Clinical research plays a critical role in health care delivery. It’s through clinical research that scientists develop new treatments, cures and preventive measures that help mediate the spread of disease. What’s more, clinical research ensures that, as these treatments are brought to market, they have been proven safe and effective, with any potential side effects disclosed.
The clinical research process is marked not only by scientific rigor but also by a commitment to ethical standards. The current COVID-19 crisis underscores this point: While clinical researchers are aware of the sense of urgency regarding the need for treatments and vaccines, they feel obliged to follow ethical protocols, ensuring their data is accurate and transparent and that any treatments are properly tested before they are brought to market.
This article provides a background to understanding the role and importance of ethics in clinical research, as well as examples of current ethical concerns and issues in the field.
What Is Clinical Research?
The National Institutes of Health (NIH) define clinical research as medical research that tests new treatments and therapies on people. The agency defines clinical trials as research studies that assign one or more interventions to human subjects to determine the effect of the interventions on health-related outcomes, both biomedical and behavioral.
The Goals of Clinical Research
The ultimate goal of clinical research is to increase medical knowledge and improve patient care. For the conclusions resulting from clinical research to be valid and applicable, the research must be conducted deliberately via systematic investigation and data collection.
The U.S. Food and Drug Administration (FDA) describes the various types of clinical research, which include the following:
- Treatment research typically studies new medicines, psychotherapy approaches, medical devices, surgical and therapeutic techniques, and other intervention innovations.
- Prevention research focuses on ways to stop the development or return of diseases via medicine, vitamins, vaccines and lifestyle changes.
- Diagnostic research looks for effective techniques to identify disorders and provide doctors and clinicians with prediction rules for spotting the diseases in patients.
- Genetic studies examine the link between genes and disease with the goal of improving disease prediction and estimating the chances of an individual contracting a specific disease.
- Epidemiological studies are intended to spot patterns, causes and ways to control diseases in certain populations by identifying risk factors and protective factors for those diseases.
- Clinical studies are also referred to as observational studies, as the NIH’s National Institute on Aging explains. Clinical studies observe people in normal settings to group volunteers by characteristic and note changes over time. The results of these studies often lead to potential new clinical trials.
Four Phases of Clinical Trials
Clinical trials are distinguished from general clinical research by their focus on the effectiveness, safety and suitability of specific treatment approaches. The two basic approaches that fall under the umbrella of clinical research are observational studies and clinical trials, as the NIH’s ClinicalTrials.gov explains:
- Observational studies evaluate the outcomes of participants based on a specific research plan. Subjects of the studies are not assigned specific interventions as they would be in a clinical trial, but they may receive some treatment as part of their standard medical care..
- Clinical trials are studies in which volunteers receive a specific intervention to evaluate the safety and effectiveness of a new medicine, surgical procedure or behavior. Researchers measure specific outcomes in the trial participants in an attempt to determine whether the intervention is helpful, harmful, no better than existing treatments or no better than no treatment at all.
Typically, clinical trials proceed through four distinct phases, as the FDA describes:
- Phase I. Researchers seek the correct dosing of a new drug or treatment and look to minimize side effects.
- Phase II. With dosing fine-tuned, researchers look to further assess safety implications.
- Phase III. Researchers compare the new treatment to old/dated treatments, ensuring the new method represents an improvement in patient outcomes.
- Phase IV. New treatments are approved by the Food and Drug Administration (FDA) for testing on hundreds or potentially thousands of patients, before finally being approved to enter the market.
To learn more about clinical research, consider these sources:
- American Society of Clinical Oncology, Clinical Trial Resources. Find resources and information on conducting and managing clinical trials.
- Food and Drug Administration, Clinical Research versus Medical Treatment. Learn more about the distinctions between clinical research and medical intervention.
- National Institutes of Health (NIH), Clinical Research Resources. View a full list of resources and guides related to clinical research.
Importance of Ethics in Clinical Research
Ethics in clinical research are emphasized for several reasons. Not only do ethical strategies ensure the integrity of the research results, they also protect the safety of patients who volunteer to participate in the trials. And ethical parameters help prevent participants from being exploited or treated unfairly by the research team.
Government regulations require that all proposed clinical trials be approved by an institutional review board to ensure that the trials are ethical and that the rights of participants will be protected, as the Hastings Center, a bioethics research institute, explains. A major ethical concern related to clinical trials is whether participants are fully informed about the risks entailed in the trials and the likelihood that they will not personally benefit from the research.
Codes of Ethics
Several formal documents and ethical frameworks provide moral guidance for clinical researchers. A few of the most prominent examples include the following:
- The Belmont Report codifies basic ethical principles that underscore biomedical research. This document was created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.
- The Declaration of Helsinki is an international agreement put forward by the World Medical Association and amended many times over the years to address new ethical concerns.
- The Nuremberg Code was ratified following World War II, in response to the abusive and exploitative clinical trials undertaken by Nazi scientists. It provides an international standard for clinical research ethics.
- The U.S. Common Rule ratifies key protections for the patients who participate in clinical trials.
In addition to these ethical codes, some core principles guide the work of clinical researchers. Noteworthy examples include the following:
- Ensuring that testing is scrupulous and fully compliant with stated clinical protocols
- Verifying the scientific validity of the results
- Choosing clinical trial participants in a way that is fair and free of prejudice
- Fully informing all volunteers about what the trial involves and potential risks before they offer their consent
For additional insight into the importance of ethics in clinical research, consider these resources:
- S. Food and Drug Administration, Clinical Trials and Human Subject Protection. Learn more about protocols for protecting human participants in clinical trials.
- World Health Organization (WHO), Ethics and Health. Consider the WHO’s guidelines for ethics in medical experimentation.
Examples of Unethical Behaviors in Clinical Research
Sadly, many of the ethical guidelines and codes of conduct in place today arose as a response to abusive, negligent or immoral medical experimentation. Here are a few examples of past clinical trials that were conducted without any ethical guardrails in place.
As part of the Manhattan Project, government researchers sought a greater understanding of the effects of plutonium on the human body. To gain insight, they arranged a study in which dozens of individuals from across the country received plutonium injections. However, documentation from that period reveals that the test subjects were likely not given explicit information about the potential risks. Additionally, the process that was used for selecting subjects remains unclear.
Many of these patients were administered plutonium doses that exceeded existing guidelines and suffered long-term health complications as a result. These “plutonium trials” led to reforms in the government’s clinical research policies, including a new emphasis on informed consent.
Tuskegee Syphilis Study
In 1932, 600 Black men were recruited by the Tuskegee Institute to participate in a new study on the transmission of syphilis. However, researchers misled the men about the nature of the treatments they were receiving; thus, these patients offered consent under deceptive circumstances.
In 1972, the nature of this study came to light and resulted in a public outcry, as well as a renewed government inquiry. According to a report from the Centers for Disease Control and Prevention (CDC), a government panel found that although the men agreed to participate, “there was no evidence that researchers had informed them of the study or its real purpose. In fact, the men had been misled and had not been given all the facts required to provide informed consent.”
The implications of the Tuskegee trials extended for years to come, resulting in the formation of a President’s Council on Bioethics in 2001.
Willowbrook Hepatitis Experiments
At the Willowbrook State School in New York, an institution for children with intellectual disabilities, hepatitis outbreaks were common during the 1950s. Researchers at the school conducted medical experiments on their students, including one experiment in which a live hepatitis virus was fed to 60 healthy students.
Public opposition caused the studies to be discontinued, and they remain a touchstone for the importance of medical ethics, particularly concerning the treatment of children and the mentally disabled.
Starting in 1953, the Central Intelligence Agency began a series of studies known as MKULTRA, in which they attempted to exert “mind control” over human subjects. Both American and Canadian citizens were used as subjects without their authorization or informed consent. As such, the program was shut down, and the results ultimately were deemed invalid.
Ethical Concerns of Clinical Research
Though these abuses may feel like they exist only in a distant past, important ethical issues confront clinical researchers even today. To curb such abuses, federal regulations mandate that any research conducted with a human participant be reviewed and approved by an institutional review board (IRB) beforehand and periodically throughout the research. The committee members may include physician-researchers, statisticians and community advocates.
Apart from a handful of exceptions, all research subjects must give their informed consent to participate, including disclosure of information about the study’s processes and goals. However, the area of informed consent is the source of much conflict and debate among medical research organizations according to the Hastings Center .
The FDA’s criteria for research approval states that research involving vulnerable populations must consider the unique characteristics of those groups and the impact their research may have as a result of these attributes of that population. Vulnerable populations include children, prisoners, pregnant women, physically and mentally disabled people and economically or educationally disadvantaged people.
An excerpt from the book “Clinical Trials in Vulnerable Populations” published by IntechOpen discusses the challenges clinical researchers face when conducting trials and other work that involves vulnerable populations:
- While it is important that women and all other segments of the population be represented in clinical research, care must be taken when tests involve women who are pregnant or breastfeeding to ensure no harm comes to their child.
- When conducting research on children, scientists must be sure they have the child’s informed consent to participate even though the child is legally considered incompetent to assent on their own. The consent of the child’s parents or legal guardians must be obtained.
- Clinical research that involves patients who have an incurable disease must make sure the patient isn’t consenting because of any false assumptions of benefiting personally from the research.
- The journal Therapeutic Innovation & Regulatory Science reports that in some developing countries, the financial incentive to participate in several trials serially or simultaneously endangers healthy volunteers. Research indicates that a high percentage of these volunteers withhold critical information so that they will qualify to participate in a paid research study.
Resources discussing the fair treatment of vulnerable populations who take part in clinical research include the following:
- AMA Journal of Ethics, “Using OCAP and IQ as Frameworks to Address a History of Trauma in Indigenous Health Research”. Learn about the principles of ownership, control, access, and possession (OCAP) and Inuit Qaujimajatuqangit (IQ) to create “culturally safe and responsible” guidelines for conducting research that involves indigenous populations.
- Frontiers in Pharmacology, “Factors Contributing to Exacerbating Vulnerabilities in Global Clinical Trials”. Find out about the characteristics that clinical researchers look for to identify potentially vulnerable populations when choosing test subjects.
Another ethical consideration for researchers is how much they should pay their participants. Many programs compensate volunteers only for their out-of-pocket expenses, but some patient advocates believe compensation should go above and beyond that, actually incentivizing participation in clinical trials.
Ethical concerns relating to paying clinical research participants center on the undue influence and coercive effect of offering money in exchange for accepting the risk of contracting a disease or otherwise being harmed by the research process. BMC Medical Ethics cites the example of research conducted in Malawi that paid participants US$10 per study visit. The lack of guidelines for establishing fair compensation brought into question the ethics of the pharmaceutical firms who funded the study and stood to profit greatly from the products being tested.
For more information on guidelines for payment to research study participants, check out these resources:
- Food and Drug Administration, Payment and Reimbursement to Research Subjects. Consult FDA guidelines for clinical research reimbursement.
- S. Department of Health and Human Services, Attachment A: Charging Subjects for Clinical Trial Participation. Read recommendations from the Health and Human Services’ Secretary’s Advisory Committee on Human Research Protections (SACHRP) on pay-to-play clinical trials.
Patient recruitment is usually the most time-consuming aspect of clinical trials. Researchers are always seeking more efficient ways of finding volunteers, without compromising clinical quality. However, an entire industry has been created to help researchers recruit patients to participate in their studies. For example, the company Antidote is one of 15 clinical trial recruitment firms that are in the business of connecting medical researchers with patients who are candidates for specific clinical trials.
Researchers may compete for patients who meet the criteria for their proposed trials, as explained in Contemporary Clinical Trials Communication. The interests and wellbeing of patients must come before any other research considerations, including the need to inform patients of all their options as well as all risks and benefits.
Further insight on the ethical aspects of patient recruitment is available here:
- National Institutes of Health, Patient Recruitment. Find out more about the ethical considerations of patient recruitment.
- Contemporary Clinical Trials Communications, “Ethical Issues in Competing Clinical Trials.” Take a look at some of the complexities associated with completing research trials.
Current Ethical Issues in Clinical Research
Salient issues in current clinical research include COVID-19 vaccine trials, stem cell research and human gene editing.
COVID-19 Vaccine Trials
The urgency of finding a COVID-19 vaccine has led to many questions about how to conduct trials in a way that is expedient but also fair, safe and clinically sound. Topping the list of ethical concerns for many researchers is the risk involved in infecting volunteers with the coronavirus as a way to test potential vaccines, as The Conversation reports.
So-called “human challenge studies” are intended to speed up the development and testing of a COVID-19 vaccine by allowing researchers to monitor the progress of the virus from pre-infection to recovery. An advisory group established by the World Health Organization devised eight ethical criteria for the human challenge studies involving COVID-19. Among these are the requirement to consult and engage with the public before, during and after the trials, and to have experts conduct an independent review of the results to determine whether the candidate vaccine’s benefits outweigh its risks.
More information can be found in these resources:
- Science, “Ethics of Controlled Human Infection to Address COVID-19.” Look at some of the ethical issues that have been raised regarding COVID-19 trials.
- World Health Organization, “Ethical Standards for Research During Public Health Emergencies: Distilling Existing Guidance to Support COVID-19 R&D.” Find out more about the implications of ethical guidelines for COVID-19 trials.
Stem Cell Research
Stem cells are able to maintain, replenish and repair all types of tissue, as the journal Nature describes. While human stem cells have proven their therapeutic value, a number of ethical considerations remain about how they can be harvested, particularly from human embryos.
Other ethical concerns related to use of stem cells in clinical research include maintaining the anonymity of human tissue donors, ownership of the tissue itself, long-term storage of the samples and manipulation of genetic material to create novel organisms. For example, recent research has led to the development of gastruloids that may ultimately achieve parity with human embryos, which would require amending current regulations limiting research on human embryos to the first 14 days after fertilization.
To learn more about these ethical considerations, check out these resources:
- International Journal of Medical Sciences, “Ethical and Safety Issues of Stem Cell-Based Therapy.” Read about the ethical challenges of embryonic stem cell research and other issues.
- Science, “Emerging Stem Cell Ethics.” Find out more about the ethical considerations surrounding stem cell treatments.
Human Gene Editing
The development of the CRISPR tool (clustered regularly interspaced short palindromic repeats) for editing the human genome opens up the possibility to edit human embryos, as explained in the Mayo Clinic Proceedings. The announcement in 2018 that Chinese researchers had used CRISPR to change the genome of twin embryos to prevent an HIV infection caused great consternation among the research community.
The biomedical research community faces the daunting task of establishing regulatory and ethical standards that apply to researchers worldwide. This is seen as the only way to prevent patients from distrusting a treatment tool that shows great promise in alleviating disease when used with appropriate industry guidelines. These sources offer more information on the ethics of human gene editing:
- Journal of General Family Medicine, Ethical Considerations of Gene Editing and Gene Selection. Find out more about gene editing techniques and the ethical questions they give rise to.
- Nature, CRISPR Babies Are Still Too Risky, Says Influential Panel. Researchers release their recommendations for safe and ethical use of gene editing of human embryos.
Ethical Considerations Are Crucial in Clinical Research
Ethical concerns continue to be paramount in shaping the procedures for clinical research in a way that protects patients while still advancing the public interest. Ongoing attention to these ethical concerns is vital to ensure that clinical trials remain valid, effective and moral.