Access to Treatment
Clinical trials held in LMIC often result in treatments that the host community cannot afford and often cannot access for decades, even though they assumed the burdens. Yet, these studies use local health conditions to learn how to improve public health. How can researchers bridge the gap between the end of the study until treatment becomes available to the host community? Better yet, how can we make the host community among the first to benefit?
Public Health
LMIC in Africa, Asia, and Latin America account for a very small percentage of clinical trials. Vaccine research, particularly, requires a population where the disease being investigated is being transmitted in order to establish the efficacy of the vaccine. Responses to the same treatment vary according to factors, including genetics, and Africa is the most genetically diverse continent in the world.
Undue Influence/Exploitation
LMIC communities might be more susceptible to undue influence and exploitation because their socioeconomic disadvantages (need for food and compensation, lack of access to health care) impede their ability to consent freely. Ethical studies focus on the health needs of the host community, so they must be well planned and regulated, and the benefits must be made available to the local community. The Declaration of Helsinki only justifies research in vulnerable communities when “the research is responsive to the health needs or priorities of this group, and the research cannot be carried out in a non-vulnerable group.”
Conflicts of Interest
Organizers with financial interests in their sponsoring companies may compromise their professional judgment, neglecting the participants’ welfare to increase their own profit. The health and well-being of clinical trial participants are the highest priority, and interests, like monetary gain, can compromise the validity of the research.
Placebos
The Declaration of Helsinki states that the use of a placebo, a dummy treatment, is acceptable where no proven intervention exists, or when compelling and scientifically sound methodological reasons make them necessary to determine the efficacy or safety of an intervention, and subjects who receive the placebo will not be subject to risk serious or irreversible harm. The 2000 Declaration of Helsinki update further limited the use of placebos in response to a study about mother-fetal transmission of HIV in LMIC, which denied active treatment to participants in the control group.
In 1997, Public Citizen, a nonprofit, nonpartisan consumer advocacy organization, drew attention to unethical clinical trials, particularly in LMIC. The majority of trials were funded by the U.S. government, and placebos were given to participants rather than researchers using the contemporary standard of care in the United States and other economically similar nations. Unethical research has devastating consequences.
In 1996, an infamously unethical clinical trial was held in Nigeria during a meningitis outbreak. Pfizer conducted a Trovan trial on children without their parents’ informed consent. Patients were unaware of the experiment, and the trial was not approved by an ethical review committee. Eleven of the children died, and others suffered brain damage and paralysis.
More recently, in India from 2011–2012, there was a vaccine study to prevent rotavirus, a common but potentially life-threatening viral infection in infants and young children. Despite the availability of two highly effective vaccines that prevent serious rotavirus infections, more than 2,000 children (one-third of study participants) received saltwater placebo injections. The saltwater was not the “best intervention”; there was no compelling scientific reason for placebo use, exposing subjects to risk of a potentially fatal infection; and there was an active treatment available to design a scientifically and ethically sound clinical trial. The use of placebo injections violated international ethical guidelines.
A placebo control group would never have been permitted in the United States, and it should not have been permitted in India. Because of this double standard, Drs. Sidney Wolfe and Peter Lurie argued for a single international ethical standard. Their concern centered around the potential exploitation of communities in LMIC, a majority being people of color. Researchers used substandard care on participants, justifying their decision by citing the “standard of care available” to impoverished host communities as their benchmark.
The Standard of Care Debate
There is a great inequality gap in health care around the world. LMIC communities struggle with access to clean water, badly needed vaccines, and effective medications, unlike their wealthier counterparts where clean water and health care are abundant. The disparities in their living conditions leave LMIC with lower life expectancies and a heavier burden of disease. This drives the debate about which standard of care researchers should apply in clinical trials abroad.
“Best Methods Available”
Harriet Washington, a medical ethicist at Columbia University, says, “In many of these [LMIC], the standard of care is nothing. So it effectively means that trials that would not be permitted here or that at least would undergo a greater ethical furor here can be legally conducted in the developing world.” In other words, it is an abdication of duty to provide a community with the standard of care available to them when that standard might be “nothing.”
The consensus among ethicists is that IRBs should default to the “worldwide best methods” standard. Some believe there should be exceptions for studies where (1) it is a scientific necessity, (2) it is relevant to the local community, (3) there is a sufficient health benefit to the local community, and (4) there is nonmaleficence; the community will not be made worse by it.
“Standard of Care Available”
On the contrary, the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) regulation is far more lenient than the Declaration of Helsinki. The required standard of care it applies to the control group depends on the population in the study. That is, control group subjects are only entitled to the standard of care they would otherwise receive locally. If a host community has no access to a particular level of care, the researcher is under no obligation to provide them that care.
Should There Be Clinical Trials in LMIC?
Unethical studies create a dangerous mistrust in public health systems and made the fight to eradicate polio extremely difficult. Today, we are witnessing the same problem in efforts to combat COVID-19.
The African continent, 3.7 percent times the population of the United States, suffered one-fifth the number of COVID-19 fatalities. Good leadership and sound prevention practices were successful. However, Cameroon and Nigeria, countries with good-quality research capabilities, did not participate in vaccine trials, despite past successes in Africa for conjugate meningitis and Ebola vaccine trials. In fact, the African Vaccine Regulatory Forum requires a short (fewer than 60-day) clinical trial approval benchmark. These are valuable opportunities to progress where vaccines need to be tested for safety and efficacy on populations that suffer the diseases. Clinical trials are needed where the newer, more infectious variant of COVID-19 is spreading in South Africa.
Without rigorous information on how vaccines work among African populations in African settings—often with higher rates of comorbidities such as HIV and tuberculosis, conditions favoring more rapid transmission, and more constrained health systems than dominant testing sites—African leaders will be left ill-equipped to make informed decisions on vaccine rollout strategies. When ethical guidelines are followed, along with scientific best practices, LMIC can benefit from local research.
Conclusion
Health justice requires that all participants in clinical trials benefit equally, host community location notwithstanding. One approach is to strengthen ethical guidelines. Another puts the onus on academic institutions, urging them to stress the importance of equitable principles in research. Still, a third way might better protect vulnerable participants from exploitation when wealthy nations conduct their studies in LMIC.
Bioethicist Washington proposes patent law reform to help LMIC that pay high prices for medical treatment they helped develop. Human subjects took risks, and local health care workers conducted the studies, cheaper and more expeditiously than would have been possible in the West. Dr. Washington states, “To me, that means that we’re in their debt.”
Clinical trials are essential to medical advancement. Without them, we would not have eradicated smallpox or have commenced a return to pre-COVID life. Scrupulous researchers rely on individuals willing to bear personal risk for society’s greater good. Self-interested researchers prey on vulnerable populations while flouting best practices. Existing ethical standards must be followed and enforced to achieve health justice, but additional measures will bring us closer to the goal, and all possible steps to protect human subjects must be taken.