The Ethical Paradox of Clinical Trials

If you have ever conducted research involving human subjects, you’ll know how extensive the institutional review board (IRB) application process is. Rightfully so—we would never want to harm a person or community in the name of research. However, through my years of conducting global health research, I have encountered projects that intentionally ignored the boundaries of ethics. Notably, these projects were designed by high-income countries (HICs) to test interventions and medications in low- and middle-income countries (LMICs).

Over the past decade, clinical researchers and sponsors in the Global North have developed a growing interest in conducting clinical trials in resource-limited settings (1). In a recent Annals study, Awan and colleagues (2) investigated the proportion of patients recruited from LMICs for pivotal trials of drugs approved by the U.S. Food and Drug Administration (FDA). They reviewed 144 trials and 66 new drugs to treat cancer, neurologic conditions, and cardiovascular diseases (2). They found that among the clinical trials, 56% for cancer drugs, 79% for cardiovascular drugs, and 56% for neurology drugs recruited participants from LMICs (2).

Several incentives drive this heavy dependence on LMICs: lowered personnel costs (3, 4), simplified participant recruitment processes (5), and the convenience of implementing placebo-controlled trials (6) that produce less ambiguous data—which can reduce the time it takes for the FDA to approve a new drug. It can often be beneficial for people living in resource-limited areas to participate in these trials because they can gain access to medical care they might otherwise be unable to afford.

At first glance, it seems mutualistic: Researchers receive the data they want, and in exchange, participants receive the medications they need. It is undoubtedly commendable when clinical trials address locally relevant diseases by delivering drugs and providing care to the local community. After all, some trials represent the only option for medical treatment for patients in resource-limited settings (3). Nevertheless, taking advantage of a population’s destitution by exposing them to the risks of health research is exploitative.

I came across a commentary in The Lancet Regional Health – Americas criticizing the use of substandard versions of trial groups in LMICs (7)—a study design one should immediately recognize as inherently immoral. As it turns out, investigators from the Global North frequently conduct clinical cancer trials in which an inferior control group is used in an LMIC setting (7).

If this is the case, how could countless IRBs from the Global North—and the Global South—give the green light to something so unethical? The short answer is it depends on who you ask. For example, the Declaration of Helsinki states that control groups in randomized controlled trials should receive the “best proven intervention,” not the standard of care in the local research setting (8). Thus, if we were to ask the study participants, clinical researchers, and governing bodies in LMICs what they thought of the trials, they would measure intervention qualities in relation to the available treatments they have—not in relation to the standard of care of an HIC. Thus, they wouldn’t see anything wrong with the research design. But just because the standard of care in a country is less developed, it doesn’t mean that we get to treat the humans there any less.

Even with identical trial groups, we would still face the issue of whether study participants will continue to have access to treatment. Many research teams offer a reasonable compromise of making the medicine available to study participants after the trial has ended. The Declaration of Helsinki even highlights that researchers should endeavor to secure posttrial access to effective interventions for all of the participants in a trial who could benefit (8). However, since drug research is mainly sponsored by big pharma companies (9), the researchers can guarantee neither that the drug will be made available at an affordable price nor that this drug will be more effective than treatments already on the LMIC markets.

By promoting exploitative trials that take advantage of strained health systems in low-resource settings, we are perpetuating the inequities that exist in global health. The responsibility to change this power dynamic lies with us, the global research community. I implore international clinical researchers, ethics committees, and governing authorities to give more consideration to the privileges and positionalities they hold. We can start by asking ourselves, “Will this research put anyone at a disadvantage?”

References 

1. Rubagumya F, Hopman WM, Gyawali B, et al. Participation of lower and upper middle-income countries in clinical trials led by high-income countries. JAMA Netw Open. 2022;5:e2227252. [PMID: 35980637] doi:10.1001/jamanetworkopen.2022.27252
   
2. Awan FA, Becker AB, Wang Y, et al. Participant recruitment from low- and middle-income countries for pivotal trials of drugs approved by the U.S. Food and Drug Administration. A cross-sectional analysis. Ann Intern Med. 2022;175:1675-1684. [PMID: 36410007] doi:10.7326/M22-1857
   
3. Grover S, Xu M, Jhingran A, et al. Clinical trials in low and middle-income countries — successes and challenges. Gynecol Oncol Rep. 2017;19:5-9. [PMID: 28004030] doi:10.1016/j.gore.2016.11.007
   
4. Jalali R, Nogueira-Rodrigues A, Das A, et al. Drug development in low- and middle-income countries: opportunity or exploitation? Am Soc Clin Oncol Educ Book. 2022;42:1-8. [PMID: 35658520] doi:10.1200/EDBK_10033
   
5. Weigmann K. The ethics of global clinical trials: in developing countries, participation in clinical trials is sometimes the only way to access medical treatment. What should be done to avoid exploitation of disadvantaged populations? [Letter]. EMBO Rep. 2015;16:566-70. [PMID: 25851646] doi:10.15252/embr.201540398
   
6. Gupta U, Verma M. Placebo in clinical trials. Perspect Clin Res. 2013;4:49-52. [PMID: 23533982] doi:10.4103/2229-3485.106383
   
7. Gyawali B, Carson LM, Berry S, et al. Challenges of globalization of cancer drug trials- recruitment in LMICs, approval in HICs. Lancet Reg Health Am. 2022;7:100157. doi:10.1016/j.lana.2021.100157
   
8. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191-4. [PMID: 24141714] doi:10.1001/jama.2013.281053
9. Kelman A, Kang A, Crawford B. Continued access to investigational medicinal products for clinical trial participants—an industry approach. Camb Q Healthc Ethics. 2019;28:124-33. doi:10.1017/S0963180118000464