In highly regulated industries such as medical devices, pharmaceuticals, biotechnology, and food safety, companies must constantly balance the demands of bringing new products to market quickly while also testing those products in a safe manner. Many of these products are tested on human subjects, and successful studies can improve human health while helping researchers learn more about diseases, human behavior, and learning patterns.
A mix of national regulations and international declarations offer numerous principles for human subjects research ethics. “The most important thing is to protect the people participating. It goes back to how vulnerable groups have been taken advantage of,” says Mary Dronitsky, a professor in the College of Professional Studies.
This article provides a closer look at three key documents that define the principles of human subjects research ethics—the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report—and offers a set of best practices for regulatory affairs professionals who manage the development, marketing approval, and utilization of highly regulated products.
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Principles of Human Subjects Research Ethics
National and international organizations have issued declarations on human subjects research ethics in response to medical experiments throughout history that were done on participants who did not consent to being treated, Dronitsky says. These include experiments on prisoners of war in German concentration camps in World War II, the Tuskegee Syphilis Study in the United States from 1932 to 1972, and various vaccine or pain study trials that took advantage of persons with mental disabilities or other underrepresented groups. The three major declarations each consist of several principles of research that act as scientific and moral guidelines for treating people who have agreed to be part of a research study.
Issued by the three judges who presided over the trials of German doctors conducting experiments in World War II, the Nuremberg Code consisted of 10 principles for research trials involving human subjects. First and foremost, the code declares that participant consent is “absolutely essential” and that participants are “at liberty” to bring the experiment to an end at any time.
Additional principles state that experiments must be conducted “for the good of society,” should not cause physical and mental injury to participants, and should not be more risky or dangerous than the problem they are trying to solve.
In a 50th anniversary retrospective, the New England Journal of Medicine noted that the Nuremberg Code has had a “profound” impact on human rights laws and medical ethics even though the code itself has never been adopted as law. For example, its guidelines on informed consent have been the basis for United Nations law and World Health Organization guidelines.
Declaration of Helsinki
Initially adopted by the World Medical Association in 1964 and amended several times since, the Declaration of Helsinki has influenced legislation and regulation worldwide. The document’s principles similarly state that the health of participants must be a physician’s “first consideration.” The document also states that it is the responsibility of healthcare professionals to protect research subjects, even though participants consent to participating.
The Declaration of Helsinki also calls for all research experiments to include a research protocol that indicates how principles of human subjects research ethics are being addressed, along with information about who is funding or otherwise sponsoring the research.
Written in 1978 in response to the Tuskegee study—in which 400 Black men with syphilis were neither informed of their diagnosis nor treated for the disease for decades—the Belmont Report provides guidance for the treatment of human subjects in research trials in the United States. The report builds on both the Nuremberg Code and the Declaration of Helsinki and consists of three key principles.
- Autonomy: This principle is based on the concept of informed consent, Dronitsky says. “When individuals are asked to participate in a clinical study, they need to be doing it voluntarily and should not face undue pressure. They must also be given sufficient information.”
- Beneficence: The risks of an experiment cannot outweigh the rewards. In addition, the risks and rewards should be clear enough that they can be interpreted by the general public, not just trial participants.
- Justice: The recruitment of volunteers must be impartial, all participants in an experiment must be treated fairly, and participants should not be exploited. “You need or provide full access to all individuals to have the opportunity to be in clinical trials—not just prisoners, those with mental disabilities, or the economically disadvantaged,” Dronitsky says.
Best Practices for Human Subjects Research Ethics
To adhere to these key principles for human subjects research ethics, organizations need to abide by rules established by the U.S. Food and Drug Administration (FDA) and regulatory agencies in any counties where a trial is taking place. A series of simple but critical best practices will help organizations ensure that a trial meets these requirements and can proceed without revisions or other delays.
1. Review consent forms.
Under FDA rules, a clinical trial that requires human subjects must have a consent form that is reviewed and approved by an Ethics Committee or Institutional Review Board (IRB). These rules also apply to physicians working in private practice, who are required to submit research proposals to a hospital, medical school, or local or state government agency. Ultimately, the IRB serves as a “check and balance” for the study, Dronitsky says, ensuring that the needs of the participants and the research teams are aligned.
FDA guidance for IRBs includes specific recommendations for obtaining informed consent, such as conducting informed consent interviews and informing participants of changes to the research study.
The FDA also provides compensation guidelines for trial participants, which the IRB must also review and accept. The agency suggests that payment should be “just and fair” without presenting undue influence that may coerce a participant to provide certain feedback, remain in a study when they would otherwise withdraw, or otherwise interfere with their ability to give voluntary, informed consent.
2. Review recruitment materials.
In the United States, the FDA also requires the IRB to look at the trial’s recruitment materials. “The IRB wants to make sure they are not unduly influencing patients or making promises that the drug will work,” Dronitsky says.
FDA guidance for recruiting human subjects stipulates that advertising material should not include terms such as “new treatment” or “new drug” without indicating that the treatment is experimental. In addition, recruitment material should not promise “free medical treatment” when the standard is not to charge participants to take part in a trial.
The recruitment material that’s reviewed should also include any information that’s given to the office personnel who first speak to potential trial participants, the FDA says. This material should help office personnel address the ways that personal, medical, and financial information are protected as well as take the necessary steps to protect that information.
3. Clearly define participant criteria.
One of the emerging trends in biotechnology is the personalized treatment of rare diseases, made possible through highly targeted treatment plans and therapies that are, in some cases, based on a patient’s genetic and molecular makeup.
These treatments are more effective than generic therapies, and the reduced cost of genetic sequencing has driven down the drug development cost. However, organizations may have difficulty finding participants who meet the very specific criteria for these clinical trials. This roadblock presents safety and ethical issues because organizations must avoid enrolling participants who do not qualify. Not only is the research’s validity in doubt, but the participants may be at a higher risk of an adverse reaction to the treatment, Dronitsky points out.
It’s often not enough to simply recruit patients who have the disease, she continues. Most research study protocols should have a set of inclusion and exclusion criteria that more specifically define and narrow the patient population that’s being recruited. These criteria can include a specific age range, other preexisting conditions, or other medications that someone is taking.
4. Monitor the trial’s progress.
As the experiment continues, investigators must monitor what’s happening to participants. The trial protocols that an IRB approves must include specific requirements for ongoing assessments. Trials that receive funding or other assistance from the National Institutes of Health are also subject to additional oversight, Dronitsky notes.
Assessments may vary depending on the nature of the trial. In a medical device trial, for example, trial organizers need to look at the data that a device generates. If numbers appear to be off, they must further investigate to see if the issue is with the way the device collects and reports data—as with a heart rate monitor in a smartwatch that’s worn incorrectly—or is indicative of a problem that requires medical attention.
In drug trials, meanwhile, the FDA offers guidance for adverse event reporting, which refers to unanticipated problems that arise in patients taking a drug. According to the FDA, certain adverse events must be reported to an IRB, while others do not—but all require investigators to intervene on behalf of a patient’s health and safety.
5. Consider additional expert help.
The sooner that a drug goes to market, the sooner that patients realize clinical benefits and companies enjoy financial benefits for their employees, investors, and shareholders. This can put pressure on investigators to complete a trial quickly, especially if other companies are developing similar drugs or devices.
To facilitate participant recruitment while still adhering to the principles of human subjects research ethics, some organizations opt to hire consultants who specialize in clinical trial recruitment, Dronitsky notes. These individuals can help investigators develop materials to bring in more potential participants—through the use of social media, for example—as well as a more diverse group of participants.
Prepare for a Future in Regulatory Affairs
Professionals in regulatory affairs roles must balance the historical precedents for human subjects research ethics with the reality of rapidly changing regulations in the United States and abroad.
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