Who should protect the rights safety and well being of subjects in clinical trials?

Clinical Researcher—December 2018 (Volume 32, Issue 10)


Maribelle Guloy, MSHS, CCRP

Academic institutions have, on occasion, been found to be in gross violation of the norms for ethical conduct of clinical research by subjecting human volunteers to experiments involving untoward risks to their safety and lives. Similarly, pharmaceutical companies have sometimes demonstrated a lack of ethical sensitivity when pursuing clinical trials in resource-poor countries. Together, these historical events suggest that clinical research should be conducted based on careful and sensitive practices following the ethical principles and regulations highlighted in the following sections.

Part I: Ethics and Federal Regulations

Basic Principles of the Belmont Report

Since its release in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, the U.S. government’s volume on “Ethical Principles and Guidelines for the Protection of Human Subjects of Research” (otherwise known as the Belmont Report) has outlined the guiding principles for the treatment of volunteers in clinical research.{1} It is the cornerstone statement of ethical principles, such as “respect for persons,” “beneficence,” and “justice,” upon which the federal regulations for the protections of subjects are based.

The principle of respect for persons requires that each person has the right to autonomy and that those with diminished autonomy should be protected. Therefore, the ethical guidelines must be clear about providing extensive protection to individuals who cannot self-determine.

A requirement of the principle of beneficence is that clinical research should be conducted with the safety of the human subjects as the primary interest.

A mandate of the principle of justice is that research involving human subjects needs to demonstrate fairness. Fairness means that individuals participating in clinical research are likely to benefit from the results or the applications of the research.

These ethical principles are fundamental for understanding the cross-cultural applicability in the era of globalization of research.{2} An issue for the global community, particularly in the low-income countries, would be the acceptability of the ethical principles developed in regions of the world with different standards of healthcare.

The Common Rule

Applicable federal regulations concerning clinical research have been derived from the ethical principles described in the Belmont Report. The regulations governing human subject research collected in the “Federal Policy for the Protection of Human Subjects” (otherwise known as the Common Rule) by the U.S. Department of Health and Human Services{3} apply to studies supported by federal agencies. These regulations establish the main protective mechanisms for safeguarding the rights and welfare of human research subjects.{4}

Review by an Institutional Review Board

Clinical research institutions are required to protect the rights, safety, and welfare of the research participants under the authority of the U.S. Food and Drug Administration (FDA).{5} An institutional review board (IRB) operating in compliance with federal regulations for human subject protection must be in place.{6} Subject to the FDA’s IRB regulations, IRBs conduct ethical, administrative, and scientific peer reviews of FDA-regulated products.{7}


The ethics of clinical research and federal regulations have evolved over the past 60-plus years. As the cornerstone of ethical principles, the Belmont Report should remain relevant today. Compliance with these ethical principles and federal regulations provides assurance that the rights, safety, and welfare of research participants are protected.

Part II: Review of Literature

Nature of the Problem

Society’s perception of research involving human subjects is shaped by the way this research is conducted by the pharmaceutical and medical device industry, clinical research organizations, medical and academic institutions, investigators, and other clinical research professionals.

Since very early in the history of medical research, violations of the rights of human subjects have been documented.{8} For example, a long-term U.S. study of untreated syphilis in the Black male population was conducted by the government without informed consent or a certainty of treatment; disabled elderly patients who were not capable of giving consent to a study at the Brooklyn Jewish Chronic Disease Hospital were injected with live cancer cells; and mentally retarded children at the Willowbrook State School in Staten Island, N.Y. were deliberately infected with hepatitis C virus.

Beyond the pillars of ethical conduct of clinical research lies the responsibility of researchers at academic medical centers and in the pharmaceutical and medical device industry to design and conduct clinical trials with consideration for the protection of human subjects. Additional ethical principles should be applied for clinical trials conducted outside the United States—particularly in resource-poor settings.

Part III: Principles of Ethical Clinical Research Conduct

Social and Clinical Value

The fundamental principle of clinical research resides in the value the study has for society.{9} However, there is ambiguity in defining social value and who decides the constitution of social value with respect to research involving human subjects. Clinical research cannot ensue without the participation of human volunteers who submit to medical experimentations, which may involve risks to their safety and lives.{1}

Nevertheless, in late-phase trials, the potential for benefit to future patients as well as the generalizable knowledge produced in the experimentation can be anticipated. Clinical research ethicists argue that the anticipated clinical value of the intervention justifies the risks involved in the experimentation. Further, they posit that social value resides in the knowledge accrued as part of the experimentation and the anticipated clinical value to future patients.{9} While clinical research offers no promise of direct therapeutic benefit to the participants, the experimentation should be justified in relation to social and clinical value.{10}

Scientific Validity

Clinical research must be designed in conformity with valid scientific principles to produce relevant results.{11} Fair subject selection is also required to ensure that the efficacy and adverse effects of the intervention are being tested in the general population, rather than a subset of the population.{12} The research question, study design, methodology, and statistical plan must be carefully considered with respect to scientific validity and relevance.{13} A systematic evaluation of the different aspects of clinical research should be ascertained by the scientific, local research, or independent ethics committees before the launching of any clinical research conduct.{5}

Fair Subject Selection

Ethical research involves promoting respect for all human beings and protecting their rights and welfare. Subject selection should be done on the basis of scientific importance, not on convenience, vulnerability, or bias.{14} Vulnerable individuals, whose decisional capacity might be limited or restrained based on impaired cognitive skills, unfavorable social, or economic condition, should not be targeted for research participation.{8} Therefore, only those prospective human subjects who meet the research criteria and voluntarily submit for participation should have an equal chance for selection to participate in the study.{11}

Informed Consent

Informed consent is one of the most important aspects of clinical research ethics. The requirement of an informed consent is designed to protect the rights of human subjects, and such rights should be treated above and beyond the interests of science.{14} Autonomy is an essential element of the consent process to ensure human subject protection; it refers to the subject having autonomy of thought, intention, and action when making decisions about participating in clinical research.

The study information disclosure should be aimed at enabling the subject to understand the clinical research process, the risks and benefits associated with clinical research procedures and the intervention, and the likelihood of success. Under the federal regulations, approval by a competent ethics committee or IRB of an informed consent is necessary before it can be executed in clinical research.{5}

Part IV: Important Concepts and Issues

Minimal Risk

The term “risk” in the human subject protection regulations refers to minimal risks—defined as being such that the probability of harm or injury, such as physical, psychological, social, or economic, occurring from research participation is not greater than that for a person involved in the context of going about their ordinary life or undergoing routine medical tests.{15} Following established professional and scientific standards, IRBs should adopt procedures to avoid the possibility of applying subjectivity leading to overestimation or underestimation of harm.{14}

Undue Influence, Coercion, and Exploitation

Payment to research subjects may be construed as undue influence if it constitutes an amount sufficient to induce an individual who would otherwise not participate in a clinical research study.{12} It raises ethical concerns when it influences individuals by distorting their perception of risks and benefits.{11}

Coercion is best exemplified in the exploitation of prisoners in clinical research because the incarcerated may be at greater risk for true coercion.{16} Additionally, the prison can be a convenient place to conduct research because of easy accessibility to research participants and the convenience of doing research in a controlled environment. Nevertheless, others view the exclusion of prisoners from clinical research equally unjust, particularly if the research study can improve the care of prisoners.{17}

Prisoners should not be excluded from research participation in the guise of human subject protection, but this view should not be interpreted without following the ethical rules and regulatory guidelines for medical research.{16} In the absence of coercion or undue influence, and if the risk-benefit ratio is justifiable, it may seem unjust to exclude prisoners from an opportunity for improved care. Nevertheless, given the wide range of prisoner abuses in the past, it is critical that the clinical research community should exercise greater care in any research conducted in settings involving incarceration.{17}

Data Integrity

The data lifecycle covers the period from data acquisition to interpretation, reporting, and archiving. Any violation of data integrity brings harmful effects, as it could pave a way for deadly treatments to reach the market, and manifestations of the problem range from falsification and fraud to poor data management.

History is rife with disaster stories related to poor data tracking after an investigational treatment has been dispensed.{18} However, these events led to the development of research regulations and changes in the drug evaluation process. As per Good Clinical Practice guidelines, validation should be conducted to ensure data completeness, accuracy, reliability, and consistency.{19} Professionals in the industry responsible for data reporting and evaluation must ensure that the data are sufficient, valid, and of highest quality.

Conflict of Interest

Investigators with financial interests in companies sponsoring their clinical research studies could create a condition in which their professional judgment may be impaired, favoring their financial interests over the welfare of their patients.{20} As per regulatory guidelines and ethical research, professional judgment regarding the welfare of patients or the validity of research should not be influenced by a secondary interest, such as financial gain.

Scientific interests may also create a condition for conflict. Reported cases of conflict of interest continue to exist, and underscore the need for more ethical oversight to promote transparency and accountability in clinical research.{8} The research community must be vigilant to prevent any potential conflict of interest from arising, and research institutions should create effective and ethical conflict of interest policies to safeguard research quality and trust.{21}

Part V: Special Ethical Concerns in Clinical Research

 Research in Resource-Poor Settings

When western pharmaceutical and biotechnology companies conduct research in resource-poor countries, questions arise about which research practice standards should govern the studies.{22} Economic conditions and local cultural traits can influence how these standards are applied.

A critical issue, mainly for low- and middle-income countries (LMICs), is the potential for exploitation. The majority of the population in an LMIC will not have the same resources as those from western countries in terms of health access and affordability.

Clinical research may offer human subjects some benefits of short-term access to care. It may also help build the infrastructure for healthcare and increase research and healthcare capacity. Nevertheless, a requirement of research in LMICs is that it must address the aforementioned questions about rights or justice.

Western pharmaceutical and biotechnology companies should think about whether healthcare economic goals alone constitute suitable reasons to conduct research in an LMIC.{22} To avoid exploitation of an LMIC’s population, the research should be relevant to the health needs of the country, better care should be provided, and responsibilities owed to human subjects should be considered.

Another critical issue in conducting clinical research in LMICs is the validity of the consent process.{23} While western standards promote autonomy, some foreign countries view consent as a collective decision-making process.{24} In LMICs in which a subset of the population may be illiterate, or when a tribal chief or elder is traditionally involved in making medical or research decisions, voluntary and fully informed consent may be an issue.

Simply put, the issues surrounding the conduct of clinical research in LMICs can be difficult and challenging, in terms of understanding and knowing which monitoring standards and ethical guidelines to enforce.{22}

The Use of Placebo

There are compelling reasons for the use of placebo in clinical trials, and one notable scenario is when there is no effective treatment available for the condition being studied.{25} The use of placebo is permitted by ethical guidelines when no effective treatment exists, when withholding treatment poses risks, or when compelling methodological reasons are allowed for the use of placebo.{26}

Nevertheless, from an ethics and science standpoint, many consider placebo as contrary to the interests of the subjects, and therefore, not ethical. That view is justified by the argument that when effective treatment exists, the use of placebo is unacceptable.{23}

The relevant question for many is not whether the investigational drug is better than placebo, but whether it is better than standard treatment. Viewed in this light, active treatment controls are because no subject goes without treatment. However, the use of placebo is permissible and ethically acceptable, as it allows researchers to determine whether the effects of a test drug are real or a result of the placebo effect.{25}


Revisiting ethics in clinical research serves to remind the research community about the ethical violations that have occurred in the past. It also serves to enforce the ethical principles and regulatory guidelines that have evolved to protect the rights and safety of human subjects.

Knowledge of the ethical and regulatory aspects of clinical research is essential for all clinical research professionals. Biomedical researchers and other research professionals in the academic community and in the pharmaceutical and device industry have the responsibility to design and conduct clinical trials—in any setting—that make consideration for the protection of human subjects a paramount concern.


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Maribelle Guloy, MSHS, CCRP, () is Director of Clinical Operations at HBT Labs, Inc. in Brea, Calif. This article is based on work she did as part of her doctoral program requirements while studying at Nova Southeastern University, from which she will receive her Doctor of Health Science degree with a concentration in global health in early 2019.

Who should protect the rights safety and well

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC): ICH E6 (R2) Good clinical practice. 3.1. 1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects.

Who is responsible for ensuring the safety and rights of study participants?

Principal Investigator (PI) The Principal Investigator has the primary responsibility for ensuring the ethical conduct of the research study. This includes protecting human subjects' rights, safety and welfare, protocol compliance, and adherence to institutional, state and federal regulations and guidance.

What organization is in place to protect human subjects during a clinical trial?

Protecting the rights, safety and welfare of people who participate in clinical trials is a critical aspect of the FDA's mission. FDA oversees clinical trials to ensure they are designed, conducted, analyzed and reported according to federal law and good clinical practice (GCP) regulations.

Who is responsible for the appropriate monitoring of clinical trials?

Safety monitoring of a clinical trial is conducted by an independent physician with relevant expertise. This is accomplished by review of adverse event, immediately after they occur, with timely follow-up through resolution.