ethics and particular ethical challenges in randomized controlled trials.

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Research Ethics for Clinical Researchers

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Karcz, M. (2021). Ethical Principles and Laws Governing Clinical Research. In: Szalados, J.E. (eds) The Medical-Legal Aspects of Acute Care Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-68570-6_28

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• Indian J Dermatol
• v.62(4); Jul-Aug 2017

Evolution of Ethics in Clinical Research and Ethics Committee

Nilay kanti das.

1 From the Department of Dermatology, Bankura Sammilani Medical College, Bankura, West Bengal, India

2 Member of Institutional Ethics Committee of Human Research, Medical College, Kolkata, West Bengal, India

3 Coordinator of Dermatology Clinical Trials Special Interest Group, IADVL Academy of Dermatology, India

4 Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India

5 Member of Institutional Ethics Committee, Institute of Neurosciences, Kolkata, India

6 Member of Dermatology Clinical Trials Special Interest Group, IADVL Academy of Dermatology, India

Ethics are the moral values of human behavior and the principles which govern these values. The situation becomes challenging for a doctor when he assumes the role of researcher. The doctor-researcher has to serve both the roles and at times the zeal of an investigator has the potential to cloud the morality of the physician inside. It is very important to realize that exploiting the faith of patients is an offence that tantamount to a crime. Medical science is one discipline where the advancement of knowledge is hugely guided by research and mankind has benefitted from many experiments. However benefit and risk are the two faces of the same coin. Various unethical human experiments made us realize that the whims of researchers need to be reined and led to the evolution of the first guidelines for researcher, the Nuremberg code. Thereafter the Good Clinical Practice guidelines serve as the guiding doctrine of clinical research. The principles of ethics rest on the four pillars of autonomy, beneficence, justice, non-maleficence and recently two more pillars are added which includes, confidentiality and honesty. Ethics committees serve as a guardian of these principles. The multidisciplinary Ethics Committee ensures a competent review of the ethical aspects of the project proposal submitted and does it free from any bias or external influence. Ethical review of clinical trial applications follows a decentralized process in India, and requires Ethics Committee approval for each trial site. All Ethics committees have to be registered with Drug Controller General of India (DCGI) without which they cannot approve any clinical trial protocol and has come into effect from 25th February 2013.

What was known?

Doctors are guided and are familiar with ‘Hippocrates oath’ or the code of medical ethics’ laid down by Medical Council of India (MCI) which mainly highlights the ‘duties and responsibilities of physician, duties of physicians to their patients/in consultation/to each other/public or paramedical profession, unethical act/misconduct related to medical practice and the punitive action if the above are breached.

Introduction

“Ethics is not definable, is not implementable, because it is not conscious; it involves not only our thinking, but also our feeling”

-Valdemar W. Setzer

Ethics are the moral values of human behavior and the principles which govern these values. Every profession is bound by code of ethics (Greek word Ethos meaning Custom or Character ) and the essence of medicine as a moral community dates back to Hippocratic Oath. This oath was a guide for the physician on professional ethics and mandates that he/she would prescribe only beneficial treatments, refrain from causing harm or hurt to his/her patients,[ 1 ] and would place the interests of their patients above their own interests.[ 2 ] The situation becomes challenging for a doctor when he assumes the role of researcher. The doctor-researcher has to serve both the roles, and at times, the zeal of an investigator has the potential to cloud the morality of the physician inside. History has in its store numerous instances when the enthusiasm for knowledge breached the principles of ethics. Thus, it was realized that code of ethics for clinical research was needed and Good Clinical Practice (GCP) guidelines for human research was framed.

Science versus Ethics Vis-à-vis Researchers versus Doctor

In clinical practice, doctors pledge to treat every individual equally, irrespective of their age, disease or disability, creed, ethnic origin, gender, nationality, political affiliation, race, sexual orientation, social standing, or any other factor;[ 3 ] but when it comes to research that pledge is blurred at times, and it is forgotten that a subject for research is also a patient who has put his/her faith in the doctor for his treatment. The statement of a first-century physician from Egypt, Celsius reflects the attitude of doctor-turned-researcher who justified experiments on condemned criminals by saying that “It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries.”[ 4 ] By making this statement, the researcher has taken for granted that they are given the liberty of being reckless because criminals can be sacrificed (such as guinea pigs in laboratory). It is very important to realize that exploiting the faith of patients is an offence that tantamount to a crime.

There is another face of research, where researchers did not hesitate in self-experimentation or experimenting on family members as subject for research. The Nobel laureate Gerhard Domagk (1895–1964) discovered prontosil sodium (a sulfonamide) and first tested it on his own 6-year-old daughter who had contracted a severe streptococcal infection from an unsterilized needle and Johann Jorg (1779–1856) swallowed 17 drugs in various doses to record their properties, are only two among many such instances.

Medical science is one discipline where the advancement of knowledge is hugely guided by research and humankind has benefitted from many experiments. However, benefit and risk are the two faces of the same coin. If there is no loss there is no gain; but the risk/loss is assumed by individuals/participants of research, and benefit/gain is reaped by a population who did not have to bear that risk. The role of ethical guideline is to establish the balance between benefit and risk and to ensure all the participants gets fair treatment that he/she expects from his/her treating physician.

Ethics is pluralistic. There can be disagreement among individuals about what is right and what is wrong, and even when they agree, the reasons can be different.

Despite the differences, the fundamental ethical principles is in harmony with the basic human rights proclaimed in the “United Nations Universal Declaration of Human Rights,” which upholds right to life, freedom from discrimination, torture and cruel inhuman or degrading treatment, freedom of opinion and expression, equal access to public services in one's country, and to medical care.[ 2 ]

Nazi experimentations during World War II are the horrendous examples of atrocious acts where thousands of war prisoners were subjected to inhuman torture in the name of research and benefit to science. This was the time when humankind realized that the whims and fancies of researchers need to be reined and led to the evolution of the first guidelines for researcher, the Nuremberg code.[ 5 ]

Evolution of Ethics Guidelines

After the World War II, trial was conducted on 23 Nazi doctors and scientists at Nuremberg for the murder of concentration camp inmates who were used as research subjects. Among the 23, 15 were convicted. Seven were condemned to death by hanging, 8 received prison sentences from 10 years to life. The trial brought to light the tortures that were conducted, and in 1947, the judgment culminated in the formulation of codes to guide research on humans, famously known as Nuremberg Code. The code highlighted on the need for informed consent, prior animal work, qualified scientists, risk justification by anticipated benefits, avoidance of physical and mental suffering, death, or disabling injury.[ 5 ]

Some researchers, however, ignored the code and continued to exploit the faith of the patients. In Willowbrook Hepatitis Study (1956), children were deliberately infected with mild form of hepatitis, and consent was obtained from parents without informing about the hazards and giving the opportunity of school admission on participation in the study.[ 6 ] In 1963, Jewish Chronic Disease Study was conducted where cancer cells were inoculated in senile subject without proper explanation on risk. Both these studies used a vulnerable group of patients who could not take independent decision.[ 7 ] The situation was highlighted in an article published in 1966 which described 22 such examples of research where there were controversies regarding the ethics, and all were conducted by reputable researchers and published in major journals (Beecher article).[ 8 ]

In view of the emerging situation, World Medical Association (WMA) General Assembly (Helsinki, Finland, 1964) developed a set of guidelines to safeguard the rights and well-being of subjects participating in clinical research. This is referred to as the Declaration of Helsinki and is revised from time to time, the last amendment in 64 th WMA general assembly in Brazil, 2013. The declaration of WMA binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient's best interest when providing medical care.” The declaration specifically defines that the duty of the physician who are involved in medical research is to promote and safeguard the health, well-being, and rights of patients.[ 9 ]

In a very shocking turn of events, unethical research conducted by the United States Public Health Service (Tuskegee Syphilis Study) surfaced in 1972. The study was initiated in 1932 to study the natural course of syphilis on African-American participants and even after the development of penicillin, the trial participants were denied of the treatment and when it came to light it has already claimed 28 lives and led to permanent disability in 100 subjects; along with 40 wives being infected resulting in 19 cases of congenital syphilis. Not only denial but also the study misinformed the subjects and claimed spinal tapas special treatment.[ 10 ] The sheer misconduct led the US government to set up ‘International Ethical Guidelines for Biomedical Research Involving Human Subjects’ that submitted the report (Belmont report) in 1979, which stressed on three basic ethical principles: autonomy, beneficence, and justice.[ 11 ]

In the following years, various countries drafted their own guidelines of GCP, and in India, the Indian Council of Medical Research (ICMR)first released a policy statement on ethical considerations involved in research on human subjects in 1980. ICMR revised the guidelines in 2000 in the face of controversies and introduced “Ethical Guidelines for Biomedical Research on Human Subjects” and latest amendments was done in 2006.[ 12 ] In India, the ethics guidelines are given the legal status by way of Schedule Y Drugs and Cosmetics Rules, 1945 (rules 122A, 122B, 122D, 122DA, 122DAA, and 122E).[ 13 ]

With the advent of multicentric studies involving different countries, having a uniform GCP was a felt-need. For this purpose, the International Conference on Harmonisation-GCP was developed in 1996 in consideration of the current GCPs of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries, and the World Health Organization[ 14 ] [ Figure 1 ].

Milestones in the evolution of ethics for clinical research

Principles of Ethics in Research Involving Human Subject

The principles of ethics rest on the four pillars of autonomy, beneficence, justice, nonmaleficence,[ 15 ] and recently, two more pillars are added which includes confidentiality and honesty.

Autonomy is the respect for the patient's “right to self-governance, choice for care, and the right to accept or refuse treatment.”[ 16 , 17 ]

The principle of autonomy states that the patient has the right to make his or her own choice as to what procedure he or she aspires to have. Thus, the patient's right to an informed consent must be respected. The patient must be given the right information as what to expect, the risks involved and the alternative options available.

Beneficence

The principle of beneficence requires the practitioner to act in the patient's “best interest.” It is important for the practitioner to assess the risks versus the benefits of the procedure and maximize benefits, minimize harms. The motivation of the patient for having the procedure and how it will affect quality of life should be gauged by the physician. The physician should be specialized in the procedure and should be able to handle risks and side effects that might occur.

This principle seeks “fair treatment.” Exploitation of the patient for the sole purpose of recruitment for the study and completion of research should be refrained. The practitioner should be respectful to the patients’ wishes, understand the depth of the problem, and educate the patient about the expectation from the procedure. Risk and benefits must be equally shared by all trial participants.

Nonmaleficence

The principle of nonmaleficence requires the practitioner to “do no harm” to the patient. The practitioner should discuss of the possible side effects and complications of the trial procedure before including a person in the trial. At this point, the practitioner may suggest alternative procedures and treatments that may be more beneficial for the patient.

Confidentiality

It is essential to maintain confidentiality of all participating study patients, security of study data, photographs, biological samples, audio-visual records, etc.

Investigator should be truthful to the study participants regarding the trial protocol, risk-benefits; and to coinvestigators, sponsors, ethics committee, and regulatory agencies regarding the adherence to trial protocol and outcome.

Indian Perspective

India in recent times has become an important country for clinical trials of international pharmaceutical companies because of abundance of patients, heterogeneous genetic population, availability of trained human resource (both doctors and support staff) and last not the least, low expenditure. A report shows that since 2004 the number of new trials has increased at 31% Compound Annual Growth Rate, and the clinical trials market has grown at 30% (almost double of the global average).[ 17 ] However, concerns were raised about ethical implications of globalization of clinical trials to developing countries[ 18 ] which are compounded by the adverse media coverage in India.

Major limitations detected at site inspection visits by regulatory authority in India include data credibility, inadequate and inaccurate records, failure to follow investigational plan, failure to notify Institutional Ethics Committee (IEC) of changes, and failure to submit progress reports. There are also concerns over areas of subject protection, namely, consent, IEC approval, reporting of adverse drug reactions (ADRs).[ 19 ]

Keeping in mind the changing situations, the Central Drugs Standard Control Organization (CDSCO) has amended the existing Schedule Y with the major thrust areas being functioning of IEC, informed consent process, ADR reporting, compensation in case of ADR.[ 13 ] Ethics committee may be considered as the “eyes and earsof CDSCO” and they are the guardian of ethics in clinical research conducted in the institute. The term, institutional review board, and independent ethics committee are used interchangeably at times. The role of ethics committee has become paramount important following the maloccurrence of events resulting from breach in ethical standard in clinical research.[ 19 ] CDSCO presently has implemented the rule for registering the ethics committee, and only those registered under CDSCO can approve the conduct of clinical trials. Thus, it has become imperative that researchers posted in those institutes having “ethics committee registered under CDSCO” can only carry out clinical trials. Thus, knowledge about ethics committee and its functioning is not only administration's prerogative but also important from researcher's view point.

Ethics Committee

Ethical review of clinical trial applications follows a decentralized process in India and requires ethics committee approval for each trial site. The ethics committees are based at clinical or academic institutions and hospitals. Ethics committee is an independent body that plays the pivotal role in ensuring that a trial is conducted in accordance with GCP guidelines and to safeguard the safety and well-being of subjects participating in a clinical trial. Ethics committee ensures a competent review of all the ethical aspects of the project proposal submitted and does it free from any bias or external influence. In institutions where a scientific review board is not present, the ethics committee assumes the additional responsibility of reviewing the scientific rationality of the research proposal submitted.

An ethics committee should be constituted with at least seven members and appoints from among its members a chairperson (from outside the institution) and a member secretary (generally from the parent institution to conduct committee business). To represent differing viewpoints, the members should be a mix of medical/nonmedical and scientific/nonscientific persons, including the lay public. The composition should be as follows:

• Chairperson
• One to two basic medical scientists (preferably one pharmacologist)
• One to two clinicians from various institutions
• One legal expert or retired judge
• One social scientist/representative of nongovernmental voluntary agency
• One philosopher/ethicist/theologian
• One lay person from the community
• Member secretary.

If the institution specializes in certain areas of research, it is desirable to include a member from specific patient groups (e.g., HIV AIDS, genetic disorders, etc.) in the ethics committee as much as possible. If required, subject experts could be invited to offer their views, but would not have any voting rights. There should be appropriate gender and age representation on the ethics committee.

According to Indian GCP, ICMR guidelines, and Schedule Y, the ethics committee review should be conducted through formal meetings and should not resort to decisions through a circulation of proposals or E-mails. The committee should meet at regular intervals and should not keep a decision pending for >3–6 months, which should be defined in the standard operating procedure (SOP). Proper record keeping of all meetings, decisions should be done. The ethics committee is not only entrusted with reviewing proposals but also reviewing ongoing trials by reviewing the periodic study progress reports furnished by the investigators, and/or monitoring and internal audit reports furnished by the sponsor, and/or by self visiting the study sites. In the case of clinical trial-related injury or death, the ethics committee should also review and make recommendations for compensation to be paid by the sponsor within a certain time frame.

A clinical trial should be initiated at an investigator site only and only after obtaining written approval of the respective IES. Any amendment to the approved trial documents requires a fresh ethics committee approval. The minimum clinical trial documents that should be reviewed by the committee are as follows:

• Protocol (for scientific rationale)
• Informed consent document (for the safety and welfare of research participants)
• Informed consent document's vernacular translation
• Investigator brochure for information regarding clinical and nonclinical data of the investigational product
• Study advertisement for participant recruitment or any other written information to the patient
• Grants, payments, insurance documents.

Added responsibility of ethics committee

In academic trials (e.g., postgraduate thesis/investigator- initiated trials in academic institutions), the ethics committee of the institute decides whether the protocol is to be sent to the regulatory body (DCGI) for approval before initiation of the trial. In the event of not receiving any reply from the office of the DCGI by 30 days, the trial can be initiated, but also the record of the communication must be retained by the ethics committee.

In a recent report, it was revealed that approval letter of IEC's has deficiencies in various aspects, including composition, quorum, and review of insurance and clinical trial agreement. This highlights the gaps in education and training of IEC members.[ 20 ] With reports of IEC malfunction pouring in the media,[ 21 ] CDSCO has taken stern steps in streamlining the IEC functioning. The Schedule Y is amended by inserting a rule 122DD which specifies the detail procedures for the registration of ethics committee.[ 22 ]

Registration of Ethics Committee

As per rule 122DD, all ethics committees have to be registered with Drug Controller General of India (DCGI) without which they cannot approve any clinical trial protocol and has come into effect from February 25, 2013.[ 22 ] For the purpose of registration, application has to be sent by the ethics committee to CDSCO as per the requirement specified in Appendix VIII of Schedule Y [Annexure I] along with a checklist available from CDSCO website.[ 23 ] The information that is required to be submitted by the applicant for registration of the ethics committee are:

• Name of the ethics committee
• Authority under which the ethics committee has been constituted, membership requirements, the term of reference, conditions of appointment, and the quorum required
• The procedure for resignation, replacement, or removal of members
• Address of the office of the ethics committee
• Name, address, qualification, organizational title, telephone number, fax number, E-mail, mailing profile of the chairman
• Name, address, qualification, organizational title, telephone number, fax number, E-mail, mailing profile of the members of the ethics committee. The information should also include member's specialty (primary, scientific, nonscientific), members affiliation with institution, and patient group representation if any
• Details of supporting staff
• Details of the type of clinical research reviewed by the existing committee (e.g., pharmaceuticals, devices, epidemiological, retrospective, herbals, etc.), documents reviewed for any clinical trial protocol, including informed Consent documents, information in respect of number of meetings of the committee and documentation of the minutes of meetings of these committees concerning clinical trial, information regarding review of serious adverse events reported during conduct of clinical trial
• The SOPs to be followed by the committee in general
• The SOPs to be followed by the committee for vulnerable population
• Policy regarding training for new and existing members along with the SOPs
• Policy to monitor or prevent the conflict of interest along with SOPs
• Details of any previous audit or inspection of the committee.

The licensing authority (CDSCO) after being satisfied with the requirements grants registration for 3 years from the date of issue after which the ethics committee has to apply for reregistration within 3 months from expiry. For reregistration, GCP training certificate of each member of the ethics committee and information on monitoring of ongoing trial has been made mandatory. By registering with the CDSCO, the IEC commits itself for safeguarding the rights, safety, and well-being of the trial subjects by:[ 23 ]

• Reviewing and according its approval to a clinical trial in accordance with Schedule Y and GCP and also to carry ongoing review of the trial at appropriate intervals
• In the case of any SAE, the committee would analyze and forward its opinion as per procedures specified under Appendix XII of Schedule Y

Maintain adequate and accurate records after the completion or termination of the study for not <5 years from the date of completion or termination of the trial (Both in hard and soft copies).

The ethics committTo comply with the regulatory environment in India, the ethics committee is required to have records and access to the written SOPs, national and international guidelines, constitution and composition of the ethics committee the curriculum vitae of all its members, copies of all the trial documents received for review, all the correspondence between the investigator and the committee, agenda and minutes of all the ethics committee meetings, final reports of all the studies it approved.

CDSCO is strict about certain parameters while registering the ethics committee and that has be kept in mind while applying:[ 23 ]

• Chairperson: The chairperson has to be outside the institute, and the principal/director of the institute cannot be chosen as the chairperson for the purpose of autonomy of the committee. The principal/director may the member secretary for operational feasibility. It also has to be kept in mind that a chairperson cannot serve the dual purpose of lay person/pharmacologist/legal expert or any other essential membership criteria of IEC laid down by Schedule Y; and separate representation of that member category has to be their in the committee. In case the chairperson is absent for a particular meeting, the committee can choose any member who are present, to function as the chairperson for that meeting; but the person has to be from outside the institute
• The lay person in the committee: The idea behind inclusion of lay person is to have a person in the committee who is representative of the study population; thus having a person from the creamy layer of the society undermines the very essence of the logic. CDSCO is strict that lay should come from the society and free of any conflict-of-interest. Appointing the secretary, account officer, librarian of the institution as the lay person is unacceptable
• Legal expert: A legal expert can be a practicing lawyer or a retired judge; not just anyone who has the degree of Bachelor of Legislative Law (LLB) and has never practiced law
• Authority under which committee is constituted: For the purpose of autonomy, it is desired that committee members (including the member secretary) are chosen by the chairperson and not by the principal/director/any other person belonging to the institute
• Conflict of interest: It should be mentioned in the SOP that all members having conflict of interest would refrain from the discussion on that particular proposal. At the end of the meeting, the members should sign the undertaking that they had no conflict of interest
• Research involving vulnerable population: The SOP must clarify how the ethics committee is going to handle the research involving vulnerable population or else it may spell out that it will be decided on case-to-case basis
• GCP training of members: It is mandatory that members of ethics committee are trained in GCP, and it is essential to submit their certificates of their training while applying for the registration.

Exemption from Institutional Ethics Committee Review

Proposals which have less than “minimal risk” are exempt from review by the IEC. “Minimal risk” is the risk anticipated not greater than that encountered in routine daily life activities of general population. Examples of such proposals are research on educational practices (instructional strategies, curricula, or classroom management), research involving the collection of or study of existing data, documents, records, pathological or diagnostic specimens if these sources are publicly available and do not identify participants.

Expedited Institutional Ethics Committee Review

Proposals with no more than minimal risk can be considered for expedited review. For example, minor deviations from originally approved research during the period of approval, continuing review of approved projects, research involving clinical materials (data, documents, records, and specimens) that have been collected for nonresearch (clinical) purposes and during emergency situations (disasters, outbreaks).

With increased number of clinical research and trials taking place, the responsibility of the ethics committee has increased manifold. Improved ethics committee functioning is the need of the hour so that the research participants are protected, and ethical clinical research is done.

Tips for Facing the Ethics Committee

The ethics committee is strict regarding certain aspects of protocol, and these are the essential elements the investigator should be careful while submitting

• Informed consent document: The protocol must contain the vernacular version of the patient information sheet and the informed consent form
• Audio-visual recording of the informed consent process: This is relevant when the research involves new molecular entity or vulnerable population
• Vulnerable population: Research involving vulnerable population is better avoided unless such subjects are specific beneficiaries of the research
• Serious adverse events: The protocol must elaborate the timeline for reporting of serious adverse events to the ethics committee, regulatory body (DCGI), sponsors (if relevant) and head of institution; and also management protocol of serious adverse events
• Compensation in serious adverse events: The insurance certificate for compensation and management of serious adverse events should be annexed with the protocol (relevant for sponsored trial). For academic trials, corpus fund earmarked for such purpose should be maintained and mentioned
• Placebo-controlled trial: Better to avoid Placebo-controlled trial if standard care exist for the disease and active-control should be used in place of placebo
• Advertisements for recruitment of trial participants: This should be better avoided
• Compensation for participation in trial: Monetary compensation in excess of travel allowance and daily wage loss should be avoided
• Registration of trial in clinical trial registry: This is to be done for all clinical trials and optional for observational studies
• Submission of progess report: It is essential to document in the protocol the plan for submission of progress report.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

What is new?

When a doctor becomes a researcher, the duties and responsibilities are compounded and he has to serve the role of both a doctor and researcher maintaining the rules and regulations of “Good Clinical Practice (GCP)” in clinical research laid down by International Conference on Harmonisation-GCP (ICH-GCP), Government of India (Indian-GCP), Schedule Y and also are guided by the meeting resolution of World Medical Association (WMA) e.g., Helsinki declaration and is guided by the principles of autonomy, non-maleficence, justice, beneficence, confidentiality and honesty.

Acknowledgment

The authors thankfully acknowledge Prof. Debabrata Bandyopadhyay (Professor and Head, Department of Dermatology, Medical College, Kolkata) and Professor Avijit Hazra (Professor, Department of Pharmacology, IPGME&R, Kolkata) for reviewing the manuscript and providing valuable inputs.

Principles of Clinical Ethics and Their Application to Practice

Affiliation.

• 1 The Medical College of Wisconsin, Milwaukee, Wisconsin, USA, [email protected].
• PMID: 32498071
• PMCID: PMC7923912
• DOI: 10.1159/000509119

An overview of ethics and clinical ethics is presented in this review. The 4 main ethical principles, that is beneficence, nonmaleficence, autonomy, and justice, are defined and explained. Informed consent, truth-telling, and confidentiality spring from the principle of autonomy, and each of them is discussed. In patient care situations, not infrequently, there are conflicts between ethical principles (especially between beneficence and autonomy). A four-pronged systematic approach to ethical problem-solving and several illustrative cases of conflicts are presented. Comments following the cases highlight the ethical principles involved and clarify the resolution of these conflicts. A model for patient care, with caring as its central element, that integrates ethical aspects (intertwined with professionalism) with clinical and technical expertise desired of a physician is illustrated.

Keywords: Autonomy; Confidentiality; Ethics; Informed consent; Integrated patient care model; Professionalism.

© 2020 The Author(s) Published by S. Karger AG, Basel.

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• Volume 14, Issue 5
• Rhetoric of research: a call for renaming the clinical research partnership
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• Anessa M Foxwell 1 , 2 , 3 ,
• Lillie M LaRochelle 4 ,
• http://orcid.org/0000-0001-5681-3463 Connie M Ulrich 1 , 2 , 3
• 1 Biobehavioral Health Sciences , University of Pennsylvania School of Nursing , Philadelphia , Pennsylvania , USA
• 2 NewCourtland Center for Transitions and Health, University of Pennsylvania , Philadelphia , Pennsylvania , USA
• 3 The Leonard Davis Institute of Health Economics, University of Pennsylvania , Philadelphia , Pennsylvania , USA
• 4 Georgetown University School of Nursing , Washington , District of Columbia , USA
• Correspondence to Dr Connie M Ulrich; culrich{at}nursing.upenn.edu

Objective Research cannot advance without the voluntary participation of human participants.

Summary of arguments Full participation of research participants is often restrained by the traditional research framework, which relegates them to a predefined participant role and allows them only quasi-scripted opportunities to contribute to research processes and outcomes. Terms commonly used to refer to research participants do not reflect their significant role or send a clear message about their value. The authors propose a shift from ‘patient participant’ to ‘participant partner.’ Recognition of the true partnership between the participant and the research team, from the consent process to the trial’s end, will encourage and enable fuller participation.

Conclusion Changing the rhetoric of research in the labelling of research participants will require dialogue. ‘Respect for persons’ demands it, and the research process will be better for it.

• Clinical Trial
• ETHICS (see Medical Ethics)
• Adult oncology

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2023-080137

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Names for a valued role

The role of persons who enroll in—and enable—clinical research has evolved, as have the terms we use to refer to these persons. Many of the sentinel research ethics guidelines still use the term ‘human subjects’, 1–3 but this nomenclature does not seem to adequately reflect the value of those who chose to participate in research opportunities. For example, the literature vacillates in its terminology where ‘subjects’ became ‘patients,’ who, in turn, became ‘patient participants’ or simply ‘participants.’ The term ‘subject’ seems different from the term ‘patient participant’—with ‘subject’ harkening back to a time in which clinical research was something done to individuals and ‘patient participant’ offering a far more active role of informed participation. However, even as we use language to reflect our evolving recognition of the valued role of the research participant, our terms suggest a hierarchy that exists in the clinical research field. In such a hierarchy, the researcher has authority and decision-making power while the outcome or impact of the research unfolds in the participant’s world.

This hierarchical relationship—and terms that try to flatten it—is an important topic of discussion as researchers attempt to redefine the role of the patient participant and reconsider terminology used in research. A new definition must function to (1) acknowledge the historical and societal context of research and research participation in order to rebalance power and incorporate values of community partnership, (2) accurately capture the duties and responsibilities of the patient-participant role and (3) define the patient-participant role in relation to the topic of the research and the research team.

Patients and public involvement

In ‘Models of Engagement: Patients as Partners in Clinical Research,’ published in Applied Clinical Trials, the authors examine how four trials have employed research programmes that both validate and integrate a partnership model to further engage participants in research. 4 The intent of employing these models was to create opportunities for more ‘meaningful and effective patient participation’. 4 The four trials sought to engage participants and caregivers at various stages of the research process. The ADAPTABLE aspirin study and CONNECT-HF trial involved patient participants as advisory board members, an industry-sponsored phase II study had patients as steering committee members, and in the PCORnet obesity studies, patients were coinvestigators. 4–6 These trials found that the increased integration of patient participants into the logistics of the trial led to optimised recruitment messages, improved researchers’ understanding of patient-participant perspectives and provided feedback on enhancing patient comfort, convenience and retention. 4–6

The perception that the patient participant has of their role in the study and its impact on participant retention has been noted by Ulrich et al in their analysis of qualitative data for patients withdrawing from cancer clinical trials (CCTs). 7 The researchers interviewed 20 patient participants regarding withdrawal from CCTs, and several interviewees cited the notion that patient participants are partners in the research process. Indeed, as one participant said:

‘I have a real patient advocate view as the clinical trials. In my opinion, doctors should recognize that the people that are in the clinical trials are partners. They’re not patients, okay? They are partners in the research process and as a result, they should be treated the same way that a doctor, for instance, would treat another doctor on staff.’ [Patient, CCT study]

All of these participants were arguably experts in their field. Each had personally lived and functioned within the framework of the trial. This lived experience affords participants insight into the processes and procedures of a trial that can be integral to its success. However, the current model of clinical research often does not allow participants to capitalise on their full potential due to their strict relegation to a predefined participant role. This role, as currently practised, adopts an overall ‘speak when spoken to’ framework that creates tightly regulated and quasi-scripted opportunities for participants to genuinely participate.

Partnership status

Some might question the meaning of ‘partner’ in research and whether it is the appropriate designation that respects the contributions of those who participate in research or if it is too lofty of a goal. To be a partner reflects a shared purpose in each activity, even though the depth of the partnership may vary. 8 However, to enable patient participants to participate at the highest level possible, a change of title seems appropriate. The shift from ‘patient participant’ to ‘participant partner’ not only allows us to employ a rhetoric that more closely matches the reality of research participation, it also does so in a relatively simple manner. The notion of participant partnership reinforces the goals of partnership outlined by Uhlenbrauck et al , 4 and offers an avenue for research outcome improvements. Although the method in which patient participants become recognised as partners in research may be individualised to the needs of the trial in question, the basic rhetoric employed around participation can be universal. During the participant consent process, the promise of partnership in the research can be explicitly outlined so that the logistical needs of the trial are met while creating the opportunity for participants to maximise their input and impact on the trial. This partnership between participant and research team is not a question of surrendering intellectual authority or decision-making power—as some might suggest—but rather a matter of incorporating patients’ expertise into the fabric of clinical trials, from design to dissemination. We also cannot forget that research participants are often supported by a significant partner, namely a caregiver whether spouse, family member or friend, that has a vested interest in the research process. These caregivers face unique challenges because they are in a triadic relationship—one with the research participant and at the same time with the researcher and research team. Caregivers can become involved in the day-to-day research decisions of the research participant and also feel a bit disjointed as they schedule and reschedule their lives, although we know very little about their roles in research. For example, one caregiver interviewed for another study by Ulrich et al described the shifts and burdens while their spouse was enrolled in a time-intensive CCT:

On a daily basis, it does depend on how he feels. If I know he’s not feeling well, then I change my schedule at work and go home early. It really depends on, you know, what’s… pretty much how he’s feeling. You know, financially it’s a stress, so it’s… I try to work as often as I can because, you know, bills don’t get paid just by whims, so, you know, that’s a… that’s a factor in some decisions we make. And if I can’t get him to [research site], which I’ve only not been able to once, I have a good support group that would take him, and that allows me to stay and do what I need to do if that in fact is the… you know, the decision to take him to… to [research site]. But I booked off Mondays and Tuesday mornings, so I take him down on Monday, and some days we have to stay over, or some days he’s just too tired to make the trip home. It’s about two-and-a-half hours—’[Spouse/Caregiver, CCT Study, unpublished transcript]

Some research suggests that caregivers, too, suffer emotional and physical burdens and moral distress when their loved one participates in research. 9 In creating a more inclusive and equitable research enterprise, broader public engagement must also include caregivers as they are in a position to bridge gaps. Caregivers are often tasked with monitoring symptoms, addressing immediate research-related concerns and communicating with front-line research coordinators and principal investigators on necessary supports—both for the patient and themselves as they travel through the often-daunting research process together. 10

Steps towards change

So, what can we do to begin this process? First, changing nomenclatures or research labels pertaining to a specific population requires discourse. A partnership designation does not take away from vulnerability concerns that might arise, nor does it necessarily imply equality in the relationship. Further, we must expect—and respect—that some individuals might prefer a passive role in the decision-making process related to their research participation, or what we might call a ‘minor partnership’ status. It does, however, seem to balance the potential vulnerability of being a participant in a research trial with the empowerment of partnering with the researcher and research team in the shared goals that each wishes to achieve in the research process.

Second, we recommend several foundational principles that recognise the shared values between the researcher, the research team, and the participants and their caregivers who enable clinical research or advocate on its behalf. Building a framework that focuses on these values of reciprocity, solidarity, advocacy, procedural justice and transparency is a start to the process. These principles may be viewed as overly idealistic within the current clinical trials landscape and creating a research environment in which such values are foundational with careful consideration and commitment to action long term. For example, even though patients undergo a carefully conducted informed consent process, they may not fully understand key aspects of the research trial, including the fact that they may be randomised to a placebo arm. As such, some current research participants cannot be said to have risen to the status of full partners in which the values described above undergird their participation. Moreover, although the Declaration of Helsinki acknowledges that all participants in research trials are entitled to ‘share any benefits that result from it, 1 ’ clinical trial participants may not have access to their personal data from the trial and thus may not fully benefit from their participation.

Third, there must be an exchange of ideas that is mutually beneficial to each partnering party, with shared support of each other’s agendas and ideas. Fourth, a process for adjudicating ethical or other concerns that arise in the course of the research should be transparent. We recognise that there are other principles and values that may be central to the participant-and-caregiver partner designation and that develop reciprocated trust in achieving partnership goals.

Adopting the ‘participant-partner’ term encompasses and acknowledges the infrastructure needed to create partnerships and to transform the experience of care and of caregiving for patients, their families and healthcare providers. Patient-centred and family-centred care describes the essential elements necessary to cultivate partnerships at the bedside, in care plan decision-making, healing relationships, and individual patient and professional interactions. More broadly, it provides a framework for formal partnerships with patient and family participation on advisory councils, committees and design teams. We concur with Graves et al who state that ‘there will never be a science for the people until all the people are in science’. 11 They call for ‘Moonshot’ thinking in research to achieve a transformative science system that produces better science, seamless translation to diverse communities, enriched societal benefits and an improved workforce climate. 11 We do not know if a change in language would increase trust in research or whether it might help people feel as though it represents a more ‘inclusive’ research paradigm, but future research could bear this out. We also do not know if a shift in language to participant partner would create more role confusion within the research team, creating unnecessary tensions in the researcher–participant relationship. It would be helpful to hear from research participants and their families on how they perceive their roles within the research paradigm and their views on partnership.

Changing the rhetoric of patient participation is a small and simple first step in supporting the evolution of the participant–partner role. In enacting this change we take an important step towards improving the quality of our research from beginning to end—and, importantly, towards valuing those who ultimately give themselves to the advancement of science in the search for treatments that can change the course of disease and its consequences in society.

Ethics approval

This study involves human participants and was approved by University of Pennsylvania IRB: PROTOCOL #820983. Participants gave informed consent to participate in the study before taking part.

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• ↵ U.S. Department of health and human services. The Belmont report: ethical principles and guidelines for the protection of human subjects of research . 1978 . Available : https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html
• ↵ International ethical guidelines for health-related research involving humans, fourth edition. Geneva. Council for international organizations of medical sciences (CIOMS) . 2016 . Available : https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf
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X @cm_ulrich

Contributors CMU initiated the collaborative project by providing access and acquisition of CMU’s data for interpretation with LL. CMU and LL participated in the conceptualisation of the manuscript and AF, LL and CMU participated in manuscript preparation and review of the manuscript in several stages. CMU, AF and LL approved the final version of the manuscript and the revisions as needed.

Funding CMU was supported in part by R01 CA196131 for this work. CMU was also supported by the NewCourtland Center for Transitions and Health for pilot funding. During the conception and development of this work, AF was supported by the National Institutes of Health (NIH), National Institute of Nursing Research under award no. T32NR009356.

Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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eAppendix. Complete Interview Guide

Data Sharing Statement

• Designing Health Care Artificial Intelligence That Comports With the Values of Patients JAMA Network Open Invited Commentary May 1, 2023 Debra J. H. Mathews, PhD, MA; Kadija Ferryman, PhD; Ruth Faden, PhD, MPH

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Thai K , Tsiandoulas KH , Stephenson EA, et al. Perspectives of Youths on the Ethical Use of Artificial Intelligence in Health Care Research and Clinical Care. JAMA Netw Open. 2023;6(5):e2310659. doi:10.1001/jamanetworkopen.2023.10659

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Perspectives of Youths on the Ethical Use of Artificial Intelligence in Health Care Research and Clinical Care

• 1 Department of Bioethics, The Hospital for Sick Children, Toronto, Ontario, Canada
• 2 Genetics & Genome Biology, Peter Gilgan Centre for Research & Learning, Toronto, Ontario, Canada
• 3 Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
• 4 Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
• 5 Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada
• 6 Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
• 7 The Hospital for Sick Children, Toronto, Ontario, Canada
• 8 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
• Invited Commentary Designing Health Care Artificial Intelligence That Comports With the Values of Patients Debra J. H. Mathews, PhD, MA; Kadija Ferryman, PhD; Ruth Faden, PhD, MPH JAMA Network Open

Question   What are the perspectives of children and youths regarding research and clinical care involving health artificial intelligence (AI) at the point of care?

Findings   In this qualitative study including 28 individuals aged 10 to 17 years, participants had a generally positive view of research, willingness to participate, knowledge about AI, engagement, and interest in AI research.

Meaning   The findings of this study suggest that engaging children and youths is important to build trust and develop social license as they express a strong desire to be included in decision-making regarding AI integration.

Importance   Understanding the views and values of patients is of substantial importance to developing the ethical parameters of artificial intelligence (AI) use in medicine. Thus far, there is limited study on the views of children and youths. Their perspectives contribute meaningfully to the integration of AI in medicine.

Objective   To explore the moral attitudes and views of children and youths regarding research and clinical care involving health AI at the point of care.

Design, Setting, and Participants   This qualitative study recruited participants younger than 18 years during a 1-year period (October 2021 to March 2022) at a large urban pediatric hospital. A total of 44 individuals who were receiving or had previously received care at a hospital or rehabilitation clinic contacted the research team, but 15 were found to be ineligible. Of the 29 who consented to participate, 1 was lost to follow-up, resulting in 28 participants who completed the interview.

Exposures   Participants were interviewed using vignettes on 3 main themes: (1) health data research, (2) clinical AI trials, and (3) clinical use of AI.

Main Outcomes and Measures   Thematic description of values surrounding health data research, interventional AI research, and clinical use of AI.

Results   The 28 participants included 6 children (ages, 10-12 years) and 22 youths (ages, 13-17 years) (16 female, 10 male, and 3 trans/nonbinary/gender diverse). Mean (SD) age was 15 (2) years. Participants were highly engaged and quite knowledgeable about AI. They expressed a positive view of research intended to help others and had strong feelings about the uses of their health data for AI. Participants expressed appreciation for the vulnerability of potential participants in interventional AI trials and reinforced the importance of respect for their preferences regardless of their decisional capacity. A strong theme for the prospective use of clinical AI was the desire to maintain bedside interaction between the patient and their physician.

Conclusions and Relevance   In this study, children and youths reported generally positive views of AI, expressing strong interest and advocacy for their involvement in AI research and inclusion of their voices for shared decision-making with AI in clinical care. These findings suggest the need for more engagement of children and youths in health care AI research and integration.

There is increasing recognition that using artificial intelligence (AI) in health care requires integration of the views and values of patients and family. 1 Public engagement is particularly important for a technology mired in social controversy, which can undermine trust in institutions, health care professionals, and scientists. 2 Social license supports trust by aligning values and stakeholder preferences beyond the requirements of law and regulatory bodies. For AI, social license calls on those developing and integrating AI systems to explore and understand patient values to develop value-aligned policies and practices.

Artificial intelligence in health care requires health data including routinely collected data during health encounters, such as hospital visits. 3 The conditions in which these data are accessed and analyzed are essential to establishing and adhering to social license for AI. Adult perceptions regarding health data use for research are well characterized worldwide. 4 - 12 Although people have a general familiarity with AI, 13 - 16 AI use in the clinical context is still novel to many. 17 Studies have reported that patients would like to take part in the development and implementation of AI and be educated about its use. 18 , 19 To support AI development directed toward improving health, people are generally willing to share their health data, but privacy remains a major concern. 13 - 15 , 20 , 21

Despite the surge of studies exploring adults’ views on the ethical issues regarding AI 1 , 9 , 13 , 20 , 22 , 23 and some research in virtual care acceptance among adolescents, 24 limited works have explored the views of children (ages, 10-12 years) and youths (ages, 13-17) regarding AI in health. Visram et al 25 reported on a workshop they delivered to youths on a hospital advisory council that resulted in high levels of engagement, suggesting that youths are ready and willing to become involved in discussions about AI. Given that maintaining trustworthiness and social license requires understanding stakeholder views, 26 , 27 it is imperative that youths are meaningfully engaged to help shape the future of health care AI. This qualitative study aimed to explore the moral perspectives and views of children and youths regarding health AI.

This qualitative study was conducted from October 2021 to March 2022. Participants were recruited at a large urban pediatric hospital (The Hospital for Sick Children [SickKids]), purposefully sampled by selecting individuals based on demographic and health care characteristics to provide a spectrum of perspectives grounded in unique experiences. SickKids is one of the largest pediatric hospitals in the world, situated in Toronto, Ontario, where there is among the greatest population diversity in Canada. Recruitment involved posting study flyers across the hospital and outpatient clinics, social media advertising, and listing on the hospital’s research database. Interested individuals initiated first contact via email with the research coordinator (K.T.) to arrange an interview and assess eligibility. Inclusion criteria were (1) age between 10 and 17 years at recruitment when a young person is capable, (2) capable to consent (parental consent for research not required in Ontario), (3) receiving or had received care at a hospital or affiliated clinic, (4) able to communicate independently or with assistance, (5) able to access the technology to attend the interview virtually, and (6) able to communicate in English. Individuals were excluded if they were deemed not capable of consenting to participate. Verbal consent was obtained via phone by the research coordinator. Participants received compensation. Ethics approval was granted by The Hospital for Sick Children’s Research Ethics Board. This study followed the Consolidated Criteria for Reporting Qualitative Research ( COREQ ) reporting guideline for reporting qualitative research.

Purposive sampling was conducted to maximize diversity among participants and enabled through inclusive communication and recruitment strategies. Participants were balanced for health care experience: acute describes those who attended the hospital for urgent issues not requiring follow-up, chronic describes those with health issues requiring regular follow-up, and complex describes those with multiple health issues supported by at least 2 different care teams. In addition to health care experience, demographic characteristics (age, gender, and ethnicity) were queried. Data on ethnicity were collected to ensure our sample was representative relative to the broader Canadian population as best we could.

Our study was guided by the perspective that youths’ voices are valuable and agential, meaning that we took their moral perspectives and intuitions at face value; their experiences, voices, and values were given ethical weight. 28 The interview was developed by the research team and designed in a vignette format, wherein participants heard fictional patients’ stories (eAppendix in Supplement 1 ). Interview topics were chosen to explore issues relevant to ethical use of AI, such as trust, informed consent, therapeutic misconception, therapeutic alliance, and social value. The stories were designed to touch on these topics while being relatable and realistic and featured a named protagonist to minimize social desirability bias. 29 Interview trialing was as follows: first within the immediate research team, second with a child life specialist (A.R.S.), and third with 2 test interviews with youths who were not participants in the study.

Interviews lasted approximately 1 hour and were conducted by a single interviewer with experience in qualitative interviewing (K.T.). No repeated interviews were required. Interviews began with introductions and questions on demographic characteristics, followed by brief educational content describing AI, research, and an example that tested participants’ knowledge (eAppendix in Supplement 1 ). Moral intuitions were explored using 3 vignettes framed around (1) health data research (protagonist identified as River), (2) interventional AI research (protagonist identified as Latisha), and (3) clinical AI use (protagonist identified as Chad). As an exploratory study, we did not explicitly pursue thematic saturation as an end point and instead had preselected a minimum of 12 interviews across 2 groups (elementary- and high-school-age youths). We identify areas in which there were disagreements in perspectives as these will be important to guide future research.

Interviews were audiorecorded and transcribed verbatim. No repeated interviews were conducted, and transcripts were not shared with participants. Transcripts were coded and analyzed (K.T., K.H.T., and M.D.M.) thematically using Dedoose, version 9.0 software (SocioCultural Research Consultants, LLC). Transcripts were first coded by each team member independently to establish an initial set of codes; the team then met to synthesize codes and establish an initial coding framework. Two team members (K.T. and K.H.T.) led the subsequent coding and met regularly with the principal investigator (M.D.M.) during coding to ensure consistency, resolve disagreements, and discuss the developing themes. A workshop was conducted at a later date with a subset of participants to verify that the findings resonated.

In total, 44 individuals contacted the research team. Fifteen were ineligible due to age. Of the 29 who consented, 1 was lost to follow-up resulting in 28 participants (mean [SD] age, 15 [2] years, range, 10-17 years) ( Table 1 ). The population included 6 children (age, 10-12 years) and 22 youths (age, 13-17 years). Participants identified their gender as female (16 [57%]); male (10 [36%]); and 2-spirit, trans, nonbinary, or gender diverse (3 [11%]); 7% preferred not to answer. Participants identified their ethnicity as Black (2%), East Asian (7%), mixed (7%), South Asian (18%), and White or European (54%); 7% preferred not to answer. Health care experience was relatively balanced, with 36% reporting acute health needs, 36% having chronic conditions, and 25% having complex health needs.

Thematic analysis was grouped as follows: AI knowledge and understanding, health data research, interventional AI research, and clinical use of AI. Some themes were revisited across stories (eg, consent). We organized our results according to the story to indicate how themes were related to the distinct stages of research. Participants were able to state their understanding of AI applications and could distinguish these from traditional computing methods. Most explained AI as a computer system that learns based on past information and the most frequently mentioned AI benefits were speed and efficiency. Participants were mostly concerned with the potential for AI systems to be hacked, have security concerns, and know too much about them. Participants reported a broad understanding of research as a process of finding information and answers. Several received formal education on AI through school or extracurricular activities. Participants broadly asserted that AI “shouldn't replace our doctors and nurses, and …can be used as a tool to benefit, but not as a replacement” (age, 16 years; female).

Participants endorsed an altruism-based view of health data research ( Table 2 ). They expressed that even though this research may not benefit them individually, they would participate because of the potential to help others in the future (“I think I would [consent to participate] because if like I knew it was going to help like other people in the future, even though it, like, may not help me directly” [age, 15 years; female]). A strong theme of permission-based data access was noted: all participants but one reported that patients should be asked for permission to use their data (“It's like information about River’s self, like, so it's like River's choice … if the researchers can see it or not” (age, 12 years; male). All participants wanted information about benefits and risks and specific uses of their data.

Participants articulated that clinical notes and health record information were for the purpose of “understanding the patient and see what they’re going through so they can help [the patient, River] out better” (age, 12 years; male). There was a general supposition that these forms of information are kept confidential and private, which underscored their interest in researchers seeking permission to access these data. Participants expected that in research this privacy is maintained, with many asserting they would “share everything with the researchers” (age, 11 years; male). Privacy violations were linked to concerns about negative consequences; for example, one participant worried about stigma if their school had access to their health information.

Participants generally were more sensitive to research using mental health data. They reported feeling that such data are more personal and overall reported greater comfort with sharing physical health data compared with mental health data. Several grounded their hesitancy in the epistemic uncertainty involved with mental health conditions compared with physical illness: “mental health isn’t something that [is] concrete…in a sense the way a heart disease is…there isn’t no accurate…reading of it” (age, 17 years; female).

Some were comfortable with sharing all health information the researchers deemed relevant, and some only with sharing specific forms of data relevant to individual studies. There was also variation in comfort levels related to the specificity and depth of information being shared and whether they felt consent should be required for sensitive data types (eg, genetic, mental health).

Participants expressed strong negative views about social media data used for health research. Data from wearable devices and health sensors were more acceptable but only under the condition that consent was sought from the wearer. Participants reported that social media information is personal—not as in private but as in relating to the core of one’s personhood—and that they share information intentionally with family and friends (“posting stuff from your life” [age, 14 years; male]). Participants described social media information as a highly curated and biased version of themselves. Several raised the point that “it would be probably bad for researchers 'cause…there’s no confirmation that whatever you’re putting on social media is actually true” (age, 11 years; male), indicating skepticism that meaningful knowledge could be gained from using social media as a medical information source.

If researchers wanted to use data from social media, all participants but one advocated for consent to be obtained, although some remarked that this might not be feasible. One participant stated that they would be okay with researchers using their health sensor data and social media posts without them knowing “because it’s not going to harm me” (age, 17 years; male).

Participants reported awareness that research typically does not benefit the participants but will benefit future patients ( Table 3 ). They were oriented to potential risks (eg, that the AI system might not work) and, where risks were minimal, they were quite willing to participate but asserted that each patient has a right to make their own choice.

Some participants detected a patient’s vulnerability and constrained choice, stating the patient may not be “mentally up for it” (age, 14 years; female) or able to “think rationally” (age, 13 years; male) to evaluate research participation. Most participants were aware that participation in research may or may not help a patient get better. Yet when asked what they would recommend, many still reported they would advise the patient to participate, asserting it would help the patient. Participants often associated the opportunity for research with a lack of first-line therapeutic options. Many remarked that if there were no other options, they would likely consent to research provided it presented limited harm: “It still might work, so if there's any chance at getting better then yeah, I'd probably take it because that it's gonna help me” (age, 13 years; male).

Respecting individual feelings was vital to participants regardless of capacity. They noted that decision-making should involve reflection on the patient’s thoughts and concerns, discussion with parents and the medical team, and addressing questions (“I’d ask her why she’s scared…try to get her reasoning” [age, 17 years; female]). If there was a disagreement between the prospective participant and parents, the immediate suggestion was to explore the reasoning of both perspectives. In the end, there was agreement among participants that the patient’s wishes, if reasonable, should be respected and not overridden. Participants recognized that this might be different for very young children. One participant remarked that the scientific quality could be compromised with an unwilling participant: “If she isn’t 100% willing, I would say it’s pointless…because she won’t give accurate responses and the study will not be accurate itself” (age, 17 years; female).

A strong theme was the idea of being treated like a person and not a number ( Table 4 ). Participants advocated for human interaction; for example, always seeing the patient at the bedside rather than relying exclusively on information from the AI. Some participants expressed surprise at the notion of an AI error, for example, “not because I would trust the input of an AI more, but I would just feel like it's so much more like data based, and it's so much more proficient in the sense that, like it analyzes everything it could” (age, 17 years; female). Others readily accepted the possibility of errors, stating that “the AI only knows like so much” (age, 15 years; female). Participants advocated that the physician could either check the AI after seeing the patient in person or, if they check the AI in advance, should refrain from making a decision until they actually saw the patient in person, and they overall presented a supportive view of AI (eg, “it should be more of a double checker” [age, 15 years; female]). Participants expressed 2 complementary rationales: the bedside evaluation provides essential information for making the correct decision for the patient and a personal connection is vital for respect, trust, and quality of care. For example, “the doctor needs to get like a full assessment as like a patient as a whole and like recognize that the patient is a person” (age, 16 years, female).

Most participants were more sympathetic toward a physician’s mistake, recognizing that physicians are human and “humans make mistakes” (age, 12 years; male). Others were more upset at AI mistakes “because if it is not accurate—it should not be used” (age, 17 years; female). Participants focused on the physician even when they attributed the mistake to the AI system because they reported that responsible use of AI was the physician’s responsibility: “I'd assume they use some of their own knowledge, but decision should not be based solely on an AI” (age, 13 years; male). Participants had a strong negative reaction if the physician did not check the patient in person but made a recommendation based on the AI alone, expressing frustration that the patient’s care was negatively impacted due to not being “properly checked up” (age, 17 years; female), calling the physician “lazy” (age, 11 years; male), and referring to “medical malpractice” (age, 13 years; male).

Our qualitative study describes perspectives of children and youths around ethical issues for health AI. We observed strong themes of respect for persons, support for autonomy, and humanistic care among a diverse and knowledgeable group of youths. Anecdotally, our team was impressed with the knowledge level these individuals had regarding AI and their thoughtfulness in responding. Many participants reported classes or extracurricular activities where they learned about AI. Concerns about youths’ capacity to understand the AI technology implications are, perhaps, unwarranted; given the experience of today’s youths with information technology, 29 they may be ideally positioned to inform AI integration.

We found good overall support for both data-driven and interventional research grounded in the desire to help others, as with adults. 30 We noted that several remarks by participants suggest therapeutic misconception—a view that the patient will derive direct clinical benefit from interventional research. Therapeutic misconception is a known problem for meaningful consent 31 and should be addressed in the informed consent process when recruiting youths into clinical trials involving AI.

We observed a stronger emphasis on consent to data use compared with adults, where the focus instead is more on transparent communication regarding health data uses. 1 , 23 The views expressed by the participants in our study are in tension with many common practices and warrant further exploration. For example, the Tri-Council Policy Statement-2 in Canada permits a research ethics board to grant a waiver of consent for research-related use of retrospective, deidentified health data. Our results suggest that even with legitimate data access, trust in AI might be compromised without addressing the gap between practices and values.

Another theme emphasized was the value of humanism in health care. The value of physician presence at the bedside is underscored by other studies. 1 Similar to adults, children and youths are concerned about risks such as replacement of human clinicians. 1 Many AI applications seek to streamline care, sometimes resulting in less interaction with the health care team. 32 Going forward, balancing efficiency with relational, person-centered care will likely be crucial to nurturing a trusting relationship between clinical AI and patients. The risks we identified included increased blame attribution and a negative perception of health care professionals.

This study has limitations. The participants may not be representative of the general population given the recruitment from a major urban hospital and requirement of having hospital-based interactions. The interview was conducted in English, which limited participation. Acknowledging that these inclusion criteria select for a population with access to technology, research awareness, and without communication barriers to understand the study information, the team recruited from organizations promoting neuro, gender, and ethnic and racial diversity and offered all participants communication assistance tools and support persons they needed to complete the interview.

In this qualitative study, we identified several opportunities for future research and education to integrate youth values in health AI, including a mismatch between data-gathering practices and values, addressing therapeutic misconception, and value misalignment regarding streamlining care delivery. We also noted several strengths, including a positive desire to be included in AI integration, strong working knowledge of AI, and a desire for a humanistic vision of medicine that includes AI. The findings of this study suggest that it may be useful for AI systems that aim to diminish contact points between health care professionals and patients be codesigned with youths and their families.

Accepted for Publication: February 27, 2023.

Published: May 1, 2023. doi:10.1001/jamanetworkopen.2023.10659

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Thai K et al. JAMA Network Open .

Corresponding Author: Melissa D. McCradden, PhD, The Hospital for Sick Children, 222 Kenilworth Ave, 1 Toronto, ON M4L3S6 Canada ( [email protected] ).

Author Contributions: Dr McCradden had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Thai, Stephenson, Menna-Dack, Zlotnik Shaul, Anderson, McCradden.

Acquisition, analysis, or interpretation of data: Thai, Tsiandoulas, Stephenson, Zlotnik Shaul, Anderson, Shinewald, Ampofo, McCradden.

Drafting of the manuscript: Thai, Ampofo, McCradden.

Critical revision of the manuscript for important intellectual content: Thai, Tsiandoulas, Stephenson, Menna-Dack, Zlotnik Shaul, Anderson, Shinewald, McCradden.

Statistical analysis: Thai, McCradden.

Obtained funding: McCradden.

Administrative, technical, or material support: Thai, Menna-Dack, Zlotnik Shaul, Shinewald, McCradden.

Supervision: Stephenson, Anderson, McCradden.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by the Edwin Leong Centre for Health Children and the Dalla Lana School of Public Health seed grant (t Ms Thai). Additional funding for recruitment materials was provided by the SickKids Foundation.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We thank the participants for their time and feedback in this study. Donna Koller, PhD (Toronto Metropolitan University), and Samantha Anthony, PhD, MSW, RSW (The Hospital for Sick Children), provided scientific review of the study protocol, Francine Buchanan, PhD (The Hospital for Sick Children), gave feedback on the interview guide and advice on recruitment strategies, Jennifer Stinson, PhD (The Hospital for Sick Children), assisted with participant recruitment, Jelena Djurkic (The Hospital for Sick Children) provided support with communications and outreach, and Cathy Maser, MN, NP (The Hospital for Sick Children), helped with inclusive interviewing methods and supported participant recruitment. No financial compensation was provided.

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For the purposes of clinical trials, regulatory approvals include any approvals by government or health authorities regarding any research that includes human subjects. Additional approvals will be necessary if the research involves the use of an FDA regulated product. The Principal Investigator (PI) is responsible for assessing and addressing all applicable regulatory approvals for the study. The study team initiates the review processes through Institutional Review Board (IRB), Stanford Scientific Review Committee (SRC) and Research Management Group (RMG) submissions. The majority of clinical trials are subject to Food and Drug Administration (FDA) regulations and human subject protection laws. The study team should include FDA approval letters for externally sponsored projects in the initial submissions to IRB and SRC. PI-initiated studies also may involve filings with the FDA prior to IRB review and approval.

The IRB evaluates and approves all protocols involving human subjects research. The SRC provides peer review of all protocols involving cancer patients. With a few exceptions, significant risk device trials conducted under an Investigational Device Exemption (IDE) require additional approval from a local Medicare fiscal intermediary (FI). The Clinical Trial Research Process Manager (CT RPM) verifies alignment of submission information and confirms that all required approvals are secured prior to contract execution.

Regulatory Approvals and Compliance Review Processes

In preparation for study activation, the PI and research team first assess all compliance requirements and then initiate any processes required to obtain the necessary approvals. The PI and/or designee:

• begins the IRB approval process;
• submits minimum documents to Clinical Trial Research Management Group Intake;
• completes all University required training (PI training and Good Clinical Practice/CITI training);
• if necessary, submits a Data Risk for review by University Privacy Office (UPO) and Information Security Office (ISO) under the Office of the Chief Risk Officer;
• if necessary, works with appropriate University and FDA offices to address regulatory requirements and approvals if necessary; and
• accurately fills out the Clinical Trial Proposal Development Routing Form (CT PDRF) , which captures conflict of interest (COI), General Data Protection Regulation (GDPR) and other information. Concurrent submission by the research team to IRB, RMG and SRC (if applicable) expedites the review process.
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What Is Exempt Research?

Research activities are exempt from the requirements of the Common Rule  when the only involvement of human participants will be in one or more of the eight categories detailed below. Studies that are exempt involve minimal-risk activities that are not FDA-regulated, are ethically consistent with the principles of the Belmont Report , and generally do not involve minors or prisoners as participants, with limited exceptions. In addition to exempt research, a study may also involve activities that are considered research not involving human participants, or activities that are not research.

Exempt research categories include:

• This is a research activity conducted in established or commonly accepted educational practices (e.g., classroom, doctors office, professional meeting, church, support group,).
• This research involves normal educational practices that are not likely to adversely impact students’ opportunity to learn required educational content or the assessment of educators who provide instructions, such as an evaluation of an educational practice, or an assessment of program designed to assist instructors with classroom management.
• May include minors if it the research meets other criteria.
• This research only includes interactions involving educational tests (e.g., aptitude, diagnostic, cognitive, or achievement), survey procedures, interview procedures, or observation of public behavior. This can include visual or auditory recordings.
• Recording the information in such a way that the identity of any participants cannot be ascertained readily (either directly or indirectly); OR
• Ensure that any disclosure of the responses outside the research would not reasonably place any participants in danger, facing criminal/civil liability, or be possibly damaging to the participants’ financial standing, employability, educational advancement, or reputation; OR
• Have other adequate provisions to protect the privacy of participant s and to maintain the confidentiality of data.
• May include minors if it is limited to educational tests and observation of public behaviors where the investigator does not participate in the activity being observed.
• This can involve behavioral interventions in conjunction with the collection of information through verbal or written responses or audiovisual recording.
• Participants must all prospectively agree to the behavioral intervention/recording.
• Brief in duration is intended to refer to the intervention as opposed to the intervention and the data collection activities together. To be brief in duration, the intervention should last a few minutes to a few hours. The entire time for the intervention should occur in a single day and not exceed a few hours in its entirety.
• The investigator has no reason to think the intervention will be embarrassing or offensive to participants.
• Ensure that any disclosure of the responses outside the research would not reasonably place any participants in danger, facing criminal or civil liability, or be possibly damaging to the participants’ financial standing, employability, educational advancement, or reputation, OR
• Have other adequate provisions to protect the privacy of participants and to maintain the confidentiality of data.
• The research cannot involve deceiving the participants regarding the nature or purposes of the research unless the participant has been informed they will be unaware or misled regarding the nature and/or purpose of the research.
• Cannot include data gathering with devices (EEG, ECG, MRI, etc.).
• This is for research that involves the use of either identifiable private information or identifiable biospecimens.
• Publicly available; OR
• Recorded in such a way that the identity of the participants cannot readily be ascertained, the investigator will not contact the participants, and the investigator will not re-identify the participants; OR
• Involves only information collection and analysis involving the investigator’s use of identifiable health information when the use is regulated under §§45 CFR 160 and 164, subparts A and E, for the purposes of “health care operations” or “research” as those terms are defined at 45 CFR §164.501 or for “public health activities and purposes” as described under 45 CFR §164.512(b) .
• The research is conducted by, or on behalf of, a Federal department or agency using government-generated or government-collected information provided for non-research activities and meets specific criteria if there is identifiable information to be generated.
• This is research conducted or supported by a federal department or agency, or otherwise participant to the approval of Federal department or agency heads.
• The research or demonstration is designed to study, evaluate, improve, or otherwise examine public benefit or service programs, including procedures for obtaining benefits or services under those programs, possible changes in or alternatives to those programs or procedures, or possible changes in methods or levels of payment for benefits or services under those programs.
• The research or demonstration project will be published on a list of research and demonstration projects exempted under this category prior to commencing the research.
• This category involves taste and food quality evaluation and consumer acceptance studies where wholesome foods without additives are consumed, or food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.
• This requires limited IRB review, but WCG processes it through the exempt submission pathway.
• This category involves storage or maintenance of identifiable private information or identifiable biospecimens collected for either research studies other than the proposed research or non-research purposes for potential secondary research use.
• Make no changes to the way the identifiable private information or biospecimens are stored or maintained; OR
• Ensure adequate protections to protect the privacy of participants and to maintain the confidentiality of data.
• Legally effective informed consent must be obtained using a standard consenting process as described for research that requires IRB review.
• If appropriate, the consent will include a statement that the participant’s biospecimens may be used for commercial profit and whether or not the participant should expect to share in this commercial profit.
• If appropriate, whether the research will or might include whole genome sequencing.
• The consent must be documented in writing or documentation must be waived in accordance with 45 CFR §46.117.
• Consent for the storage, maintenance, and secondary research use of the identifiable private information or identifiable biospecimens must have been obtained in a study that was reviewed in accordance with Category 7 above.
• The research must have adequate provisions to protect the privacy of participants and to maintain the confidentiality of data.
• The research must be within the scope of the consent.
• The investigator must not include returning individual research results to participants as part of the study plan.

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The Ethics of Clinical Research

Clinical research attempts to address a relatively straightforward, and extremely important challenge: how do we determine whether a new medical intervention represents an advance over current methods, whether the new intervention would avoid harms currently incurred, whether it would save lives currently lost? Clinicians may one day be able to answer these questions by relying on computer models, thereby avoiding reliance on clinical research and the ethical concerns it raises. Until that day, clinical researchers begin by testing potential new medical interventions in the laboratory, and often in animals. While these methods can provide valuable information and, in the case of animal research, raise important ethical issues of their own, potential new interventions eventually must be tested in humans. Potential new interventions which work miracles in test tubes and rats, often leave humans untouched, or worse off.

The human tests of a new medical intervention typically pose some, possibly serious Risks to subjects, no matter how many laboratory and animal tests have preceded them. These studies thus provide a clear example of what the central ethical concern raised by clinical research: the possibility of exploitation. Put generally, the process of exposing subjects to risks in order to collect data introduces the possibility of exploiting subjects for the benefit of future patients. The present entry focuses on this concern, and canvasses the most prominent attempts to address it. The present entry largely ignores the range of interesting and important ethical issues that arise in the course of conducting clinical research: How should it be reviewed? Who may conduct it? What must potential subjects understand to give valid consent? May it be conducted in countries that will not be able to afford the intervention being tested? Do investigators have any obligations to treat unrelated medical conditions they uncover in the course of their research?

One might attempt to address the potential exploitation of research subjects by locating the evaluation of potential new interventions, and their attendant risks, within the clinical setting, offering experimental interventions to patients who want to try them. This approach, which has the virtue of evaluating new interventions in the process of trying to help individual patients, poses enormous scientific and practical problems. On the practical side, who would be willing to manufacture a new intervention without knowing whether it works? What dose should be used? How often should the new drug be taken? More importantly, this approach might not yield reliable information as to whether the new treatment is useful or harmful until hundreds, perhaps thousands of people have received it. Clinical research is designed to address these concerns by systematically exposing a small number of individuals, including very sick ones, to potential new treatments.Many of our actions, driving a car, smoking a cigarette, flushing our waste down the drain, expose others to risk of harm. Nonetheless, there has been surprisingly little philosophical analysis of the conditions under which it is acceptable to do this (Hayenhjelm and Wolff 2012). Therefore, in addition to being of value in its own right, evaluation of the ethics of clinical research provides an opportunity to consider one of the more fundamental concerns in moral theory: when is it acceptable to expose some individuals to risks of harm for the potential benefit of others?

1. What is Clinical Research?

2. early clinical research, 3. abuses and guidelines, 4. clinical research and clinical care, 5. a libertarian analysis, 6. contract theory, 7. minimal risks, 8. goals and interests, 9. industry sponsored research, bibliography, academic tools, other internet resources, related entries.

Human subjects research is research which involves humans, as opposed to animals, atoms, or asteroids, as the subjects of study. A study to evaluate whether humans prefer 100 dollars or a 1% chance of 10,000 dollars constitutes human subjects research. Clinical research refers to the subset of human subjects research which focuses on improving human health and well-being. To focus on the issues that have featured most prominently in debates over the ethics of clinical research, we shall limit the discussion to research designed to improve human health and well-being by identifying better methods to treat, cure or prevent illness. This focus on treating, curing and preventing illness is intended to bracket the more recent question of whether research on enhancements qualifies as clinical research. Such research has the potential to improve well-being, allowing us to live longer and better, without identifying methods to address illness.

We shall also bracket the question of whether quality improvement and quality assurance projects qualify as clinical research. To briefly consider the type of research at the heart of this debate, consider a hospital which proposes to evaluate the impact of checklists on the quality of patient care. Half the nurses in the hospital are told to continue to provide care as usual; the other half are provided with a checklist and instructed to mechanically check off each item as they complete it when caring for their patients. Comparing the outcomes in the two groups could provide important information for how to treat future patients. The question of whether this activity constitutes clinical research is of theoretical interest for clarifying the precise boundaries of the concept. Should we say that this is not clinical research because the checklist is used by the nurses, not administered to the patients? Or should we say this is clinical research because it involves the systematic testing of a hypothesis which is answered by collecting data on the patients' outcomes? The results of this conceptual analysis are of significant practical implications because they help to determine whether these activities are subject to existing regulations for clinical research, including whether the clinicians need to obtain patients' informed consent to use the checklist.

While clinical medicine is enormously better than it was 100 or even 50 years ago, there remain many diseases against which current clinical medicine offers an inadequate response. To name just a few, malaria kills over a million people, mostly children, every year; chronic diseases, chief among them heart disease and stroke, kill millions each year, and there currently are no effective treatments for Alzheimer disease. The social value of clinical research lies in its ability to collect information that might be useful to identifying improved methods to treat these conditions. Yet, it is the rare clinical research study which definitively establishes that a particular method is effective and safe for treating, curing or preventing some illness. The success of specific research studies more commonly lies in the gathering of information needed to inform future studies.

Prior to establishing the efficacy of an experimental treatment for a given condition, researchers typically need to identify the cause of the condition, possible mechanisms for treating it, a safe and effective dose, and ways of testing whether the drug is having an effect on the disease.

The process of testing potential new treatments can take 10Ð15 years, and is standardly divided into phases. Formalized phase 0 studies are a relatively recent phenomenon involving the testing of interventions and methods which might be used in later phase studies. A phase 0 study might be designed to determine the mechanism of action of a particular drug and evaluate different ways to administer it. Phase 1 studies are the earliest tests of a new intervention and are conducted in small numbers of individuals. Phase 1 studies are designed to evaluate the pharmacokinetics and pharmacodynamics of new treatments, essentially evaluating how the drug influences the human body and how the human body influences the drug. Phase 1 studies also evaluate the risks of the treatment and attempt to identify an appropriate dose to be used in subsequent phase 2 studies. Phase 1 studies pose risks and frequently offer little if any potential for clinical benefit to subjects. As a result, a significant amount of the ethical concern over clinical research focuses on phase 1 studies.

If phase 1 testing is successful potential new treatments go on to larger phase 2 studies which are designed to further assess risks and also to evaluate whether there is any evidence that the treatment might be beneficial. Successful phase 2 studies are followed by phase 3 studies which involve hundreds, sometimes thousands of patients. Phase 3 studies are designed to provide a rigorous test of the efficacy of a treatment and frequently involve randomization of subjects to the new treatment or a control, which might be standard existing treatment or a placebo. Finally, post-marketing or phase 4 studies evaluate the use of interventions in clinical practice.

Clinical trials of experimental treatments typically include purely research procedures, such as blood draws, imaging scans, or biopsies, that are performed to collect data regarding the treatment under study. Analysis of the ethics of clinical research thus requires evaluation of three related risk-benefit profiles: (a) the risk-benefit profile of the potential new interventions(s) under study; (b) the risk-benefit profile of the included research procedures; and (c) the risk-benefit profile of the study as a whole.

Potential new treatments sometimes are in the ex ante interests of research subjects. For example, the risks posed by an experimental cancer treatment might be justified by the possibility that it will extend subjects' lives. Moreover, the risk/benefit profile of the treatment might be as favorable to subjects as the risk/benefit profile of the available alternatives. In these cases, receipt of the experimental intervention ex ante promotes subjects' interests. In other cases, participation in research poses ‘net’ risks, that is, risks of harm which are not, or not entirely, justified by the potential clinical benefits to individual subjects. Experimental interventions sometimes pose net risks. A first in human trial of an experimental treatment might involve a single dose to see whether humans can tolerate it. This intervention poses risks to subjects and offers essentially no chance for clinical benefit. Research procedures included in clinical trials can offer some chance for clinical benefit, finding a previously unidentified and treatable condition, for example. However, the chance for such benefit is typically so remote that it is not sufficient to compensate for the risks of the procedure. Whether a study as a whole poses net risks depends on whether the potential benefits of the experimental intervention compensate for its risks plus the net risks of the research procedures included in the study.

Clinical research which poses net risks raises important ethical concern. Net-risk studies raise concern that subjects are being used as mere means to collect information to benefit future patients. Research procedures that pose net risks may seem to raise less concern when they are embedded within a study which offers a favorable risk-benefit profile overall. Yet, since these procedures pose net risks, and since the investigators could provide subjects with the new potential treatment alone, they require justification. An investigator who is about to insert a needle into a research subject to obtain some blood purely for laboratory purposes faces the question of whether doing so is ethically justified. The goal of ethical analyses of clinical research is to provide an answer. Clinical research poses three types of net risks: absolute, relative, and indirect (Rid and Wendler 2011). Absolute net risks arise when the risks of an intervention or procedure are not justified by its potential clinical benefits. Most commentators focus on this possibility with respect to research procedures which pose some risks and offer no chance of clinical benefit, such as blood draws to obtain cells for laboratory studies. Research with healthy volunteers is another example which frequently offers no chance for clinical benefit. Clinical research also poses absolute net risks when it offers a chance for clinical benefit which is not sufficient to justify the risks subjects face. A kidney biopsy to obtain tissue from presumed healthy volunteers may offer some very low chance of identifying an unrecognized and treatable pathology. This intervention nonetheless poses net risks if the chance for clinical benefit is not sufficient to justify the risks of undergoing the biopsy.

Relative net risks arise when the risks of a research intervention are justified by its potential clinical benefits, but the intervention's risk-benefit profile is less favorable than the risk-benefit profile of one or more available alternatives. Imagine that investigators propose a randomized-controlled trial to compare an inexpensive drug against an expensive and somewhat more effective drug. Such trials make sense when, in the absence of a direct comparison, it is unclear whether the increased effectiveness of the more expensive drug justifies its costs. In this case, receipt of the cheaper drug would be contrary to subjects' interest in comparison to receiving the more expensive drug. The trial thus poses relative net risks to subjects.

Indirect net risks arise when a research intervention has a favorable risk-benefit profile, but the intervention diminishes the risk-benefit profile of other interventions provided as part of or in parallel to the study. For example, an experimental drug for cancer might undermine the effectiveness of other drugs individuals are taking for their condition. Commentators often focus on the chance of physical harm to which subjects are exposed. Administration of an experimental treatment might lead to nausea or kidney damage; undergoing a research lumbar puncture might result in bleeding or a headache. The physical risks of research participation can be compounded if these harms are realized and clinical responses are undertaken which pose additional risks. Kidney damage might lead to short-term dialysis which poses its own set of risks; a postlumbar puncture headache might lead to a ‘blood patch’ which involves the low risk, but not risk free injection of blood into the epidural space. Participation in clinical research can pose other types of risks as well, including psychological, economic, and social risks. Depending on the study and the circumstances, individuals who are injured as the result of participating in research might incur significant expenses. Most guidelines and regulations stipulate that evaluation of the acceptability of clinical research studies should take into account all the different risks to which subjects are exposed.

To assess the ethics of exposing subjects to risks, one needs an account of why exposing others to risks raises ethical concern in the first place. Being exposed to risks obviously raises concern to the extent that the potential harm to which the risk refers is realized: the chance of a headache turns into an actual headache. Being exposed to risks also can lead to negative consequences as a result of the recognition that one is at risk of harm. Individuals who recognize that they face a risk may become frightened; they also may take costly or burdensome measures to protect themselves. In contrast, the literature on the ethics of clinical research implicitly assumes that being exposed to risks is not itself harmful. The mere fact that one is exposed to a risk does not make one worse off. To assess the ethics of exposing subjects to risk, one also needs an understanding of what counts as a harm. Does a brief experience of nausea constitute a harm? The time spent waiting in the clinic to see the research nurse? The scar that remains after a research biopsy?

Increasingly, researchers are storing human biological samples and using them in future research projects. These studies raise difficult questions regarding the possibility of what might be called ‘contribution’ and ‘information’ risks. The former question concerns the conditions under which it is acceptable to ask individuals to contribute to answering the scientific question posed by a given study (Jonas 1969). The frequent neglect of this issue may trace to a narrow understanding of subjects' interests. Individuals undoubtedly have an interest in avoiding the kinds of physical harms they face in clinical research. It seems that individuals' interests also may be implicated, and possibly thwarted, when they contribute to particular projects, activities and goals.

Imagine that an individual provides a blood sample which investigators store and use in future research projects designed to promote goals which the individual strongly opposes. Can such research harm the individual if they never learn about the results and are never personally affected by them? Are the interests of an individual who fundamentally opposes cloning, and constructs her life around efforts to oppose it, set back if she contributes to a research study that identifies improved methods to clone human beings? With respect to information risks, investigators used DNA samples obtained from members of the Havasupai tribe to study “theories of the tribe's geographical origins.” The study's conclusion that early members of the tribe had migrated from Asia across the Bering Strait contradicted the tribe's own views that they originated in the Grand Canyon (Harmon 2010). Can learning the truth about the origins of one's tribal group harm members of the tribe?

Exposing research subjects to risks of harm is considered morally problematic largely because it has the potential to result in their being harmed. In addition, guidelines and regulations on clinical research are replete with admonitions to expose subjects to risks only when doing so is justified by the value of the study in question. This focus reveals an important although typically implicit feature of most analyses of the ethics of clinical research. It is often said that the ethics of clinical research concerns the protection of research subjects. One might conclude that exposing subjects to risks is regarded as problematic only to the extent that it has the potential to harm them. On this view, analysis of the appropriateness of investigators exposing subjects to risks would be limited to the possibility of harming the subjects they enroll. In fact, while the protection of research subjects is important, it does not exhaust the ethics of clinical research. Guidelines and regulations also reflect implicit principles regarding what constitutes appropriate investigator behavior that are independent of the possibility of harming individual subjects. Put generally, the ethics of clinical research is concerned both with the protection of research subjects and the behavior of researchers.

The future oriented aspect of clinical research is worth emphasizing. The fundamental ethical concern raised by clinical research is whether and when it can be acceptable to expose some individuals to risks and burdens for the benefit of others. In general, the answer to this question depends crucially on the others in question, and their relationship to those who are being exposed to the risks. It is one thing to expose a consenting adult to risks to save the health or life of an identified and present other, particularly when the two individuals are first degree relatives. It is another thing, or seems to many to be another thing, to expose consenting individuals to risks to help unknown and unidentified, and possibly future others. Almost no one objects to operating on a healthy, consenting adult to obtain a kidney that might save an ailing sibling, even though the operation poses some risk of serious harm to the donor and offers no potential for clinical benefit. Greater concern is raised by attempts to take a kidney from a healthy, consenting adult and give it to an unidentified individual. Commentators express even greater ethical concern as the path from risk exposure to benefit becomes longer and more tenuous. Many clinical research studies expose subjects to risks in order to collect generalizable information which, if combined with the results of other, as yet non-existent studies, may eventually benefit future patients, assuming the appropriate regulatory authorities approve it, some company or group chooses to manufacture it, and patients can afford to purchase it. The potential benefits of clinical research may thus be realized someday, but the risks and burdens are clear and present.

Attempts to determine when it is acceptable to conduct clinical research have been significantly influenced by its history, by how it has been conducted and, in particular, by how it has been misconducted (Lederer 1995; Beecher 1966). Thus, to understand the current state of the ethics of clinical research, it is useful to know something of its past.

Modern clinical research may have begun on the 20 th of May, 1747, aboard the HMS Salisbury. James Lind, the ship's surgeon, was concerned with the costs scurvy was exacting on British sailors, and was skeptical of some of the interventions, cider, elixir of vitriol, vinegar, sea-water, being used to treat it. A significant advance occurred when Lind did not simply assume he was correct and treat his patients accordingly. Instead, he designed a study to test whether he was right. He chose 12 sailors from among the 30 or 40 Salisbury's crew members who were suffering from scurvy, and divided them into six groups of 2 sailors each. Lind assigned a different intervention to each of the groups, including two sailors turned research subjects who received 2 oranges and 1 lemon each day. Within a week these two were nearly healthy; the others were sicker, and several were dying.

The ethics of clinical research begins by asking how we should think about the fate of these latter sailors. Do they have a moral claim against Lind? Did Lind treat them appropriately? It is widely assumed that physicians should do what they think is best for the patient in front of them. Lind, despite being a physician, did not follow this maxim. He felt strongly that giving sea water to individuals with scurvy was a bad idea, but he gave sea water to 2 of the sailors in his study to test whether he, or others, were right. To put the fundamental concern raised by clinical research in its simplest form: did Lind sacrifice these two sailors, patients under his care, for the benefit of future patients?

Lind's experiments represent perhaps the first modern clinical trial because he attempted to address one of the primary challenges facing those who set out to evaluate medical treatments. How does one show that the comparative results of two or more treatments are a result of the treatments themselves, and not a result of the patients who received them, or other differences in their environment or diet? How could Lind be confident that the improvements in the two “Limeys” were the result of the oranges and lemons, and not a result of the fact that Lind happened to give this particular treatment to the two patients who were going to get better anyway? Lind tried to address this question by beginning with patients who were as similar as possible. He carefully chose the 12 subjects for his experiment from a much larger pool of ailing sailors; he also tried to ensure that all 12 received the same rations each day, apart from the treatments provided as part of his study. It is also worth noting that Lind's dramatic results were largely ignored for decades, leading to uncounted and unnecessary deaths, and highlighting the importance of combining clinical research with clinical implementation. The Royal Navy did not adopt citrus rations until 1795 (Sutton 2003), at which point scurvy essentially disappeared from the Royal Navy.

Lind's experiments, despite controlling for a number of factors, did not exclude the possibility that his own choices of which sailors got which treatment influenced the results. More recent experiments, including the first modern randomized, placebo controlled trial of Streptomycin for TB in 1948 (D'Arcy Hart 1999), attempt to address this concern by assigning treatments to patients using a random selection process. By randomly assigning patients to treatment groups these studies ushered in the modern era of controlled, clinical trials. And, by taking the choice of which treatment a given patient receives out of the hands of the treating clinician, these trials underscore and, some argue, exacerbate the ethical concerns raised by clinical research (Hellman and Hellman 1991). A foundational principle of clinical medicine is the importance of individual judgment. A physician who decides which treatments her patients receive by flipping a coin is guilty of malpractice. A clinical investigator who uses the same methods is conducting state of the art clinical research. One might conclude that the sacrifice of the interests of some, often sick patients, for the benefit of future patients, hence, the potential for ethical abuse, is essentially mandated by the norms governing the scientific method (Miller & Weijer 2006; Rothman 2000). Unfortunately, the potential for abuse inherent in clinical research has been all too frequently realized.

The Nazis and the Japanese conducted horrific experiments on their prisoners during World War II. US public health clinicians were responsible for the abuses perpetrated during the infamous Tuskegee syphilis experiments. And one account maintains that the history of pediatric research is “largely one of child abuse” (Lederer and Grodin 1994, 19; also see Lederer 2003). This history of abuses has had a significant influence on how commentators understand the ethical concerns raised by clinical research and on how commentators attempt to address them. One prominent feature of this history has been to respond to scandals by developing guidelines intended to prevent their recurrence.

Perhaps the most infamous abuses, those perpetrated by Nazi physicians during WW II, led to the Nuremberg Code (Grodin & Annas 1996; Shuster 1997). The Nuremberg Code (1947) is often regarded as the first set of formal guidelines for clinical research, an ironic claim on two counts. First, there is some debate over whether the Nuremberg Code was intended to apply generally to clinical research or whether, as a legal ruling in a specific trial, it was intended to address only the cases before the court (Katz 1996). Second, the Nuremberg Code is not the first set of research guidelines; the Germans themselves had developed systematic guidelines in 1931 (Vollmann & Winau 1996). These guidelines were still legally in force at the time of the Nazi atrocities and clearly prohibited a great deal of what the Nazi doctors did.

In addition to being ignored by practicing researchers, wide consensus developed by the end of the 1950s that the Nuremberg Code was inadequate to the ethics of clinical research. Specifically, the Nuremberg Code did not include a requirement that clinical research receive independent ethics review and approval. In addition, the first and longest principle in the Nuremberg Code states that informed consent is “essential” to ethical clinical research (Nuremberg Military Tribunal 1947). This requirement provides a powerful safeguard against the abuse of research subjects. It also appears to preclude clinical research with individuals who cannot consent.

One could simply insist that informed consent of subjects is necessary to ethical clinical research and accept the opportunity costs thus incurred. Representatives of the World Medical Association, who hoped to avoid these costs, began meeting in the early 1960s to develop guidelines, which would become known as the Declaration of Helsinki, to address the perceived shortcomings of the Nuremberg Code (Goodyear, Krleza-Jeric, and Lemmens 2007). They recognized that insisting on informed consent as a necessary condition for clinical research would preclude a good deal of research designed to find better ways to treat dementia and conditions affecting children, as well as research in emergency situations. Regarding consent as necessary precludes such research even when it poses only minimal risks or offers subjects a compensating potential for important clinical benefit. The challenge, still facing us today, is to identify protections for research subjects which are sufficient to protect them without being so strict as to preclude appropriate research designed to benefit the groups to which they belong.

The Declaration of Helsinki (World Medical Organization 1996) allows individuals who cannot consent to be enrolled in clinical research based on the permission of the subject's representative. The U.S. federal regulations governing clinical research take a similar approach. These regulations are not laws in the strict sense of being passed by Congress and applying to all research conducted on U.S. soil. Instead, the regulations represent administrative laws which effectively attach to clinical research at the beginning and the end. Research conducted using U.S. federal monies, for instance, research funded by the NIH, or research involving NIH researchers, must follow the U.S. regulations (Department of Health and Human Services 2005). Research that applies for approval from the U.S. FDA also must have been conducted according to FDA regulations which, except for a few exceptions, are essentially the same. Although many countries now have their own national regulations (Brody 1998), the U.S. regulations continue to exert enormous influence around the world because so much clinical research is conducted using U.S. federal money and U.S. federal investigators, and the developers of medical treatments often want to obtain approval for the U.S. market.

The abuses perpetrated as part of the infamous Tuskegee syphilis study were made public in 1972, 40 years after the study was initiated. The resulting outcry led to the formation of the U.S. National Commission, which was charged with evaluating the ethics of clinical research with humans and developing recommendations regarding appropriate safeguards. These deliberations resulted in a series of recommendations for the conduct of clinical research, which became the framework for existing U.S. regulations. The U.S. regulations, like many regulations, place no clear limits on the risks to which competent and consenting adults may be exposed. In contrast, strict limits are placed on the level of research risks to which those unable to consent may be exposed, particularly children. In the case of pediatric research, the standard process for review and approval is limited to studies that offer a ‘prospect of direct’ benefit and research that poses minimal risk or a minor increase over minimal risk. Studies that do not qualify in one of these categories must be reviewed by an expert panel and approved by a high government official. While this process provides important flexibility, this 4th category for pediatric research, at least in principle, does not establish a ceiling on the risks to which pediatric research subjects may be exposed for the benefit of others. This reinforces the importance of considering how we might justify exposing subjects to research risks, both minimal and greater than minimal, for the benefit of others.

Several attempts have been made to justify exposing research subjects to risks for the benefit of future patients. Lind's experiments on scurvy exemplify the fact that clinical research is often conducted by clinicians and often is conducted on patients. Many commentators have thus assumed that the ethics of clinical research should be governed by the ethics of clinical care, and the methods of research should not diverge from the methods regarded as acceptable in clinical care. On this approach, subjects should not be denied any beneficial treatments available in the clinical setting and they should not be exposed to any risks not present in the clinical setting.

Some proponents (Rothman 2000) argue that this approach is implied by the kind of treatment that patients, understood as individuals who have a condition or illness needing treatment, are owed. Such individuals are owed treatment that promotes, or at least is consistent with their medical interests. Others (Miller & Weijer 2006) argue that the norms of clinical research derive largely from the obligations that bear on clinicians. These commentators argue that it is unacceptable for a physician to participate in, or even support the participation of her patients in a clinical trial unless that trial is consistent with the patients' medical interests. To do less is to provide substandard medical treatment and to violate one's obligations as a clinician.

The claim that the treatment of research subjects should be consistent with the norms which govern clinical care has been applied most prominently to the ethics of randomized clinical trials (Hellman & Hellman 1991). Randomized trials determine which treatment a given research subject receives based on a random process, not based on clinical judgment of which treatment would be best for that patient. Lind assigned the different existing treatments for scurvy to the sailors in his study based not on what he thought was best for them, but rather based on what he thought would yield an effective comparative test. Lind did not give each intervention to the same number of sailors because he thought that all the interventions had an equal chance of being effective. To the contrary, he did this because he was confident that several of the interventions were harmful and this design was the best way to prove it. Contemporary clinical researchers go even further, assigning subjects to treatments based on the dictates of a random computer program. Because this aspect of clinical research represents a clear departure from the practice of clinical medicine it appears to sacrifice the interests of subjects in order to collect valid data.

Many commentators (Freedman 1987) argue that randomization is acceptable when the study in question satisfies what has come to be known as ‘clinical equipoise.’ Clinical equipoise obtains when, for the population of patients from which subjects will be selected, the available clinical evidence does not favor one of the treatments being used over the others. In addition, it must be the case that there are no treatments available outside the trial that are better than those used in the trial. Satisfaction of these conditions seems to imply that the interests of research subjects will not be undermined in the service of collecting scientific information. If the available data do not favor any of the treatments being used, randomizing subjects seems as good a process as any other for choosing which treatment they receive.

Proponents determine whether equipoise obtains not by appeal to the belief states of individual clinicians, but based on whether there is consensus among the community of experts regarding which treatment is best. Lind believed that sea water was ineffective for the treatment of scurvy. Yet, in the absence of agreement among the community of experts, this view essentially constituted an individual preference rather than a clinical guideline. This suggests that it was acceptable for Lind to randomly assign sailors under his care to the prevailing treatments in order to test, in essence, whose preferred treatment was the best. In this way, the existence of uncertainty within the community of experts seems to offer a way to reconcile the methods of clinical research with the norms of clinical medicine.

Critics respond that even when clinical equipoise obtains for the population of patients, the specific circumstances of individual patients within that population may imply that one of the treatments under investigation is better for them (Gifford 2007). A specific patient may have reduced liver function which places her at greater risk of harm if she receives a treatment metabolized by the liver. And some patients may have personal preferences which incline them toward one treatment rather than another (e.g., they may prefer a one-time riskier procedure to multiple, lower risk procedures which pose the same collective risk). Current debate focuses on whether randomized clinical trials can take these possibilities into account in a way that is consistent with the norms of clinical medicine.

Even if clinical equipoise can be used to justify at least some randomized clinical trials, a significant problem remains. Clinical equipoise cannot be used to justify all of the important types of clinical research that are regularly undertaken. The primary challenge for the claim that clinical research must be consistent with the norms of clinical medicine is that certain studies and procedures which are crucial to the identification and development of improved methods for protecting and advancing health and well-being are clearly inconsistent with individual subjects' medical interests. This concern arises for many phase 1 studies which offer essentially no chance for medical benefit and pose at least some risks, and to that extent are inconsistent with the subjects' medical interests.

Phase 3 studies which randomize subjects to a potential new treatment or existing standard treatment, and satisfy clinical equipoise, typically include non-beneficial procedures, such as additional blood draws, to evaluate the drugs being tested. These studies may be in subjects' medical interests in the sense that the overall risk-benefit ratio that the study offers is at least as favorable as the available alternatives. However, this type of study-level evaluation masks the fact that the study includes individual procedures which are contrary to subjects' medical interests, and contrary to the norms of clinical medicine.

The attempt to protect research subjects by appeal to the obligations clinicians have to promote the medical interests of their patients also seems to leave healthy volunteers unprotected. Alternatively, proponents might characterize this position in terms of clinicians' obligations to others in general: clinicians should not perform procedures on others unless doing so promotes the individual's clinical interests. This approach seems to preclude essentially all research with healthy volunteers. For example, many phase 1 studies are conducted in healthy volunteers to determine a safe dose of the drug under study. These studies, vital to drug development, are inconsistent with the principle that clinicians should expose individuals to risks only when doing so is consistent with their clinical interests. It follows that appeal to clinical equipoise alone cannot render clinical research consistent with the norms of clinical practice.

Commentators sometimes attempt to justify net-risk procedures that are included within studies, and studies that overall pose net risks by distinguishing between ‘therapeutic’ and ‘non-therapeutic’ research. The claim is that the demand of consistency with subjects' medical interests applies only to therapeutic research; non-therapeutic research studies and procedures may diverge from these norms to a certain extent, provided subjects' medical interests are not significantly compromised. The distinction between therapeutic and non-therapeutic research is sometimes based on the design of the studies in question, or based on the intentions of the investigators. Studies designed to benefit subjects, or investigators who intend to benefit subjects are conducting therapeutic studies. Those designed to collect generalizable knowledge or in which the investigators intend to do so constitute non-therapeutic research.

The problem with the distinction between therapeutic and non-therapeutic research so defined is that research itself often is defined as a practice designed to collect generalizable knowledge and conducted by investigators who intend to achieve this end (Levine 1988). On this definition, all research qualifies as non-therapeutic. Conversely, most investigators intend to benefit their subjects in some way. Perhaps they design the study in a way that provides subjects with clinically useful findings, or they provide minor care not required for research purposes, or referrals to colleagues. Even if one can make good on the distinction between therapeutic and non-therapeutic research in theory, these practices appear to render it irrelevant to the practice of clinical research. More importantly, it is not clear why investigators' responsibilities to patients, or patients' claims on investigators, should vary as a function of this distinction. Why might one think that investigators are allowed to expose patients to some risks for the benefit of others, but only in the context of research that is not designed to benefit the subjects? To take the example of pediatric research, how might one defend the view that it is acceptable to expose infants to risks for the benefit of others, but only in the context of studies which offer the infants no chance for personal benefit?

To take one possibility, it is not clear that this view can be defended by appeal to physicians' role responsibilities. A prima facie plausible view holds that physicians' role responsibilities apply to all encounters between physicians and patients who need medical treatment. This view would imply that physicians may not compromise patients' medical interests when conducting therapeutic studies, but also seems to prohibit non-therapeutic research procedures with patients. Alternatively, one might argue that physicians' role responsibilities apply only in the context of clinical care and so do not apply in the context of clinical research at all. This articulation yields a more plausible view, but does not support the use of the therapeutic/ non-therapeutic distinction. It provides no reason to think that physicians' obligations differ based on the type of research in question.

Recent critics argue that these problems highlight the fundamental confusion that results when one attempts to evaluate clinical research based on norms appropriate for clinical medicine. They instead distinguish between the ethics of clinical research and the ethics of clinical care, arguing that it is inappropriate to assume that investigators are subject to the claims and obligations which apply to physicians, despite the fact that the individuals who conduct clinical research often are physicians (Miller and Brody 2007).

The claim that clinical research should satisfy the norms of clinical medicine does have this strong virtue: it provides a clear method to protect individual research subjects and reassure the public that they are being so protected. If research subjects must be treated consistent with their medical interests, we can be reasonably confident that improvements in clinical medicine will not be won at the expense of exploiting them. Most accounts of the ethics of clinical research now recognize the limitations of this approach and struggle to find ways to ensure that research subjects are not exposed to excessive risks without assuming that the claims of clinical medicine apply to clinical researchers (Emanuel, Wendler, and Grady 2000; CIOMS 2002). Dismissal of the distinction between therapeutic and non-therapeutic research thus yields an increase in both conceptual clarity and concern regarding the potential for exploitation.

Clinicians, first trained as physicians taught to act in the best interests of the patient in front of them, often struggle with the process of exposing some patients to risky procedures for the benefit of others. It is one thing for philosophers to insist, no matter how accurately, that research subjects are not patients and need not be treated according to the norms of clinical medicine. It is another thing for clinical researchers to regard research subjects who are suffering from disease and illness as anything other than patients. These clinical instincts, while understandable and laudable, have the potential to obscure the true nature of clinical research, as investigators and subjects alike try to convince themselves that clinical research involves nothing more than the provision of clinical care. One way to try to address this collective and often willful confusion would be to identify a justification for exposing research subjects to net risks for the benefit of others.

It is often said that those working in bioethics are obsessed with the principle of respect for individual autonomy. Advocates of this view cite the high esteem accorded to the requirement of obtaining individual informed consent and the frequent attempts to resolve bioethical challenges by citing its satisfaction. One might assume that this approach is based on a libertarian analysis according to which it is permissible for competent and informed individuals to do whatever they prefer, provided those with whom they interact are competent, informed and in agreement. In the words of Mill, investigators should be permitted to conduct research and expose subjects to risks provided they obtain subjects' “free, voluntary, and undeceived consent and participation” (On Liberty, page 11). While this characterization of bioethics is widely endorsed, it does not apply to the vast majority of work done on the ethics of clinical research. In particular, almost no one in the field argues that it is permissible for investigators to conduct any research they want provided they obtain the free and informed consent of the subjects they enroll.

Current research ethics does place significant weight on informed consent and many regulations and guidelines devote much of their length to articulating the requirement for informed consent. Yet, as exemplified by the response to the Nuremberg Code, almost no one regards informed consent as necessary and sufficient for ethical research. Most regulations and guidelines, beginning with the first Declaration of Helsinki (World Medical Organization 1996), allow investigators to conduct research on human subjects only when it has been approved by an independent group charged with ensuring that the study is ethically acceptable. Most regulations further place limitations on the types of research that independent ethics committees may approve. They must find that the research has important social value and the risks have been minimized before approving it, thereby restricting the types of research to which even competent adults may consent. Are these requirements justified, or are they inappropriate infringements on the free actions of competent individuals? The importance of answering this question goes beyond its relevance to debates over Libertarianism. Presumably, the requirements placed on clinical research have the effect of reducing to some extent the number of research studies that get conducted. The fact that at least some of the prohibited studies likely would have important social value, helping to identify better ways to promote health and well-being, provides a normative reason to eliminate the restrictions, unless there is some compelling reason to retain them.

One might regard the limitations as betraying the paternalism embedded in most approaches to the ethics of clinical research. Although the charge of paternalism often carries with it some degree of condemnation, there is a strong history of what is regarded as appropriate paternalism in the context of clinical research. This too may have evolved from clinical medicine. Clinicians are charged with protecting and promoting the interests of the patient “in front of them”. Clinician researchers, who frequently begin their careers as clinicians, may regard themselves as similarly charged. However, if we accept the thesis that clinical research is normatively distinct from clinical care, we need some reason to think that these norms for clincal care are relevant to clinical research. The fact that these restrictions on the options available to competent adults in the context of clinical research trace to its close relationship with clinical care does not constitute a justification for applying the restrictions in this normatively distinct context. As noted, this is especially important given that the restrictions at least sometimes block otherwise socially valuable research.

The libertarian claim that valid informed consent is necessary and sufficient to justify exposing research subjects to risks for the benefit of others seems to imply, consistent with the first principle of the Nuremberg Code, that research with individuals who cannot consent is unethical. This plausible and tempting claim commits one to the view that research with children, research in many emergency situations, and research with the demented elderly all are ethically impermissible. One could consistently maintain such a view but the social costs of adopting it would be great. It is estimated, for example, that approximately 70% of medications provided to children have not been tested in children, even for basic safety and efficacy (Roberts, Rodriquez, Murphy, Crescenzi 2003; Field & Behrman 2004; Caldwell, Murphy, Butow, and Craig 2004). Absent clinical research with children, pediatricians will be forced to continue to provide sometimes inappropriate treatment, leading to significant harms that could have been avoided by pursuing clinical research to identify better approaches.

One response would be to argue that the Libertarian analysis is not intended as an analysis of the conditions under which clinical research is acceptable. Instead, the claim might be that it provides an analysis of the conditions under which it is acceptable to conduct clinical research with competent adults. Informed consent is necessary and sufficient for enrolling competent adults in research. While this view does not imply that research with subjects who cannot consent is impermissible, it faces the not insignificant challenge of providing an account for why such research might be acceptable.

Bracketing the question of individuals who cannot consent, many of the limitations on clinical research apply to research with competent adults. How might these limitations be justified? One response has been essentially to grant the Libertarian analysis on theoretical grounds, but then argue that the conditions for its implementation are rarely realized in practice. In particular, there are good reasons, and significant empirical data, to question how often clinical research actually involves subjects who are sufficiently informed to provide valid consent. Even otherwise competent adults often fail to understand clinical research sufficiently to make their own informed decisions regarding whether to enroll (Flory and Emanuel 2004).

To consider an example which is much discussed in the research ethics literature, it is commonly assumed that valid consent for randomized clinical trials requires individuals to understand randomization. It requires individuals to understand that the treatment they will receive, if they enroll in the study, will be determined by a process which does not take into account which of the treatments is better for them (Kupst 2003). There is an impressive wealth of data which suggests that many, perhaps most individuals who participate in clinical research do not understand this (Snowden 1997; Featherstone and Donovan 2002; Appelbaum 2004). The data also suggest that these failures of understanding often are resistant to educational interventions. It appears that many competent adults cannot understand randomization within the time limits feasible for clinical research.

The problem appears to trace, at least in part, to the fact that it is difficult to truly understand randomization and the impact it will have on the interventions one receives, unless one understands the scientific rationale for using randomization. To see this, imagine going into your doctor's office and being informed by the nurse that the doctor will decide which treatment you will receive based on the flip of a coin. If the coin comes up heads you will receive treatment A; if it comes up tails you will receive treatment B. In one sense, this fact is relatively easy to understand. Most competent adults have little trouble understanding the process of making decisions based on the flip of a coin, as evidenced by its common usage to make decisions at the beginning of sporting events, such as which team will get the ball first in soccer matches. But, in the context of receiving medical treatment it seems initially bizarre that decisions will be made based on the flip of a coin given that there is an alternative and ostensibly better approach: assign treatments based on clinical judgment regarding which one is better for the individual in question.

Given this possibility, you might have significant difficulty understanding the claim that your doctor will treat you based on the flip of a coin because you do not understand why your doctor might do this. This suggests that, in order to help research subjects understand randomization, it may be necessary to explain the scientific rationale for its use. This, in contrast, is not an easy thing to explain. And, of course, it is only one of many items that potential subjects need to understand to provide valid informed consent for randomized clinical trials. It seems to follow that the libertarian approach, indeed any approach which claims that sufficient understanding is necessary for valid consent, and valid consent is necessary for ethical clinical research, seems to imply that randomized trials, which provide what are regarded as the gold standard of evidence regarding the efficacy of clinical interventions, may be impermissible.

Some commentators argue that the restrictions placed on clinical research studies, such as the requirements for independent review and minimizing risks, are justified on the grounds of soft paternalism. Paternalism involves interfering with the liberty of agents for their own benefit (Feinberg 1986; see also entry on paternalism ). As the terms are used in the present debate, ‘soft’ paternalism involves interfering with the liberty of an individual in order to promote their interests on the grounds that the action being interfered with is the result of impaired decision-making: “A freedom-restricting intervention is based on soft paternalism only when the target's decision-making is substantially impaired, when the agent lacks (or we have reason to suspect that he lacks) the information or capacity to protect his own interests—as when A prevents B from drinking the liquid in a glass because A knows it contains poison but B does not” (Miller & Wertheimer 2007). ‘Hard’ paternalism, in contrast, involves interfering with the liberty of an individual in order to promote their interests, despite the fact that the action being interfered with is the result of an informed and voluntary choice by a competent individual.

If the myriad restrictions on clinical research were justified on the basis of hard paternalism they would represent restrictions on individuals' autonomous actions. However, the data on the extent to which otherwise competent adults fail to understand what they need to understand to provide valid consent suggests that the limitations can instead be justified on the grounds of soft paternalism understood as interfering with the liberty of an individual in order to promote their interests on the grounds that the action being interfered with is the result of impaired decision-making . This suggests that while the restrictions may limit the liberty of adult research subjects, the restrictions do not limit their autonomy. In this way, one may regard many of the regulations on clinical research not as inconsistent with the libertarian ideal, but instead as starting from that ideal and recognizing that otherwise competent adults often fail to attain it.

The soft paternalism justification for research regulations is based on the empirical fact that many otherwise competent adults appear not to understand what they need to understand to give valid informed consent. Granting these data, it does not seem unreasonable to assume that investigators will someday identify improved processes for obtaining informed consent which enable adults to understand what they need to understand. Data suggest that targeted interventions can be very effective at helping research subjects understand. Further research in this area may well identify methods which enable many, perhaps most adults to provide valid consent. Importantly, it does not follow that, in this case, there should be no limitations on permissible research with competent adults (apart from ensuring that they provide valid consent). This conclusion follows from the general fact, one that libertarian approaches explicitly or not so explicitly ignore, that the conditions on what one individual may do to another are not exhausted by what the second individual consents to. Perhaps some individuals may choose for themselves to be treated with a lack of respect, even tortured. It does not follow that it is acceptable for me or you to treat them accordingly. As independent moral agents we need sufficient reason to believe that our actions, especially the ways in which we treat others, are appropriate, and this evaluation concerns, in typical cases, more than just the fact that the affected individuals consented to them.

Understood in this way, many of the limitations on the kinds of research to which competent adults may consent are not justified, or at least not solely justified, on paternalistic grounds. Instead, these limitations point to a crucial and often overlooked concern in research ethics. The regulations for clinical research often are characterized as protecting the subjects of research from harm. Although this undoubtedly is an important and perhaps primary function of the regulations, they also have an important role in limiting the extent to which investigators harm research subjects, and limiting the extent to which society supports and benefits from a process which exploits others. It is not just that research subjects should not be exposed to risk of harm without compelling reason. Investigators should not expose them to such risks without compelling reason, and society should not support and benefit from such a project either.

This aspect of the ethics of clinical research has strong connections with the view that the obligations of clinicians restrict what sort of clinical research they may conduct. On that view, it is the fact that one is a physician and is obligated to promote the best interests of those with whom one interacts professionally which determines what one is allowed to do to subjects. This connection highlights the pressing questions that arise once we attempt to move beyond the view that clinical research is subject to the norms of clinical medicine. There is a certain plausibility to the claim that a researcher is not acting as a clinician and so may not be subject to the obligations that bear on clinicians. Or perhaps we might say that the researcher/subject dyad is distinct from the physician/patient dyad and is not necessarily subject to the same norms. But, once one decides that we need an account of the ethics of clinical research, as distinct from the ethics of clinical care, one is left with the question of which limitations apply to what researchers may do to research subjects.

It seems clear that researchers may not expose research subjects to risks without sufficient justification, and also clear that this claim applies even to those who provide free and informed consent. The current challenge then is to develop an analysis of the conditions under which it is acceptable for investigators to expose subjects to risks and determine to what extent current regulations need to be modified to reflect this analysis. To consider briefly the extent of this challenge, and to underscore and clarify the claim that the ethics of clinical research go beyond the protection of research subjects to include the independent consideration of what constitutes appropriate behavior on the part of investigators, consider an example.

Physical and emotional abuse cause enormous suffering, and a good deal of research is designed to study various methods to reduce instances of abuse and also to help victims recover after being abused. Imagine that a team of investigators establishes a laboratory to promote the latter line of research. The investigators will enroll consenting adults and, to mimic the experience of extended periods of abuse in real life, they will abuse their subjects emotionally and physically for a week. The abused subjects will then be used in studies to evaluate the efficacy of different methods for helping victims to cope with the effects of abuse.

The proper response to this proposal is to point out that the fact the subjects are competent and give informed consent does not establish that it is ethically acceptable. One needs to consider many other things. Is the experiment sufficiently similar to real life abuse that its results will have external validity? Are there less risky ways to obtain the same results? Finally, even if all these questions are answered in a way which supports the research, the question remains as to whether investigators may treat their subjects in this way. The fact that essentially everyone working in research ethics would hold that this study is unethical—investigators are not permitted to treat subjects in this way—suggests that research ethics, both in terms of how it is practiced and how it should be practiced, goes well beyond respect for individual autonomy to include independent standards on investigator behavior. Defining those standards represents one of the more important challenges for research ethics.

As exemplified by Lind's experiments on treatments for scurvy, clinical research studies were first conducted by clinicians wondering whether the methods they were using were effective. To answer this question, the clinicians altered the ways in which they treated their patients in order to yield information that would allow them to assess their methods. In this way, clinical research studies intially were part of, but an exception to standard clinical practice. As a result, clinical research came to be seen as an essentially unique activity. And widespread recogition of clinical research's scandals and abuses led to the view that this activity needed its own extensive regulations.

More recently, some commentators have come to question the view that clinical research is a unique human activity, as well as the regulations and guidelines which result from this view. In particular, it has been argued that this view has led to overly restrictive requirements on clinical research, requirements that hinder scientists' ability to improve medical care for future patients, and also fail to respect the liberty of potential research subjects. This view is often described in terms of the claim that many regulations and guidelines for clinical research are based on an unjustified ‘research exceptionalism’ (Wertheimer 2010).

The central ethical concern raised by clinical research involves the practice of exposing subjects to risks for the benefit of others. Yet, our everday activities frequently expose some to risks for the benefit of others. When you drive to the store, you expose your neighbors to some increased risk of pollution for the benefits you derive from shopping; speeding ambulances expose pedestrians to risks for the benefit of the patients they carry; factories expose their workers to risks for the benefit of their customers; charities expose volunteers to risks for the benefit of recipients. Despite this similarity, non-beneficial clinical research is widely regarded as ethically problematic and is subject to significantly greater regulation, review, and oversight (Wilson and Hunter 2010). Almost no one regards driving, ambulances, charities, or factories as inherently problematic. Even those who are not great supporters of a given charity do not argue that it treats its volunteers as guinea pigs. And no one argues that charitable activities should satisfy the requirements that are routinely applied to clinical research, such as the requirements for independent review and written consent based on an exhaustive description of the risks and potential benefits of the activity, its purpose, duration, scope, and procedures.

Given that many activities expose some to risks for the benefit of others, yet are not subject to such extensive regulation, some commentators conclude that many of the requirements for clinical research are unjustified (Sachs 2010, Stewart et al. 2008, and Sullivan 2008). This work is based on the assumption that, when it comes to regulation and ethical analysis, we should treat clinical research the way we treat other activities in daily life which involve exposing some to risks for the benefit of others. And this assumption leads to a straightforward solution to our central ethical problem of justifying the practice of exposing research subjects to risks for the benefit of others.

Exposing factory workers to risks for the benefit of others is deemed acceptable when they agree to do the work and are paid a fair wage. The solution then to the ethical concern of non-beneficial research similarly is to continue to obtain consent and pay research subjects a sufficient wage for their efforts. This view is much less restrictive than current regulations for clinical research, but seems to be less permissive than a Libertarian analysis. The latter difference is evident in claims that research studies should treat subjects fairly and not exploit them, even if individuals consent to being so treated.

The gap between this approach and the traditional view of research ethics is evident in the fact that advocates of the traditional view tend to regard payment of research subjects as exacerbating rather than resolving its ethical concerns, raising, among others, worries of undue inducement and commodification. Those who are concerned about research exceptionalism, in contrast, tend to regard payment as it is regarded in most other contexts in daily life: some is good and more is better.

The claims of research exceptionalism have led to valuable discussion of the extent to which clinical research differs from other activities which pose risks to participants for the benefit of others and whether any of the differences justify the extensive regulations and guidelines standardly applied to clinical research. Proponents of research exceptionalism who regard many of the existing regulations as unjustified face the challenge of articulating an appropriate set of regulations for clinical research. While comparisons to factory work provide a useful lens for thinking about the ethics of clinical research, it is not immediately obvious what positive recommendations follow from this perspective. After all, it is not as if there is general consensus regarding the regulations to which industry should be subject. Some endorse minimum wage laws; others oppose them. There are further arguments over whether workers should be able to unionize; whether governments should set safety standards for industry; whether there should be rules protecting workers against discrimination.

A few commentators (Caplan 1984; Harris 2005; Heyd 1996) have considered the possibility of justifying the exposure of subjects to risks for the benefit of others on the grounds that there is an obligation to participate in clinical research. One might try to ground this obligation in the fact that current individuals have benefited from clinical research conducted on individuals in the past. At least all individuals who have access to medical care have benefited from the efforts of previous research subjects in the form of effective vaccines and better medical treatment.

Current participation in clinical research typically benefits future patients. However, if we incur an obligation for the benefits we have received from previous research studies, we presumably are obligated to the patients who participated in those studies, an obligation we cannot discharge by participating in current studies. This approach also does not provide a way to justify the very first clinical trials, such as Lind's, which of necessity enrolled subjects who had never benefitted from previous clinical research.

Alternatively, one might argue that the obligation to participate does not trace to benefits the individuals in fact received from the efforts of previous research participants. Rather, the obligation is to the overall social system of which clinical research is a part (Brock 1994). For example, one might argue that individuals acquire this obligation as the result of being raised in the context of a cooperative scheme or society. We are obligated to do our part because of the many benefits we have enjoyed as a result of being born within such a scheme.

The first challenge for this view is to explain why the mere enjoyment of benefits, without some prospective agreement to respond in kind, obligates individuals to help others. Presumably, your doing a nice thing for me yesterday, without my knowledge or invitation, does not obligate me to do you a good turn today. This concern seems even greater with respect to pediatric research. Children certainly benefit from previous research studies, but typically do so unknowingly and often with vigorous opposition. The example of pediatric research makes the further point that justification of non-beneficial research on straightforward contractualist grounds will be difficult at best. Contract theories have difficulties with those groups, such as children, who do not accept in any meaningful way the benefits of the social system under which they live (Gauthier 1990).

In a Rawlsian vein, one might try to establish an obligation to participate in non-beneficial research based on the choices individuals would make regarding the structure of society from a position of ignorance regarding their own place within that society, from behind a veil of ignorance (Rawls 1999). To make this argument, one would have to modify the Rawlsian argument in several respects. The knowledge that one is currently living could well bias one's decision against the conduct of clinical research. Those who know they are alive at the time the decision is being made have already reaped many of the benefits they will receive from the conduct of clinical research.

To avoid these biases, we might stretch the veil of ignorance to obscure the generation to which one belongs—past, present or future (Brock 1994). Under a veil of ignorance so stretched, individuals might choose to participate in clinical research, including non-beneficial research as long as the benefits of the practice exceed its overall burdens. One could then argue that justice as fairness gives all individuals an obligation to participate in clinical research when their turn comes. This approach seems to have the advantage of explaining why we can expose even children to some risks for the benefit of others, and why parents can give permission for their children to participate in such research. This argument also seems to imply not simply that clinical research is acceptable, but that individuals have an obligation to participate in it. It implies that adults are obligated to participate in clinical research, although for practical reasons we might refrain from forcing them to do so.

This justification for clinical research faces several challenges. First, Rawlsian arguments typically are used to determine the basic structure of society, that is, to determine a fair arrangement of the basic institutions in the society (Rawls 1999). If the structure of society meets these basic conditions, members of the society cannot argue that the resulting distribution of benefits and burdens is unfair. Yet, even when the structure of society meets the conditions for fairness, it does not follow that individuals are obligated to participate in the society so structured. Competent adults can decide to leave a society that meets these conditions (whether they have any better places to go is another question). The right of exit suggests that the fairness of the system does not generate an obligation to participate, but rather defends the system against those who would argue that it is unfair to some of the participants over others. At most, then, the present argument can show that it is not unfair to enroll a given individual in a research study, that this is a reasonable thing for all individuals, including those who are unable to consent.

Second, it is important to ask on what grounds individuals behind the veil of ignorance make their decisions. In particular: are these decisions constrained or guided by moral considerations? (Dworkin 1989; Stark 2000). An obvious response is to think that the decisions would be constrained in this way. After all, we are asking what is the ethical approach or policy with regard to clinical research. The problem, then, is that the answer we get in this case may depend significantly on which ethical constraints are built into the system, rendering the approach question begging. If we include the oft-endorsed constraint that it is unethical, even for a good cause, to expose to risks those who cannot consent, the policy chosen from behind the veil of ignorance would be one that prohibits at least non-beneficial pediatric research, as well as non-beneficial research with incompetent adults.

Proponents might avoid this dilemma by assuming that individuals behind the veil of ignorance will make decisions based purely on self-interest, unconstrained by moral limits or considerations. Presumably, many different systems would satisfy this requirement. In particular, the system that produces the greatest amount of benefits overall may well be one that we regard as unethical. Many endorse the view that clinical research studies which offer no potential benefit to subjects and pose a high chance of serious risk, such as death, are unethical, independent of the magnitude of the social value to be gained. For example, most would regard as unethical a study which intentionally infects a few subjects with the HIV virus, even if the study offers the potential to identify a cure for AIDS. Yet, individuals behind the veil of ignorance who make decisions based solely on self-interest might well allow this study on the grounds that it offers a positive cost-benefit ratio overall: the high risks to a few subjects are clearly outweighed by the potential to save the lives of millions.

Many endorse the view that clinical research studies which offer no potential benefit to subjects and pose a high chance of serious risk, such as death, are unethical, independent of the magnitude of the social value to be gained. For example, most would regard as unethical a study which intentionally infects a few subjects with the HIV virus, even if the study offers the potential to identify a cure for AIDS. Yet, individuals behind the veil of ignorance who make decisions based solely on self-interest might well allow this study on the grounds that it offers a positive cost-benefit ratio overall: the high risks to a few subjects are clearly outweighed by the potential to save the lives of millions. The question here is not whether a reasonable person would choose to make the poor even worse off in order to elevate the status of those more privileged. Rather, both options involve some individuals being in unfortunate circumstances, namely, infected with the HIV virus. The difference is that the one option (not conducting the study) involves many more individuals becoming infected over time, whereas the other option involves significantly fewer individuals being infected, but some as the result of being injected with HIV in the process of identifying an effective vaccine. Since the least desirable circumstances (being infected with HIV) are the same in both cases, the reasonable choice, even if one endorses the maximin strategy, seems to be whichever option reduces the total number of individuals who are in those circumstances, revealing that, in the present case at least, the Rawlsian approach seems not to take into account the way in which individuals end up in the positions they occupy.

The difficulties in justifying non-beneficial research simply by appeal to subjects' informed consent suggest that a more promising approach may be to restrict the risks to which research subjects may be exposed. Indeed, limits on risks are a central part of almost all current research regulations and guidelines. For those who can consent, there is an essentially implicit agreement that the risks should not be too high in the context of non-beneficial research (as noted some argue that there should not be any net risks to even competent adults in the context of so-called therapeutic research). However, there is no agreement regarding how to determine which risks are acceptable in this context.

With respect to those who cannot consent, many commentators argue that non-beneficial research is acceptable provided that the net risks are very low. The challenge, currently faced by many in clinical research, is to identify a standard, and find a reliable way to implement it, for what constitutes a sufficiently low risk in this context. An interesting and important question in this regard is whether the level of acceptable risks varies depending on the particular class of individuals who cannot consent. Is the level of acceptable risks the same for individuals who were once competent, such as previously competent adults with Alzheimer disease, individuals who are not now but are expected to become competent, such as healthy children, and individuals who are not now and likely never will be competent, such as individuals born with severe cognitive disabilities?

Some argue that the risks of clinical research qualify as sufficiently low when they are ‘negligible’, understood as risks that do not pose any chance of serious harm (Nicholson 1986). Researchers who ask children a few questions for research purposes may expose them to risks no more worrisome than that of being mildly upset for a few minutes. It seems not implausible that exploitation requires some risk or realization of serious harm, implying that this study raises no concerns regarding exploitation. Or one might argue that the possible harms posed by this study are so insignificant that the potential for exploitation does not constitute a serious ethical concern. Despite the theoretical plausibility of these views, very few actual studies satisfy the negligible risk standard. Even routine procedures that are widely accepted in pediatric research, such as single blood draws, pose some, typically very low risk of more than negligible harm.

Others (Kopelman 2000; Resnik 2005) define risks as sufficiently low or ‘minimal’ when they do not exceed the risks individuals face during the performance of routine examinations. This standard provides a clear and quantifiable threshold for acceptable risks. One concern is that the risks of routine medical procedures for healthy individuals are extremely low to the extent that this standard prohibits a good deal of clinical research, including studies that seem intuitively acceptable. This approach faces the additional problem that, as the techniques of clinical medicine become safer and less invasive, increasing numbers of procedures used in non-beneficial research would be deemed excessively risky. And, at a theoretical level, one might wonder why we should think that the risks we currently happen to accept in the context of clinical care should define the level of risks that is acceptable in clinical research.

Many guidelines (U.S. Department of Health and Human Services 2005; Australian National Health and Medical Research Council 1999) and commentators take the view that non-beneficial research is ethically acceptable as long as the risks do not exceed the risks individuals face in daily life. The strength of this claim is supposed to derive from the fact that such research does not increase the risks to which the subjects are exposed. However, its intuitive appeal often traces to a common attitude regarding the risks of daily life. Many of those involved in clinical research implicitly assume that the minimal risk standard is essentially equivalent to the negligible risk standard. If the risks of research are no greater than the risks individuals face in daily life, then the research does not pose risk of any serious harm. As an attitude toward many of the risks we face in daily life, this view makes sense. We could not get through our daily lives if we were conscious of all the risks we face. Crossing the street poses more risks than one can catalog, much less process readily. When these risks are sufficiently low, psychologically healthy individuals place them in the background so to speak, ignoring them unless the circumstances provide reason for special concern (e.g. one hears a siren, or sees a large gap in the sidewalk).

Paul Ramsey reports that during the deliberations of the National Commission on pediatric research, members often used the terms minimal and negligible risks in a way which seemed to imply that they were willing to allow minimal risk research, even with children, on the grounds that it poses no chance of serious harm (Ramsey 1978). The members then went on to argue that an additional ethical requirement for such research is a guarantee of compensation for any serious research injuries. This approach to minimal risk pediatric research highlights nicely the somewhat confused attitudes we often have toward risks, especially those of daily life.

We go about our daily lives as though very low risks are not going to occur, effectively treating low probability events as zero probability events. To this extent, we are not Bayesians about the risks of daily life. We treat some possible harms as impossible for the purposes of getting through the day. This attitude, crucial to living our lives, does not imply that there are no serious risks in daily life. The fact that our attitude toward the risks of everyday life is justified by its ability to help us to get through the day undermines its ability to provide an ethical justification for exposing research subjects to the same risks in the context of non-beneficial research (Ross & Nelson 2006).

First, the extent to which we ignore the risks of daily life is not a fully rational process. In many cases, our attitude regarding risks is a function of features of the situation that are not correlated directly with the risk level, such as our perceived level of control and our familiarity with the activity (Tversky, Kahneman 1974; Tversky, Kahneman 1981; Slovic 1987; Weinstein 1989). Second, to the extent that the process of ignoring some risks is rational, we are involved in a process of determining which risks are worth paying attention to. Some risks are so low that they are not worth paying attention to. Consideration of them would be more harmful (would cost us more) than the expected value of being aware of them in the first place.

To some extent, then, our attitudes in this regard are based on a rational cost/benefit analysis. To that extent, these attitudes do not provide an ethical argument for exposing research subjects to risks for the benefit of others. The fact that the costs to an individual of paying attention to a given risk in daily life are greater than the benefits to that individual does not seem to have any relevance for what risks we may expose them to for the benefit of others. Finally, there is a chance of serious harm from many of the activities of daily life. This reveals that the ‘risks of daily life’ standard does not preclude the chance of some subjects experiencing serious harm. Indeed, one could put the point in a much stronger way. Probabilities being what they are, the risks of daily life standard implies that if we conduct enough minimal risk research eventually a few subjects will die and scores will suffer permanent disability.

As suggested above, a more plausible line of argument would be to defend clinical research that poses minimal risks on the grounds that it does not increase the risks to which subjects are exposed. It seems plausible to assume that at any given time an individual will either be participating in research or involved in the activities of daily life. But, by assumption, the risks of the two activities are essentially equivalent, implying that enrollment in the study, as opposed to allowing the subject to continue to participate in the activities of daily life does not increase the risks to which he is exposed. The problem with this argument is that the risks of research often are additive rather than substitutive.

Participation in a study might require the subject to drive to the clinic for a research visit. The present defense succeeds to the extent that this trip replaces another trip in the car, or some similarly risky activity in which the subject would have been otherwise involved. In practice, this often is not the case. The subject instead may simply put off the car trip to the mall until after the research visit. In that case, the subject's risk of serious injury from a car trip may be doubled as a result of her participation in research. Moreover, we accept many risks in daily life because the relevant activities offer those who pursue them a chance of personal benefit. We allow children to take the bus because we assume that the benefits of receiving an education justify the risks. The fact that we accept these risks given the potential benefits provides no reason to think that the same risks or even the same level of risk would be acceptable in the context of an activity, including a non-beneficial research study, which offers no chance of medical benefit. Finally, and strictly speaking, this justification seems to imply that investigators should evaluate what risks individuals would face if they did not enroll in the research, and enroll only those who would otherwise face similar or greater levels of risk.

In one of the most influential papers in the history of research ethics, Hans Jonas (1969) argues that the progress clinical research offers is normatively optional, whereas the need to protect individuals from the harms to which clinical research exposes them is mandatory. He writes:

… unless the present state is intolerable, the melioristic goal [of biomedical research] is in a sense gratuitous, and this is not only from the vantage point of the present. Our descendants have a right to be left an unplundered planet; they do not have a right to new miracle cures. We have sinned against them if by our doing, we have destroyed their inheritance not if by the time they come around arthritis has not yet been conquered (unless by sheer neglect). (Jonas 1969, 230–231)

Jonas's view does not imply that clinical research is necessarily unethical, but the conditions on when it may be conducted are very strict. This argument may seem plausible to the extent that one regards, as Jonas does, the benefits of clinical research to be ones that make an acceptable state in life even better. The example of arthritis cited by Jonas characterizes this view. Curing arthritis, like curing dyspepsia, baldness, and the minor aches and pains of living and aging, may be nice, but may be thought to address no profound problem in our lives. If this were all that clinical research had to offer, we might be reluctant to accept many risks in order to achieve its goals. We should not, in particular, take much chance of wronging individuals, or exploiting them to realize these goals.

This argument makes sense to the extent that one regards the status quo as acceptable. Yet, without further argument, it is not clear why one should accept this view; it seems almost certain that those suffering from serious illness that might be addressed by future research will not accept it. Judgments regarding the present state of society concern very general level considerations and a determination that society overall is doing fairly well is consistent with many individuals suffering terrible diseases. Presumably, the suffering of these individuals provides some reason to conduct clinical research. In response, one might understand Jonas to be arguing that the present state of affairs involves sufficiently good medicine and adequately flourishing lives such that the needs which could now be addressed by additional clinical research are not of sufficient importance to justify the risks raised by conducting it. It might have been the case, at some point in the past, that life was sufficiently nasty, brutish and short to justify running the risk of exploiting research subjects in the process of identifying through clinical research ways to improve the human lot. But, we have advanced, in part thanks to the conduct of clinical research, well beyond that point. This reading need not interpret Jonas as ignoring the fact that there remain serious ills to be cured. Instead, he might be arguing that these ills, while real and unfortunate, are not of sufficient gravity, or perhaps prevalence to justify the risks of conducting clinical research.

This view implicitly expands the ethical concerns raised by clinical research. We have been focusing on the importance of protecting individual research subjects. However, Jonas assumes that clinical research also threatens society in some sense. There are at least two possibilities here. First, it might be thought that the conduct of unethical research reaches beyond individual investigators to taint society as a whole. This does not seem unreasonable given that clinical research typically is conducted in the name of and often for the benefit of society. Second, one might be concerned that allowing investigators to expose research subjects to some risks for the benefit of others might put us on a slippery slope that ends with serious abuses throughout society.

An alternative reading would be to interpret Jonas as arguing from a version of the active-passive distinction. It is often claimed that there is a profound moral difference between actively causing harm versus merely allowing harm to occur, between killing someone versus allowing them to die, for example. Jonas often seems to appeal to this distinction when evaluating the ethics of clinical research. The idea is that conducting clinical research involves investigators actively exposing individuals to risks of harm and, when those harms are realized, it involves investigators actively harming them. The investigator who injects a subject with an experimental medication in the context of a non-beneficial study actively exposes the individual to risks for the benefit of others and actively harms, perhaps even kills those who suffer harm as a result. And, to the extent that clinical research is conducted in the name of and for the benefit of society in general, one can say without too much difficulty that society is complicit in causing these harms. Not conducting clinical research, in contrast, involves our allowing individuals to be subject to diseases that we might otherwise have been able to avoid or cure. And this situation, albeit tragic and unfortunate, has the virtue of not involving clear moral wrongdoing.

The problem with at least this version of the argument is that the benefits of clinical research often involve finding safer ways to treat disease. The benefits of this type of clinical research, to the extent they are realized, involve clinicians being able to provide less harmful, less toxic medications to patients. Put differently, many types of clinical research offer the potential to identify medical treatments which harm patients less than current ones. This not an idle goal. One study found that the incidence of serious adverse events from the appropriate use of clinical medications (i.e. excluding such things as errors in drug administration, noncompliance, overdose, and drug abuse) in hospitalized patients was 6.7%. The same study, using data from 1994, concludes that the approved and properly prescribed use of medications is likely the 5 th leading cause of death in the US (Lazarou, Pomeranz, and Corey 1998).

These data suggest that the normative calculus is significantly more complicated than the present reading of Jonas suggests. The question is not whether it is permissible to risk harming some individuals in order to make other individuals slightly better off. Instead, we have to decide how to trade off the possibility of clinicians exposing patients to increased risks of harm in the process of treating them versus clinical researchers exposing subjects to risk of harm in the process of trying to identify improved methods to treat others. This is not to say that there is no normative difference between these two activities, only that that difference is not accurately described as the difference between harming individuals versus improving their lot beyond some already acceptable status quo. It is not even a difference between harming some individuals versus allowing other individuals to suffer harms. The argument that needs to be made is that harming individuals in the process of conducting clinical research potentially involves a significant moral wrong not present when clinicians harm patients in the process of treating them.

Jonas's primary concern is that, by exposing subjects to risks of harm, the process of conducting clinical research involves the threat of exploitation of a particular kind. It runs the risk of investigators treating persons as things, devoid of any interests of their own. The worry here is not so much that investigators and subjects enter together into the shared activity of clinical research with different, perhaps even conflicting goals. The concern is rather that, in the process of conducting clinical research, investigators treat subjects as if they had no goals at all or, perhaps, that any goals they might have are normatively irrelevant.

Jonas argues that this concern can be addressed, and the process of experimenting on some to benefit others made ethically acceptable, only when the research subjects share the goals of the research study. The goals must, to some extent, be their own goals so that, in facing research risks, subjects are working to promote their own interests. In this way, ethically appropriate research, on Jonas's view, is marked by: “appropriation of the research purpose into the person's own scheme of ends” (Jonas 1969, 236). And assuming that it is in one's interests to achieve one's, at least, proper goals, it follows that, by participating in research, subjects will be acting in their own interests, despite the fact that they are thereby being exposed to risky procedures which are performed to collect information to benefit others. One might want to add here the further condition that there must be some appropriate proportionality between the risks to which the individuals are exposed and the extent to which furthering, pursuing and perhaps attaining, these goals advances subjects' own interests.

Jonas claims in some passages that research subjects, at least those with an illness, can share the goals of a clinical research study only when they have the condition or illness under study (Jonas 1969). These passages reveal something of the account of human interests on which Jonas's arguments rely. On standard preference satisfaction accounts of human interests, what is in a given individual's interests depends on what the individual happens to want or prefer, or the goals the individual happens to endorse, or the goals the individual would endorse in some idealized state scrubbed clean of the delusions, misconceptions and confusion which inform our actual preferences (Griffin 1986). On this view, participation in clinical research would promote an individual's interests as long as she was well informed and wanted to participate. This would be so whether or not she had the condition being studied. Jonas's view, in contrast, seems to be that there are objective conditions under which individuals can share the goals of a given research study. They can endorse the cause of curing or at least finding treatments for Alzheimer disease only if they suffer from the disease themselves.

One possible objection would be to argue that there are many reasons why an individual might endorse the goals of a given study, apart from the fact of having the disease themselves. One might have family members with the disease, or co-religionists, or have adopted improved treatment of the disease as an important personal goal. The larger question is whether subjects endorsing the goals of a clinical research study is a necessary condition on its acceptability. Recent commentators and guidelines rarely, if ever, adopt this condition, although at least some of them might be assuming that the requirement to obtain free and informed consent will ensure its satisfaction. It might be assumed, that is, that competent, informed, and free individuals will enroll in research only when they share the goals of the study in question.

Jonas was cognizant of the extent to which the normative concerns raised by clinical research are not exhausted by the risks to which subjects are exposed, but also include the extent to which investigators and by implication society are the agents of the risk exposure. For this reason, he recognized that the libertarian response is inadequate, even with respect to competent adults who truly understand. Finally, to the extent Jonas's claims rely on an objective account of human interests, one may wonder whether he adopts an overly restrictive one. Why should we think, on an objective account, that individuals will have an interest in contributing to the goals of a given study only when they have the disease it addresses? Moreover, although we will not pursue the point here, appeal to an objective account of human interests raises the possibility of justifying the process of exposing research subjects to risks for the benefit of others on the grounds that contributing to valuable projects, including presumably some clinical research studies, is objectively in (most) individuals' interests (Wendler 2010).

The fundamental ethical challenge posed by clinical research is whether it is acceptable to expose some to research risks for the benefit of others. In the standard formulation, the one we have been considering to this point, the benefits that others enjoy as the result of subjects' participation in clinical research are medical and health benefits, better treatments for disease, better methods to prevent disease.

Industry funded research introduces the potential for a very different sort of benefit and thereby potentially alters, in a fundamental way, the moral concerns raised by clinical research. Pharmaceutical companies typically focus on generating profit and increasing stock price and market share. Indeed, it is sometimes argued that corporations have an obligation to their shareholders to pursue increased market share and share price (Friedman 1970). This approach may well lead companies to pursue new medical treatments which have little or no potential to improve overall health and well-being (Huskamp 2006; Croghan and Pittman 2004). “Me-too” drugs are the classic example here. These are drugs identical in all clinically relevant respects to approved drugs already in use. The development of a me-too drug offers the potential to redistribute market share without increasing overall health and well-being.

There is considerable debate regarding how many me-too drugs there really are and what is required for a drug to qualify as effectively identical (Garattini 1997). If the existing treatment needs to be taken with meals, but a new treatment need not, is that a clinically relevant advance? Bracketing these questions, a drug company may well be interested in a drug which clearly qualifies as a me-too drug. The company may be able, by relying on a savvy marketing department, to convince physicians to prescribe, and consumers to request the new one, thus increasing profit for the company without advancing health and well-being.

The majority of clinical research was once conducted by governmental agencies, such as the U.S. NIH. It is now estimated that a majority, perhaps a significant majority of clinical research studies are conducted by industry: “as recently as 1991 eighty per cent of industry-sponsored trials were conducted in academic health centers…Impatient with the slow pace of academic bureaucracies, pharmaceutical companies have moved trials to the private sector, where more than seventy per cent of them are now conducted” (Elliott 2008, Angell 2008, Miller and Brody 2005). Moreover, during the very early years of the 21st century, the research budget of the US NIH, likely the largest governmental sponsor of clinical research in the world, has declined (Mervis 2004, 2008).

In addition to transforming the fundamental ethical challenge posed by clinical research, industry sponsored research has the potential to transform the way that many of the specific ethical concerns are addressed within that context. Commentators on the ethics of clinical research tend to be skeptical of the appropriateness of paying research subjects, despite the prevalence of the practice, on the grounds that it might undermine the ethical protection of free and informed consent (Grady 2005). The concern is that the offer of payment may act as an “undue” inducement, it may cloud individuals' judgment to the extent that they end up temporarily overwhelmed by the promise of profits and make a decision contrary to their long-terms interests (Macklin 1981).

Insulating the review, conduct and reporting of clinical research trials from the influence of money also is regarded as important for investigators and funders. The possibility that investigators and funders may earn significant amounts of money from their participation in clinical research might, it is thought, warp their judgment in ways that conflict with appropriate protection of research subjects (Fontanarosa, Flanagin, and DeAngelis 2005). When applied to investigators and funders this concern calls into question the very significant percentage of research funded by and often conducted by for-profit organizations. Skeptics might wonder whether the goal of making money has any greater potential to influence judgment inappropriately compared to many other motivations that are widely accepted, even esteemed in the context of clinical research, such as gaining tenure and fame, impressing one's colleagues, or winning the Nobel Prize.

Financial conflicts of interest in clinical research point to a tension between relying on profits to motivate business versus insulating drug development and testing from the profit motive as a way of protecting research subjects and future patients (Psaty and Kronmal 2008). To this extent, financial conflicts may not be amenable to the commonly pursued remedy of addressing ethical concerns in clinical research by promulgating a few new guidelines. While more fundamental changes may be necessary, it is not clear what changes would be sufficient to address this concern, much less how likely it might be that those changes would be adopted.

Finally, if industry can make billions of dollars from the development of a single drug one wonders what constitutes an appropriate response to the subjects who were vital to the development of the drug in question. Exploitation occurs when some individuals do not receive a fair level of benefits from a shared activity (see entry on exploitation ). On a standard definition, what constitutes a fair level of benefits depends on the risks and burdens that a party experiences as a result of a transaction and the extent to which others benefit from the participation of the party in the transaction. A series of clinical research studies can result in a company earning billions of dollars in profits. Recognizing that a fair level of benefit is a complex function of participants' inputs compared to the inputs of others, and the extent to which third parties benefit from those inputs, it is difficult to see how one might fill in the details of this scenario to show that the typically minimal, or non-existent compensation offered to research participants is fair.

At the same time, addressing the potential for exploitation by offering payments to research participants would introduce its own set of ethical concerns: is payment an appropriate response to the kind of contribution made by research participants; might payment constitute an undue inducement to participate; will payment undermine other participants' altruistic motivations; to what extent does payment encourage research subject to provide misleading or false information to investigators in order to enroll and remain in research studies? In the end, then, as commentators struggle to address the existing ethical concerns raised by clinical research, its conduct in the real world raises new ethical concerns and, thereby, offers opportunities for philosophers looking for interesting, not to mention practically very important issues in need of analysis and resolution.

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How to cite this entry . Preview the PDF version of this entry at the Friends of the SEP Society . Look up this entry topic at the Indiana Philosophy Ontology Project (InPhO). Enhanced bibliography for this entry at PhilPapers , with links to its database.

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• SARETI , The South African Research Ethics Training Initiative

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• The RELIEF feasibility trial: topical lidocaine patches in older adults with rib fractures
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• Madeleine Clout 1 ,
• Nicholas Turner 1 ,
• Clare Clement 2 ,
• Philip Braude 3 ,
• http://orcid.org/0000-0001-6131-0916 Jonathan Benger 4 ,
• James Gagg 5 ,
• Emma Gendall 6 ,
• Simon Holloway 7 ,
• Jenny Ingram 8 ,
• Rebecca Kandiyali 9 ,
• Amanda Lewis 1 ,
• Nick A Maskell 10 ,
• David Shipway 11 ,
• http://orcid.org/0000-0002-6143-0421 Jason E Smith 12 ,
• Jodi Taylor 13 ,
• Alia Darweish Medniuk 14 ,
• http://orcid.org/0000-0002-2064-4618 Edward Carlton 15 , 16
• 1 Population Health Sciences , University of Bristol , Bristol , UK
• 2 University of the West of England , Bristol , UK
• 3 CLARITY (Collaborative Ageing Research) , North Bristol NHS Trust , Westbury on Trym , UK
• 4 Faculty of Health and Life Sciences , University of the West of England , Bristol , UK
• 5 Department of Emergency Medicine , Somerset NHS Foundation Trust , Taunton , UK
• 6 Research and Innovation , Southmead Hospital , Bristol , UK
• 7 Pharmacy Clinical Trials and Research , Southmead Hospital , Bristol , UK
• 8 Bristol Medical School , University of Bristol , Bristol , UK
• 9 Warwick Clinical Trials Unit , Warwick Medical School , Coventry , UK
• 10 Academic Respiratory Unit , University of Bristol , Bristol , UK
• 11 Department of Medicine for Older People, Southmead Hospital , North Bristol NHS Trust , Bristol , UK
• 12 Emergency Department , University Hospitals Plymouth NHS Trust , Plymouth , UK
• 13 Bristol Trials Centre, Population Health Sciences , University of Bristol , Bristol , UK
• 14 Department of Anaesthesia and Pain Medicine , Southmead Hospital , Bristol , UK
• 15 Emergency Department , Southmead Hospital , Bristol , UK
• 16 Department of Emergency Medicine, Translational Health Sciences , University of Bristol , Bristol , UK
• Correspondence to Dr Edward Carlton, Emergency Department, Medicine Translational Health Sciences, Southmead Hospital, Bristol, BS10 5NB, UK; eddcarlton{at}gmail.com

Background Lidocaine patches, applied over rib fractures, may reduce pulmonary complications in older patients. Known barriers to recruiting older patients in emergency settings necessitate a feasibility trial. We aimed to establish whether a definitive randomised controlled trial (RCT) evaluating lidocaine patches in older patients with rib fracture(s) was feasible.

Methods This was a multicentre, parallel-group, open-label, feasibility RCT in seven hospitals in England and Scotland. Patients aged ≥65 years, presenting to ED with traumatic rib fracture(s) requiring hospital admission were randomised to receive up to 3×700 mg lidocaine patches (Ralvo), first applied in ED and then once daily for 72 hours in addition to standard care, or standard care alone. Feasibility outcomes were recruitment, retention and adherence. Clinical end points (pulmonary complications, pain and frailty-specific outcomes) and patient questionnaires were collected to determine feasibility of data collection and inform health economic scoping. Interviews and focus groups with trial participants and clinicians/research staff explored the understanding and acceptability of trial processes.

Results Between October 23, 2021 and October 7, 2022, 206 patients were eligible, of whom 100 (median age 83 years; IQR 74–88) were randomised; 48 to lidocaine patches and 52 to standard care. Pulmonary complications at 30 days were determined in 86% of participants and 83% of expected 30-day questionnaires were returned. Pulmonary complications occurred in 48% of the lidocaine group and 59% in standard care. Pain and some frailty-specific outcomes were not feasible to collect. Staff reported challenges in patient compliance, unfamiliarity with research measures and overwhelming the patients with research procedures.

Conclusion Recruitment of older patients with rib fracture(s) in an emergency setting for the evaluation of lidocaine patches is feasible. Refinement of data collection, with a focus on the collection of pain, frailty-specific outcomes and intervention delivery are needed before progression to a definitive trial.

Trial registration number ISRCTN14813929 .

• feasibility studies
• frail elderly

Data availability statement

Data are available on reasonable request. Further information and patient-facing materials (including model consent forms) are available at https://relief.blogs.bristol.ac.uk/ . Data available on request.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/ .

https://doi.org/10.1136/emermed-2024-213905

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Studies have evaluated the use of lidocaine patches in patients with rib fractures showing reductions in opioid use, improvements in pain scores and reductions in length of hospital stay.

Importantly, none has focused on older patients, who stand to gain the most benefit from improved analgesic regimens to reduce adverse pulmonary complications.

WHAT THIS STUDY ADDS

In this feasibility trial, prespecified progression criteria around recruitment, follow-up and adherence were met, demonstrating it is feasible to conduct randomised controlled trials in older patients, who are in pain, in an emergency setting.

There were challenges in data collection for pain and frailty-specific measures, together with treatment crossover, that require consideration in definitive trial design.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Researchers can adapt study processes to be inclusive of older patients in the emergency setting.

There are challenges in terms of data collection around pain and frailty-specific outcome measures which future research should consider.

Introduction

Rib fractures represent the most common non-spinal fracture in older people. 1 Age ≥65 years remains a predictor of morbidity and mortality in patients with rib fractures. 2 Pain can compromise normal respiratory function, with over 15% of older patients experiencing complications including pneumonia and death. 3

The mainstay for treatment of rib fracture pain remains strong opioid analgesia. However, as a result of poor physiological reserve, older patients are more vulnerable than younger people to the side effects of strong opioid medication such as nausea, constipation, sedation, delirium and respiratory depression. 4 Invasive approaches, such as thoracic epidural anaesthesia, have been used to reduce the likelihood of these side effects, but require specialist anaesthetic support, monitoring in a high-dependency environment and are only used in around 20% of admitted patients. 5 6

Lidocaine patches applied over rib fractures have been suggested as a non-invasive method of local anaesthetic delivery to improve respiratory function, reduce opioid consumption and consequently reduce pulmonary complications. 7 Studies have evaluated the use of lidocaine patches in patients with rib fractures showing reductions in opioid use, 8 improvements in pain scores 9 10 and reductions in length of hospital stay. 11 However, these studies are limited by retrospective design and low patient numbers with consequent bias and low precision. Importantly, none has focused on older patients, who are more susceptible to the development of pulmonary complications, 2 or tested lidocaine patches as an intervention in the ED where opioid analgesia is the mainstay of treatment.

Older people have often been excluded from research, relating to multiple long-term health conditions, social and cultural barriers and potentially impaired capacity to provide informed consent. 12 In addition, recruitment of older patients who are in pain in an emergency setting may pose further challenges around information provision and collection of clinical and patient-reported outcomes.

The aim of this trial was to establish whether a definitive randomised controlled trial (RCT) to evaluate the benefit of lidocaine patches, first applied in the ED, for older people requiring admission to hospital with rib fracture(s) is feasible.

Detailed methods, including detailed consent procedures, are described in full elsewhere. 13

Design, setting and participants

The Randomised Evaluation of topical Lidocaine patches in Elderly patients admitted to hospital with rib Fractures (RELIEF) study was a multicentre, parallel-group, open-label, individually randomised, feasibility RCT, conducted in seven NHS hospitals: five major trauma centres (Southmead Hospital; Royal Infirmary of Edinburgh; Derriford Hospital, Plymouth; Queen Elizabeth University Hospital, Glasgow; St George’s Hospital, London) and two trauma units (Musgrove Park Hospital, Taunton; Royal Devon and Exeter Hospital). The trial included a health economic scoping analysis and an integrated qualitative study. Patients were eligible for recruitment if they were aged ≥65 years, presented at any time after injury with traumatic rib fracture(s) (including multiple fractures, flail chest and traumatic haemothorax/pneumothorax even if this required intercostal chest drainage), confirmed radiologically (by CXR or CT conducted as part of routine care) and required hospital admission for ongoing care. Exclusion criteria are detailed in figure 1 .

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Exclusion criteria.

Randomisation and blinding

Participants were randomised in the ED by trained research or clinical staff, using an online randomisation system, with the randomisation sequence generated by Sealed Envelope (London, UK). Participants were allocated to the intervention or standard care in a 1:1 ratio. Randomisation was stratified by trial site and gender and blocked within strata. Allocations were blinded only to those performing central review of data for the assessment of outcomes.

Intervention

Participants randomised to the intervention received up to 3×700 mg lidocaine patches (Ralvo) at a time applied over the most painful area of rib injury. Patches were first applied in the ED, then once daily for 12 hours in accordance with the manufacturer’s (Grünenthal, Aachen, Germany) instructions. Treatment continued for up to 72 hours or until discharge from hospital. The intervention was additive to standard care (below). If participants subsequently underwent regional anaesthesia, patches were removed and no further patches were applied but data collection continued according to group allocation.

Standard care

All participants received standard local analgesic treatment for patients with rib fractures; this was not controlled for trial purposes. Data were collected on paracetamol, weak opioid, strong opioid and other non-opioid analgesia prescriptions in ED and for the 72-hour intervention period in both arms of the trial. 14

Patient and public involvement

Patient and public involvement was ensured at all stages of trial design, and continued throughout the trial’s lifetime via a patient advisory group and patient representation on the trial steering committees.

Clinical outcomes and measurement

Outcomes were measured at baseline, 72 hours (during or on completion of intervention) and 30-day postrandomisation. A full schedule of clinical data, questionnaires and end points is included in the published protocol. 13 Clinical end points were collected only to understand the feasibility of data collection and not to conduct hypothesis testing. Key clinical data and their measurement are briefly summarised as follows (further details on scales used are provided in the online supplemental material ):

Supplemental material

Demographics, injury details, relevant medical history and Clinical Frailty Scale (CFS) 15 : collected by researcher from clinical notes.

Retrospective pre-injury and baseline post-injury health EQ-5D-5L 16 : completed with participant/relative/carer.

Timed Up and Go test. 17

72 hours postrandomisation (intervention period) collected until discharge if sooner

Patient-reported pain scores: 4-hourly pain assessment using a Visual Analogue Scale (VAS) (scaled from 0 to 100). Recorded in a booklet provided to the patient.

Frailty-specific outcomes: Abbey Pain Scale, 18 4-AT delirium assessment tool, 19 constipation (Bristol Stool Chart), Timed Up and Go test. 17 Obtained by researchers.

Analgesia; ED and inpatient (72 hours) analgesic prescriptions, advanced analgesic provision (patient controlled analgesia (PCA), epidural, nerve block). Obtained by researchers from medical records.

30 days (+10 days) postrandomisation

Pulmonary complications: a priori proposed primary outcome for a definitive trial. Collected after review of medical records and adjudicated by site lead clinician.

Delirium: binary measure of any inpatient episode of delirium recorded in clinical notes.

Resource use: including admitted hospital length of stay, intensive care unit length of stay, unplanned readmission, discharge destination (notes review).

Questionnaires: booklets containing EQ-5D-5L and ICECAP-O 16 20 were sent by post to participants. Participants were permitted to complete these with the assistance of carers, although formal proxy versions of questionnaires were not provided.

Sample size

As this was a feasibility trial, it was not appropriate to calculate a sample size to detect a specified treatment effect size. In line with published ‘rules-of-thumb’, we determined that a total sample size of 100 would be sufficient to provide estimates of feasibility measures (recruitment, retention, data completion and adherence). 21 Recruitment was originally planned to take place over 18 months across three sites. However, trial set-up was delayed due to the COVID-19 pandemic. To achieve target recruitment within the funding period, the recruitment period was shortened to 12 months across seven sites.

Statistical methods

Feasibility measures were analysed and reported following the Consolidated Standards of Reporting Trials guidance extension for feasibility studies to include descriptive and summary statistics both overall and by treatment arm. 22

Descriptive statistics for participant characteristics and clinical outcome data were reported as means or medians with measures of dispersion for continuous outcomes and frequencies and percentages for categorical outcomes.

A priori thresholds for recruitment, follow-up and adherence were established to inform the feasibility of progression (table 2).

Integrated qualitative study

Telephone interviews were undertaken with trial participants around 1 month (and up to 90 days) postrandomisation. Interviews and focus groups were conducted with clinicians/research staff closely involved in the trial set-up, recruitment and follow-up. These explored trial participation experiences including understanding and acceptability of processes, pain control including perceived benefits of lidocaine patches and views on trial outcomes (topic guides are included in the online supplemental material ). Interviews and focus groups were audio-recorded, transcribed and analysed using thematic analysis. 23 Qualitative findings were integrated with other elements using a ‘following a thread’ approach. 24 This involved analysing each dataset and then using insights from the qualitative themes to contextualise and explain quantitative outcomes with data presented together.

Health economic scoping

An evaluation of the feasibility of identifying and measuring health economics outcome data was completed, with the focus on establishing the most appropriate outcome measures for inclusion in a future economic evaluation alongside the definitive trial. The EQ-5D-5L (health-related quality of life) patient-reported questionnaire 16 was completed at baseline, to capture retrospective pre-injury state and baseline post-injury state, and 30 days postrandomisation. In addition to the standard EQ-5D questionnaire, which typically elicits post-injury health status, we additionally assessed pre-injury status by making an approved change to the wording. The ICECAP-O (measure of capability in older people) 20 was also collected at 30 days. Information on key resources, including length of stay, intensive care use and medication prescribing, was also collected.

Between 23 October 2021 and 7 October 2022, 447 patients were assessed for eligibility, of which 206 were eligible; of these, 29 declined and 77 were not approached. Therefore, 100 patients were randomised; 48 participants were allocated to lidocaine patches and 52 to standard care ( figure 2 ). Six participants died prior to the 30-day follow-up timepoint and three participants withdrew from questionnaire completion, but had clinical data retained for analysis. Baseline characteristics were well balanced between groups ( table 1 ).

Screening, recruitment, allocation and follow-up (Consolidated Standards of Reporting Trials diagram).

• View inline

Baseline demographics and injury characteristics

Participants were predominantly women (47%), of white British ethnicity (92%), with a median age of 83 years (IQR 74–88). Participants were predominantly admitted from their own homes (92%), were independent (75%) but were living with very mild frailty (median CFS 4; IQR 3–5). The most common mechanism of injury was a fall from <2 m (81%). On average, participants sustained four rib fractures (SD 2.0)and they were at high risk of developing pulmonary complications at baseline (median STUMBL score 21 (IQR 16–33)), equating to a 70% risk. 3

Feasibility outcomes

Table 2 details the prespecified progression criteria around recruitment, follow-up and adherence together with observed results.

Prespecified progression criteria and observed results

Recruitment and consent

An average of 14 participants were recruited per site (range 3–37) in 12 months. Participants were predominately recruited from major trauma centres (n=87).

Agreement to participate was largely obtained from patients (70%): personal consultees (in England) or legal representatives (in Scotland) were approached in 27% of cases, and professional consultees were used in 3% of cases.

In the qualitative research, clinical and research staff closely involved in delivering the trial reported challenges in recruiting within the ED setting. These challenges included general ED pressures, reliance on referrals from wider clinical teams not directly engaged in the research, resource-intensive monitoring of ED attendances for potentially eligible patients, the necessity to rapidly attend ED (when not based in the department) to approach patients and lack of out-of-hours research staff (although some engaged clinicians were able to recruit out of hours). However, they were able to recruit well by raising awareness of the trial and fostering good collaborative relationships with the wider ED clinical team members, who were able to actively participate in patient identification. Insights from older patients were limited due to challenges with interview engagement (of 26 participants approached for interviews, 7 took part, 5 declined, 14 did not respond). However, older patients interviewed welcomed being approached and were willing to participate in the trial because they wanted to help, but were sometimes unsure of trial details. Staff needed to consider older patients’ vulnerability, and carefully manage consent processes to avoid overwhelming them, while ensuring their full understanding of involvement and the option not to participate.

Follow-up and data completeness

The proposed primary outcome of adverse pulmonary complications at 30 days was completed for 86% of participants (data missing in 14%, due to transfer to remote facilities or discharge home and no further records were available). For the 30-day patient-completed questionnaires, in total 71 were returned (fully or partially completed), 15 were unreturned despite repeated contact and 14 had reasons recorded for non-return (7 deaths, 4 remained unwell/confused, 3 withdrawals). This equates to an overall return rate of 71% but rising to 83% when return was anticipated. Qualitative findings regarding questionnaire completion highlighted the unblinded nature of the intervention, with standard care participants not feeling part of the trial, potentially impacting their understanding of completing questionnaires in future research.

Pain and frailty-specific outcomes (important secondary outcomes but not included in prespecified progression criteria) were not feasible to collect as completeness was <65%. Table 3 summarises data completeness on these measures and qualitative exploration of factors influencing data collection.

Pain and frailty-specific outcomes that were not feasible to collect and qualitative exploration of factors influencing data collection

In the intervention arm, 44/48 (92%) participants had at least one lidocaine patch applied in ED at a median time of 393.5 min after arrival. In the standard care arm, 17/52 (33%) participants also had a lidocaine patch applied in ED and were therefore classed as non-adherent. However, overall adherence was 79% meeting the prespecified green criteria for feasibility (>75%). Themes identified in the qualitative research with clinical/research staff addressing variation in care included standard care (some hospitals use patches as standard care, others do not), patch application (eg, where best to place patches in the presence of multiple fractures), provision of nerve blockade (the ongoing use of lidocaine patches when nerve blocks are subsequently used), equipoise (mixed views on the benefits of patches) and patch acceptability (perceived benefits of patches to patients) (see online supplemental material for details).

Clinical outcomes

72-hour outcomes

Data on ED and inpatient (72 hours) analgesic prescriptions, together with advanced analgesic provision (PCA, epidural, nerve blocks) were collected in >75% of participants ( table 4 ) Analgesic prescriptions within ED and as an inpatient were similar between arms. Overall, 33/97 (34%) participants had advanced analgesia with 21/97 (22%) receiving some form of nerve blockade and 12/97 (13%) receiving PCA within the 72-hour intervention period.

30-day outcomes

Overall, 46/86 (53%) participants with complete data met the outcome of composite pulmonary complications within 30 days; 20 (48%) in the lidocaine patch arm and 26 (59%) in the standard care arm. The median length of hospital stay was 9.1 days (IQR 5.2–15.4) and over 30% of participants did not return to their baseline level of function on discharge (requiring increased package of care, residential, nursing or rehabilitation). Descriptive data on all 30-day outcomes is included in table 4 .

We achieved our objectives in terms of piloting instruments of data collection: administration of EQ-5D-5L and ICECAP-O measures and case report forms to record length of stay, use of analgesia and discharge destination ( table 4 ).

As anticipated EQ-VAS at baseline (measuring overall health status with 100 being best imaginable health) were reported as higher pre-injury (median 80 (60–90)) compared with post-injury (median 50 (25–70)). At 30 days, EQ-5D-5L completeness was 44% and ICECAP-O was 65%. In terms of the trajectory of health status, as anticipated the baseline EQ-5D-5L post-injury tariff had the lowest median (0.44 (0.25–0.63)) while at 30 days these data indicated participants had only partially recovered in terms of health status (0.59 (0.27–0.74)) ( table 4 ). The overall median ICECAP-O tariff at 30 days was 0.77, which is slightly below a published population norm of 0.81. 25

This trial suggests it is feasible to recruit older patients with rib fracture(s) in an emergency setting. Consent processes modified for older patients were effective and acceptable to patients and carers. However, pain and frailty-specific outcomes were not feasible to collect. While these were not anticipated primary outcomes for a future trial, they are clearly important secondary outcomes in this population. Our qualitative work highlighted areas for improvement in this regard. These include bespoke training for researchers when unfamiliar with measures (Abbey Pain Scale, 4-AT delirium assessment tool), embedding measures such as 4-AT delirium assessment tool into clinical practice and increased recognition of the potential to overwhelm older injured patients through research procedures when designing trials. It should be noted that the World Hip Trauma Evaluation platform study appears to have overcome many of these barriers to data collection in a similar population. 26

Data collection for the suggested primary outcome of a definitive trial (adverse pulmonary complications) was feasible, and the high rates of this outcome within the population confirm that it remains a target outcome for early analgesic interventions in older patients with rib fracture(s).

Paper-based, mailed out, patient-completed questionnaires were returned at high rates, suggesting that this remains an acceptable option for older participants in research. This aligns with consensus recommendations that alternatives should be offered to digital data collection to avoid digital exclusion in older patients. 12 However, for those patients with cognitive impairment, consideration of formal proxy versions of questionnaires should be considered where available.

While adherence to the intervention was high and overall adherence was deemed feasible, significant crossover in the standard care arm was seen. This finding suggests clinicians may lack equipoise in sites where lidocaine patches are already in use; this was confirmed in our healthcare professional focus groups. However, these focus groups also highlighted discrepancies in prescribing/availability and a recognition of the potential harm of overuse of lidocaine patches (at the expense of other analgesic modalities). In order to overcome these challenges in equipoise, avoid crossover and fully understand the clinical effectiveness of topical lidocaine, a definitive trial would need to test active patches against placebo patches rather than standard care.

In this trial, older patients admitted to hospital with radiologically confirmed rib fracture(s) were living with very mild frailty (median CFS 4) and were predominantly injured after a fall from standing (<2 m), a finding consistent with previous reports. 27 Despite having isolated rib fracture(s), many participants had prolonged hospital stays (median 9 days) and >30% did not return to baseline functional status on discharge. STUMBL scores recorded at baseline suggested a population at high risk of developing adverse pulmonary complications and this finding was confirmed in 30-day outcome collection. Development of delirium appeared lower than reported in other cohorts, 6 but may reflect a lack of robust data collection. Notable findings that may provide targets for service improvements include prolonged times between injury and hospital arrival (20 hours) and low rates of prehospital analgesia administration. In addition, in-hospital (72 hours) analgesic prescriptions appear to rely heavily on strong opioid analgesia, with more advanced analgesic modalities being used in only around one-fifth of this vulnerable patient group.

Rib fracture(s) were diagnosed by CT in over 90% of cases. This may reflect a more liberal use of CT in older patients with suspected trauma following influential reports such as Trauma Audit Research Network Major Trauma in Older People 28 and the majority of sites being major trauma centres. However, this finding may also reflect selection bias towards more severely injured patients, given that our inclusion criteria required radiological confirmation of rib fracture(s) and prior studies have demonstrated a poor sensitivity of X-ray diagnosis, with only 40% accuracy in older patients. 29 Amending the inclusion criteria to include patients with clinically suspected (rather than radiologically confirmed) rib fractures may mitigate against this selection bias and also allow the inclusion of those patients who are less severely injured and potentially more frail.

Our health economic scoping revealed key findings to be considered in future research involving older adults in emergency settings. Modification of the standard EQ-5D to obtain retrospective pre-injury health status may be beneficial in assessing specific impacts of injury in economic modelling. However, since response rates to the ICECAP-O were higher than for the EQ-5D at 30 days, which may reflect a patient preference for completing a measure specifically designed for use in older people, it is possible that this is a more appropriate measure for use in a definitive trial.

Conclusions

This trial has demonstrated that recruitment of older patients with rib fracture(s) in an emergency setting for the evaluation of early analgesic interventions (in the form of lidocaine patches) is feasible. Refinement of data collection, with a focus on collecting pain and frailty-specific outcomes, as well as intervention delivery, is needed before progressing to a definitive trial.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

The protocol (V.4.0 4 March 2022) and other related participant-facing documents were approved by the UK Health Research Authority and UK Research Ethics Committees (REC): 21/SC/0019 (South Central—Oxford C REC; IRAS reference 285096) and 21/SS/0043 (Scotland A REC; IRAS reference 299793). Participants gave informed consent to participate in the study before taking part.

Acknowledgments

Sponsor: North Bristol NHS Trust (R&I reference: 4284). Trial management: this trial was designed and delivered in collaboration with the Bristol Trials Centre, a UKCRC registered clinical trials unit, which is in receipt of National Institute for Health Research CTU support funding. The trial management group included all authors and particular thanks are given to Gareth Williams who led patient and public contributions on the trial management group. Trial Steering Committee: the RELIEF trial team would like to thank all members of the independent members of the committee who gave up their time to provide oversight of this work: Fiona Lecky (Clinical Professor in Emergency Medicine and TSC Chair), Rachel Bradley (Consultant in General, Geriatric and Orthogeriatric Medicine), Sean Ewings (Associate Professor of Medical Statistics, Southampton Clinical Trials Unit, University of Southampton), Gordon Halford (Patient and Public Involvement Contributor). Participating sites: the RELIEF trial team would like to thank all staff involved at the seven participating sites (Southmead Hospital, North Bristol NHS Trust, Principal Investigator (PI): Edward Carlton, Associate PI: Fraser Birse; Royal Infirmary of Edinburgh, NHS Lothian, PI: Rachel O’Brien; Derriford Hospital, University Hospitals Plymouth NHS Trust, co-PIs: Jason Smith and Robert James, Associate PI: Rory Heath; Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, co-PIs: Fraser Denny and David Lowe, Associate PI: Nathalie Graham; St George's Hospital London, St George's University Hospitals NHS Foundation Trust, PI: Melanie Lynn; Musgrove Park Hospital, Somerset NHS Foundation Trust, PI: James Gagg; Royal Devon and Exeter Hospital, Royal Devon University Healthcare NHS Foundation Trust, PI: Andy Appelboam).

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Handling editor Kirsty Challen

X @DrPhilipBraude, @eddcarlton

Presented at Results were presented in part at the Royal College of Emergency Medicine Annual Scientific Conference on 26 September 2023 and Age Anaesthesia Annual Scientific Meeting on 12 May 2023.

Contributors MC and NT have had full access to all data in the study and take full responsibility for the integrity of the data and accuracy of data analysis. Study concept and design: EC, NT, CC, PB, JB, JG, JI, RK, NAM, DS, JS, ADM. Analysis and interpretation of data: all authors. Drafting of manuscript: EC, CC, MC, RK, NT. Critical revision of manuscript for important intellectual content: all authors. Statistical analysis: NT. Obtained funding: EC, NT, CC, PB, JB, JG, JI, RK, NAM, DS, JS, ADM. EC is the guarantor of the study.

Funding This study is funded by the NIHR [Advanced Fellowship (NIHR300068)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care

Disclaimer The funder was not involved in the design, execution, analysis and interpretation of data or writing up of the trial.

Competing interests None declared.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the 'Methods' section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Health research ethics board of alberta approves atma's phase ii psilocybin clinical trial with group and individual therapy settings.

This trial will assess the efficacy of psilocybin-assisted therapy in treating mental healthcare professionals suffering from Major Depressive Disorder, in group and individual dosing sessions, commencing Q3 2024.

CALGARY, AB , May 22, 2024 /PRNewswire/ - ATMA Journey Centers Inc. ("ATMA"), a pioneering Canadian company with a primary focus on advancing innovative psychedelic-assisted therapy solutions, has received approvals for its Phase II Psilocybin-assisted Therapy Clinical Trial from the Health Research Ethics Board of Alberta (HREBA) and Health Canada (No Objection Letter). The primary objective of this trial will be to evaluate the potential of psilocybin-assisted therapy in treating frontline mental healthcare professionals diagnosed with Major Depressive Disorder (MDD), administered in either a group or individual setting.

While a considerable portion of the Canadian population continues to struggle with mental distress stemming from the repercussions of COVID-19, healthcare professionals themselves have faced significant mental hurdles. Indeed, despite the immense physical and psychological burdens imposed by the pandemic – both direct and indirect – many mental healthcare professionals have prioritized the well-being of their patients over their own, resulting in an unaddressed need for mental support; healthcare professionals, like the general population, experience psychological trauma leading to mental health challenges. However, evidence suggests that these challenges are more prevalent among frontline workers due to the nature of their work. From compassion fatigue to vicarious traumatization, these workers often do not use effective coping mechanisms to navigate their depression while continuing their professional duties. Consequently, many have inadvertently normalized chronic depression.

As such, the primary objective of this study is to examine the efficacy of psilocybin-assisted therapy in treating frontline mental healthcare workers diagnosed with MDD. This will be accomplished by comparing the scores on standardized self-assessment questionnaires administered to participants before and after their psilocybin session. The secondary exploratory objective of this study is to investigate the effect psilocybin has on personal and professional characteristics that enhance competency as a mental healthcare worker, as well as participants' self-assessment of their competency and confidence in administering psilocybin-assisted therapy.

Additionally, in collaboration with experts in psychedelic group therapy such as Dr. Mark Atkinson of Human Potential Academy and Dr. Simon Ruffell of Onaya Science, ATMA is exploring a novel protocol for this Phase II trial. This sub-group analysis aims to investigate the potential efficacy of psilocybin-assisted therapy through both group and individual administration frameworks. Based on research exploring the potential benefits of group therapy for addressing depression, ATMA's protocol offers options for either individual sessions or a group setting. The group therapy hypothesis suggests that the group approach may foster social connectedness and well-being by inducing states of communitas and facilitating psychological safety, potentially promoting empathy, cooperation, and aiding in psychological integration and self-regulation. Plans are in motion to prepare for future Phase III trials with a focus on refining the group therapy design. Furthermore, although the primary goal of these trials is not necessarily to improve accessibility to psilocybin, there is a possibility that these trials could enhance affordability and accessibility, possibly alleviating the financial burden on both the healthcare system and participants.

Considering the size and nationwide scope of this trial, ATMA has partnered with KGK Science to ensure successful execution. KGK is an experienced clinical research company specializing in product development. With preparations underway for Canada's largest Phase II clinical trial on psilocybin-assisted therapy, this initiative will encompass three sites nationwide, including the ATMA CENA Psychedelic Therapy Clinics in Calgary, AB and London, ON , along with Qi Integrated Health in Vancouver, BC .

The trial will be open to frontline mental healthcare professionals who have completed an approved psychedelic-assisted therapy training program; this includes the 750+ ATMA alumni and others who have equivalent training and meet the other eligibility requirements.  ATMA believes that training in psychedelic therapy as well as a thorough understanding of psychedelic medicines are crucial for participants in this trial. Such training equips participants with the necessary knowledge and skills to navigate the psychedelic experience safely and effectively. It enables them to understand the potential effects of psilocybin on their mental health and well-being, and how to integrate these experiences into their therapeutic journey, which will provide the field with valuable data in terms of the secondary exploratory objective.

Graduates of ATMA's Advanced Psychedelic Therapy Training Program – predominantly qualified therapists with psychedelic-assisted therapy training and facilitating experience – will be offered the opportunity to contribute to ATMA's Phase II and III clinical trial therapist staffing needs, amounting to up to 6,000 hours. ATMA's training program has equipped hundreds of therapists and healthcare practitioners for this role, offering a valuable chance for those interested in the psychedelic-assisted therapy field to gain more experience in this field as clinical trial staff facilitators and therapists.

CEO Vu Tran emphasizes the potential of the group protocol as a pivotal advancement for the psychedelic therapy industry, not only by enhancing accessibility, but also by validating the effectiveness of group healing practices rooted in non-Western and ancient cultures. He highlights the epidemic of loneliness as a contributing factor to the current mental health crisis and advocates for embracing group healing formats as a means of addressing this challenge.

ABOUT ATMA JOURNEY CENTERS INC.

We care about improving the lives and practices of mental healthcare professionals.

ATMA is pioneering a healthcare practitioner-centered business model for the psychedelic industry. By providing education, training, clinical trials leading to IP protocols, support services, and developing a network of clinics, we are building and supporting a vast community of psychedelic practitioners in adopting psychedelic-assisted therapy and thereby improving access for many.

View original content: https://www.prnewswire.com/news-releases/health-research-ethics-board-of-alberta-approves-atmas-phase-ii-psilocybin-clinical-trial-with-group-and-individual-therapy-settings-302151814.html

SOURCE ATMA Journey Centers Inc