South Africa, SOLIDARITY and COVID-19: Law and Ethics in Clinical Trials
On 3 April 2020, it was reported in Nature that African nations were largely not involved in clinical trials for the development of a COVID-19 vaccine. The World Health Organization (WHO) has called for increased participation by African states in its SOLIDARITY trial, a global study of four potential COVID-19 treatments. Researchers are pushing for faster action on clinical research in countries with weaker health systems such as those in Africa and South America, where the number of infected persons may burden limited state resources. The WHO has also offered to help co-ordinate the process so that researchers from Africa can more easily join the COVID-19 Clinical Research Coalition project, which was launched on 2 April and comprises universities and research organisations around the world, as well as philanthropic research-funding bodies such as the Bill & Melinda Gates Foundation in Seattle, Washington, and the Wellcome Trust in London.
The SOLIDARITY clinical trial aims to compare the effectiveness of four drugs and drug combinations in treating COVID-19. By combining the results from many separate studies that are adhering to the same protocol, the WHO hopes that the trial will yield strong evidence due to a large sample of several thousand participants. South Africa was one of 10 countries (Argentina, Bahrain, Canada, France, Iran, Norway, Spain, Switzerland and Thailand) to confirm its participation in the trial, but so far, it is the only country in Africa to do so. It has been reported that Senegal and Burkina Faso are in the process of being enrolled. To encourage wider participation, the WHO has offered to assist countries that lack funds.
The trial is described as relatively simple and can be administered by existing hospital staff treating patients with COVID-19. The four therapies being tested are remdesivir; chloroquine; a combination of lopinavir and ritonavir; and this combination plus interferon beta. Remdesivir was tested in 2019 during the Ebola outbreak in the Democratic Republic of Congo, and has been shown to inhibit the coronaviruses that cause SARS and MERS in test tube and animal studies. Chloroquine and hydroxychloroquine are used to treat malaria and rheumatology conditions. The combination drug ritonavir/lopinavir is used in South Africa for to treat HIV in some people, and has shown efficacy in marmosets infected with the MERS virus.
A combination of lopinavir/ ritonavir and interferon-beta, which is used to treat multiple sclerosis, is also part of the trial. These four drugs were recommended following a meeting of infectious disease experts called by the WHO in February. A WHO global data and safety monitoring committee will monitor safety results and treatment outcomes, and make recommendations on when results are sufficiently conclusive to be communicated, as well as whether changes are needed. The idea is that enrolling patients in a single randomised trial will facilitate rapid global comparison of unproven treatments. This will overcome the risk of multiple small trials and failure to generate the strong evidence required to determine the relative effectiveness of potential treatments. However, the WHO has also noted that it may be possible to add treatments and clinical procedures that are not included in SOLIDARITY but are being tested in separate clinical trials.
The clinical trials
Fourteen hospitals across South Africa are enrolling COVID-19 positive patients in the SOLIDARITY clinical trial. The protocol involves the following steps:
(i) A Principal Investigator in each hospital must determine whether patients with confirmed cases of COVID-19 are eligible for enrolment in the study. Patients must be 18 years or older, and currently in or recently admitted to hospital.
(ii) Each trial participant must sign an informed consent form that is scanned and sent to the WHO electronically. If eligible, the patient’s data will be entered into a WHO website, and disclosure of any underlying condition which may change the course of the disease, such as diabetes or HIV infection, must be disclosed.
(iii) The Principal Investigator will then inform the WHO which drugs are available at the hospital, and the trial randomisation centre at the WHO will indicate which of five treatment groups the patient is randomly allocated to; one of the four treatment arms or the usual standard of care for COVID-19 in the country.
(iv) Physicians must then record the day the patient left the hospital or died, the duration of the hospital stay, and whether the patient required oxygen or ventilation.
This information will indicate which treatments reduce mortality, affect time spent in hospital and reduce the need for ventilation or intensive care.
While stakeholders are under pressure to develop effective therapeutics and vaccines, it is important that the standards for clinical trials be maintained. In South Africa, the National Health Research Ethics Committee sets the norms and standards for clinical trials and there is also guidance from the national Department of Health. The Health Act 61 of 2003 contains a number of provisions relating to such trials. Section 7 states that the recipient of treatment must provide written consent unless they are unable to, in which case consent may be provided by next of kin such as a spouse, parent, adult child, etc. A healthcare provider must take all reasonable steps to obtain the user’s informed consent. It is important that informed consent documentation be thorough, descriptive and clear, without being unreasonably long. The form being used in the SOLIDARITY trial is three pages long, and has been translated into all local languages. In this trial, patients are required to sign the form themselves.
Section 11 of the Health Act states that before a health service for experimental or research purposes is provided, the recipient must be informed in the prescribed manner that the health service is for experimental or research purposes or part of an experimental or research project. Similarly, authorisation for the provision of the healthcare service must be provided at the outset.
Section 71 of the Act speaks to research on or experimentation with human subjects, and provides that this is only legally permissible where:
(i) Such research is conducted in the prescribed manner; and
(ii) The written consent of the person is obtained after he or she has been informed of the objectives of the research or experimentation and any possible positive or negative consequences for his or her health.
It is important for healthcare practitioners to provide full information about the risks and potential benefits of the study that the patient is considering participating in, and it must be clearly explained that their treatment may or may not involve one of the study treatments. Neither the patient nor the medical staff choose which of the study options a patient will receive, as a computer makes this allocation at random. The nature of a pandemic is that it creates urgency to develop treatment, which may justify not performing rigorous preclinical testing on animals. This must be clearly explained to volunteers, so that they understand that they may not necessarily be successfully treated for COVID-19, but their participation has the potential to benefit the human population as a whole.
The nature of a pandemic is that it is a global healthcare emergency. There is pressure on researchers to develop safe and effective therapies to treat the sick, and vaccines to immunise populations against infection. The SOLIDARITY clinical trial is a global call to countries to assist in this research by initiating local clinical trials, so that the results can be collated and an effective therapy identified. However, the legal requirement for informed consent and standards for clinical trials will continue to apply despite the speed at which the trials are progressing. While we need to act together in the fight against COVID-19, this should not be at the expense of ethical and legal standards.
Ms Sheetal Soni (PhD) is the Deputy Academic Leader for Teaching and Learning in the School of Law, Pietermaritzburg campus. She is a lecturer in the field of Bioethics, International Law, Security and Insolvency and Intellectual Property Law.