Exploring the ethics and legality of conducting clinical trials in developing nations

Feature article

Rosemary B Kirk

 

The number of clinical trials conducted in developing countries has increased dramatically in recent decades due to globalisation and increased need for trial subjects. For example, between 2002 and 2007 the number of United States (US) sponsors conducting pharmaceutical research abroad increased by 15% annually, while US-based trials decreased by 5.5%.[1] All trials involving human subjects require ethical discussion, and this is of particular importance in developing nations, where risk of exploitation is high. In this article I will describe the legislation surrounding these trials, summarise the benefits of clinical trials to developing nations and researchers, analyse the ethical issues raised by this practice through a principles-based and utilitarian lens, and discuss how future legislation could align the potential benefits of these trials with reality.

Legislation surrounding clinical trials

To understand why clinical trials in developing countries are conducive to exploitation, the issues with the legislation in place must first be understood.

International

Numerous international bodies have created documents outlining clinical trial guidelines. One of the most commonly referenced documents is the Declaration of Helsinki (DoH), developed and regularly updated by the World Medical Association. International guidelines such as this are not legally binding, but are referred to in the legislation of many countries.[2] These international guidelines have been criticised for being vague and thereby allowing researchers to circumvent their recommendations.[3] For example, the DoH states that new interventions must be tested against the current best intervention, that researchers should make provisions for post-trial access to their intervention, and that medical research on a group is only justified if  it is responsive to their health needs.[4] However, the DoH lists circumstances in which placebo use is acceptable, does not specify the duration of availability or price of the intervention post-trial, and does not define how significant a health need must be for a community to justify participation in a trial.

Developed nations

Developed nations have regulations to protect subjects in trials within their country that are enforced by ethics committees. However, depending on who is funding the research, such regulations do not always have to be followed regulations do not always have to be followed when conducting research internationally.[5] It can also be problematic to apply laws from one culture to another. For example, in the US, sponsors do not have to compensate subjects for treatment of research-related injuries, but this cannot reasonably be applied to nations where subjects cannot afford treatment.[6]

Developing nations

Developing nations are less likely to have established and financially-supported clinical trial regulation, and the increase in clinical trials in developing nations in recent years has overwhelmed existing ethical review systems.[7] This makes it easy for researchers to avoid investigation, and a 2004 study found that 44% of studies in developing nations did not undergo any review from the country in which they took place.[8]

Arguments for clinical trials in developing countries

For companies

The advantages for companies of conducting clinical trials in developing countries are numerous. Costs are significantly reduced as a result of lower salaries, cheaper facilities, and less time being required to receive approval for a trial. [9] Participant recruitment is also easier, due to the higher prevalence of diseases and paucity of treatment options.[10] Finally, subjects are less likely to have received prior treatment, increasing result significance.[2]

For communities

While it can be easy to assume that clinical trials in developing nations are inherently exploitative, these trials are not without their benefits to local communities. Trials provide pharmaceuticals to people who may otherwise have extremely limited access, and if the recommendations made in the DoH are implemented, these communities may have continued access to the drugs being tested.[11] Furthermore, through conducting clinical trials, researchers can provide equipment and knowledge to advance local research, and can boost local economies.[12]

Ethical perspectives

If research is conducted ethically and following international guidelines, it is possible for all of the benefits described above to be realised. However, as long as clinical trials in developing countries are not properly policed, there are ethical issues implicit in this practice and a risk of exploitation. While there are countless ethical issues to be considered in this area, I will focus on the issues of informed consent, the dangers of trials, placebo use, testing of interventions that target health needs, and post-trial availability of interventions. These will be analysed using a principles based and a utilitarian lens.

Autonomy

Autonomy describes a state in which individuals are free to make their own decisions; one consequence of the principle of autonomy is informed consent. To make decisions, people must be provided with the relevant information in a form they can understand.[13] Informed consent has particular relevance for trials in developing nations, because gaining consent requires understanding local languages and analogies, and obtaining written consent can be difficult in the context of low education rates.[14,15] Additionally, in many communities it is essential to also obtain consent from elders, religious leaders, or heads of families. [16] Thus, in order for clinical trials in developing countries to be considered ethical from the perspective of autonomy, researchers must show cultural awareness in acquiring informed consent.

Beneficence and non-maleficence

Non-maleficence is the principle that actions should not expose individuals to unnecessary harm, while beneficence describes acting in a manner that benefits others.[13] In any clinical trial there is potential for significant harm to come to study subjects. This is particularly true when clinical trials are poorly regulated. For example, up to 2,644 people died in clinical trials of 475 new drugs over a 7-year period in India, with the majority of these trials being conducted by international sponsors.[17] In the context of murky international legislation and the potential for negligent trial structure and administration, such deaths can be considered a violation of the principle of non-maleficence by the researchers. Conversely, clinical trials can also be a force for beneficence in developing nations through the provision of medication and research infrastructure, as previously described. It is thus important that the potential harms and benefits of any trial to a community be carefully considered in order to maximise both principles of beneficence and non-maleficence. A further ethical issue relating to beneficence and non-maleficence is the use of placebos in clinical trials, a pertinent case study being the 1994 African Zidovudine trials. These trials tested Zidovudine as a means of preventing vertical transmission of HIV, with comparison to control groups who received a placebo.[18] During the trial, many women in the control group transmitted HIV to their offspring. This violates the principle of beneficence, as researchers did not act to benefit all trial subjects (which could have been achieved by giving the control group an existing intervention). Whether or not this violates the principle of non-maleficence depends on how harm is defined. If harm requires an individual to be worse-off relative to a baseline, then this placebo use could be considered ethical in a nation where women otherwise receive no treatment.[10,19] However, this creates a double standard for developing countries, as using a placebo when there is existing treatment would be unethical in developed nations, as per recommendations established in the DoH. Views on placebos from this perspective, therefore, may vary.

Justice

The principle of justice involves fair distribution of scarce resources and respect for personal rights and laws.[20] Trials in developing countries are often for ailments primarily affecting developed nations, such as overactive bladder and allergic rhinitis, rather than for diseases that disproportionately affect developing countries.[1] People in developing nations are therefore assuming the risks of research while receiving little benefit. This practice is possible because there are many health needs in developing nations and, as previously stated, the DoH does not specify how important a health need must be for it to be an appropriate research target.[21] From a justice perspective, in order for a trial to be ethical it should target a health priority, not just a health issue present in a community. If this principle is followed, clinical trials may become a means of combatting global healthcare inequalities; indeed, as it stands today, 90% of the global healthcare budget targets illnesses responsible for only 10% of the global disease burden.[22] Another issue pertaining to the principle of justice is continued access to interventions post-trial. Basic medications are often absent or expensive in developing countries; therefore, continuing to offer treatments after a trial ends is one way of fighting this distributive injustice, especially if the intervention is offered to a wider community and the researchers are allied with broader access programmes.[11]

Utilitarianism

Utilitarianism deems actions good if such actions maximise the amount of good for a maximum number of people.[13] Using a utilitarian lens, it can be argued that since clinical trials in developing countries are mutually beneficial, imposing further constraints is not justified.[23] For example, if placebo use was not permitted in the African Zidovudine trials, the trial may not have been conducted, meaning no one would receive treatment. In the context of extreme utilitarianism, it can even be argued that all clinical trials in developing countries are ethically justifiable because the results can potentially help many more people than might be harmed in the trial process. Utilitarianism thus provides a very different overall view of clinical trials in developing countries than a principles-based perspective. In practice, the views of most ethical theorists and international guidelines align with a principles-based perspective, while some developed nations follow the utilitarian perspective and favour scientific arguments and economic advantages over ethical concerns for people in developing countries.[24]

Proposed future changes

It is evident that the current guidelines and legislation surrounding international clinical trials are inadequate to protect trial subjects from exploitation. Because of deficiencies in international legal capacity and infrastructure in developing nations, the responsibility for protecting subjects of clinical trials in developing countries must fall to developed nations. Examples of beneficial changes to current legislation include adjusting laws to be culturally appropriate for developing communities,[24] enforcing governments to commit a portion of tax revenue to research that is responsive to the health priorities of developing countries,[21] and having governments provide incentives to support health policy improvement and appropriate research practices in developing nations.[25] However, such legislation is far from being realised, and is unlikely to be implemented provided that current legislation remains beneficial to developed nations and wealthy researchers.

Conclusion

There are many layers of legislation to be considered when conducting a clinical trial in a developing nation, with considerable potential for contradiction or legislative gaps. Trials can therefore result in exploitation, and require numerous ethical issues to be considered. Exploring these issues using a principles-based perspective reinforces the need for improved legislation surrounding trials; conversely, however, purely utilitarian perspectives support maintenance of the current status quo. While legislation is unlikely to change dramatically in the near future, many ethicists agree that if developed countries improve their legislation, clinical trials in developing nations can become a part of the solution to global health inequality, rather than part of the problem.

 

Acknowledgements

None

Photo credit

Louis Reed, accessed from https://unsplash.com/photos/pwcKF7L4-no

Conflict of interest

None declared

Correspondence

rosemary.kirk@unsw.edu.au

 

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