Clinical trials are a necessary stepping stone for the development of safe and effective therapeutic agents. Each year approximately 900 new clinical trials are approved in Canada alone, emphasizing the immense focus and investment of healthcare funding towards the discovery of novel treatments. A significant amount of clinical research takes place in low-income developing countries, sponsored by private companies and public institutions in developed nations. This is unsurprising, particularly in infectious diseases research, as it is much more efficacious to test a rift valley fever virus vaccine in sub-Saharan Africa where individuals may encounter the causative pathogen than it would be to test these vaccines in North America. However, this trend of academic institutions and pharmaceutical companies setting up clinical trials in resource poor countries has raised various concerns over the underlying ethics of these trials.
Communication is key
Much of the controversy surrounding these clinical trials stems from the potential for exploitation of those enrolled in these studies. Since clinical trials aim to assess the efficacy of new therapeutics, there are inherent safety risks from possible adverse side effects associated with an experimental drug. Thus, the risks involved with clinical trials must be appropriately communicated to those enrolled, particularly if proven alternatives are already available on the market. The outcome and implications of a clinical trial provide additional concerns as the completion of a trial does not guarantee the introduction of a new and more effective drug. In fact, in many cases drug development ceases following the completion of a clinical trial when safety or efficacy standards are not met. The focus of a trial may also be problematic – clinical trials in resource poor countries should function to directly address a local and immediate health priority. It would be unethical for an academic or pharmaceutical institution to utilize the limited healthcare resources of a developing nation to pursue research in an area that is not addressing or benefiting the public health of the host country.
Individuals from resource-poor countries face the risks and uncertainties associated with trials directly while those in developed nations may benefit from the outcome of a trial while never encountering the risks. These issues become amplified in the context of social factors such as poverty, limited healthcare, high illiteracy rates, language barriers and cultural differences, which could increase the possibility of exploitation. Many individuals from these countries may mistake these trials as an opportunity to receive proper health care without fully understanding the risks involved. It becomes very important for those involved with trial recruitment to overcome such challenges when communicating these risks and uncertainties to potential participants.
Placebo controls and withholding treatment
The specific design of clinical trials used in resource-poor countries is another area of controversy and concern. The use of placebos in trials can be an effective tool in determining whether a new treatment is safer and more effective than no treatment at all by controlling for any confounding effects associated with the act of taking the drug itself. However, it is unethical for a group of researchers to offer a placebo in the place of a proven and effective treatment, even if this means decreasing the strength of a trial. A study conducted in 1994 and published in the New England Journal of Medicine detailed a randomized trial showing that the antiretroviral drug zidovudine reduced the rate of transmission of HIV from mother to infant from 25% to 7%, compared to a placebo control group. However, at the time, there were already proven and available antiretroviral drugs that had replaced placebos as controls in clinical trials conducted in developed countries, while several placebo-controlled trials were still held in Côte d’Ivoire and Thailand in the late 1990s. The fact that trials such as these, which would easily be rejected in developed nations, have been authorized and carried out in resource-poor countries emphasizes the ethical concern for exploitation of those enrolled and the need for improved guidelines for human experimentation.
In 1964, the World Medical Association produced the Declaration of Helsinki to outline principles for human experimentation and clinical research. Since its creation, the Declaration has undergone several revisions. For example, revisions made in the year 2000 state that new medical therapies should be tested against the current best therapeutic options, thus the control group should receive the best treatment available at the time. This revision came following a significant amount of backlash and controversy in the scientific community from trials such as the 1994 zidovudine trial and others like it held at the time. Thanks to documents such as the Declaration of Helsinki as well as increased pressure from the international scientific community, the ethics of human experimentation continues to move to an improved state.
With infectious diseases such as HIV and malaria representing major public health concerns in several resource poor countries, there will inevitably be further human clinical research to combat these diseases. It is of utmost importance that those organizing these trials remain committed to overcoming social and cultural differences to ensure the highest possible standard of care for those enrolled. This commitment is embodied in the research of Dr. Eleanor Fish, a professor of Immunology at the University of Toronto who has recently focused her research program on investigating the effectiveness of interferon therapy on Ebola virus disease. Following the 2013 outbreak, Dr. Fish began organizing a proof of concept clinical trial to determine the effectiveness of interferon (IFN) β-1a compared to standard supportive care available at the time. In 2015 the trial began in Guinea, one of the countries hardest-hit by the Ebola outbreak. The outcome of the trial demonstrated that combining standard supportive care with IFNβ-1a treatment increased survival from 19% to 67%, providing rationale for further evaluation of IFNβ-1a as a potential therapeutic agent. In this issue of IMMpress, we speak to Dr. Fish about some of the ethical considerations that need to be made behind the scenes when organizing a trial in a resource-poor country.
Were there any major cultural differences that served as obstacles during patient recruitment? How were these obstacles overcome?
Unlike most clinical trials that are conducted in resource-poor regions on the African continent, our trial was unique in that the attending doctors were all Guinean nationals, so there were not any cultural differences. Our challenge, however, was to explain in lay terms that we were offering an experimental drug that had never been tested in humans infected with Ebola virus. They needed to understand that there was no approved treatment for Ebola virus infection beyond supportive care and we did not know whether the drug might exacerbate or clear the infection. There was also considerable mistrust of a foreign drug, supplied by foreigners – were we giving patients Ebola virus? Notably, it was invariably the males in the family of the patient – the husband, father or brother – who gave consent for their family members to receive treatment.
Did the climate or geography of Guinea result in any issues or have any impact on how this trial was conducted?
Absolutely, yes. The treatment unit where individuals gathered with Ebola virus infection was in a rural region in Guinea. Access by road was problematic, since the roads were not well paved – invariably loose gravel – and if it rained, the roads became impassable. So, in a very short time we realized that the trial team needed to be housed close by the treatment unit. This required us to find a house we could rent, purchase a generator to ensure a power supply, engage a driver to drive the team to and from the treatment unit, rent a car, and employ a cook for the house.
Because of the high temperatures in Guinea, this was also a problem in the treatment unit, where there was no air-conditioning. The tents and structures in the treatment unit had to be enclosed to provide isolation. Temperatures often rose to above 40°C in the ward. Personal protection equipment was made of materials to provide a barrier between the health care worker and the infected patient – rubber boots, rubber gloves, plastic clothing, etc. to block any air passage – and that resulted in the wearer suffering from intense heat. Therefore, an individual can only spend a limited amount of time in the equipment – about 45 minutes maximum. This meant that time with each patient was very limited, since there were not enough health care workers to man the units 24 hours a day, 7 days a week, during the peak of the outbreak. Moreover, it was essential that the interferon we used to treat the patients was kept refrigerated so we had to install a fridge and generator in the treatment unit. Any blood samples drawn from infected patients had to be transported immediately to the lab for analysis, and kept cool.
Given the urgency of the situation and severity of the outbreak at the time, a single-armed trial – in which all patients enrolled received the experimental treatment – seemed to be the most appropriate to conduct. What kind of factors determine the type of study design that is most appropriate for a clinical trial?
The gold standard for all clinical trials is a randomized control trial. This allows one to compare treatment with no treatment/placebo treatment, while matching patients for age, sex and severity of disease. During the Ebola outbreak, when fatalities were extremely high at the outset of the outbreak (70-90%), there were those of us who considered it unethical to randomize patients to a high likelihood of death. I argued that we could retrospectively match IFN β-1a -treated patients with untreated patients since we had historical data on age, sex, severity of disease and outcomes for many. Fortunately, the Guinean government officials were like-minded and did not accept any randomized control trials during the outbreak.
How much influence does the host country have over the specific design of a clinical trial? Did the Guinea government have any major input into this trial?
For the interferon trial, the government of Guinea did not have any input on trial design. However, it was their decision to approve or decline the protocols. The World Health Organization (WHO) did provide protocol guidelines for trials during the outbreak, which we adhered to, other than the fact that our trial had to be a single-armed trial. Uniformity in the protocol in terms of measuring viral load, supportive care, analyses of patient samples, and clinical records, allowed us to compare outcomes between different trials.
One of the benefits of clinical trials in resource-poor countries is that they can have a positive impact on the host country economy and create much needed healthcare infrastructure. Can you comment on how this trial impacted the lives of local residents?
Ours was the only trial in all of West Africa that: (i) trained local physicians in how to operationally run a clinical trial according to first world standards, thus there is now a team in place in Guinea that can run a clinical trial, and (ii) purchased equipment during the trial – and subsequent to the trial – that has remained in Guinea as much-needed infrastructure to support their research investigations. I continue to provide funding for salaries for the team so that they are able to run a survivor study and interrogate patient samples. The impact on the local community is that there is now a clinic in the rural community that offers health care. This was not the case prior to the outbreak.
The focus of your study, IFNβ-1a, is readily available, and stable across a broad range of temperatures, making it an ideal drug for use in low-income countries. How much weight goes into choosing potential drugs that have real world application versus simply testing a drug that may have potential, even if said drug is too expensive for the residents of the country in which it is being tested?
Availability and access are key issues. The WHO struck a committee during the outbreak to examine potential experimental treatments since there are no currently approved drugs. The drugs that were considered only had seven treatment courses (i.e. could only treat seven patients), required storage at -80°C (there is only one -80°C freezer in all of Guinea), required infusions (which is not feasible in the makeshift treatment units) or could be ingested through multiple tablets per day (>20 – Ebola infection causes vomiting, so bio-availability/absorption for 20 tablets was not feasible). I argued quite strongly against consideration of any potential treatment that was unrealistic for delivery or stability in West Africa, or for which there was a very limited supply. The reality is that most pharmaceutical companies will not be interested in developing any drugs unless there is a return on their investment of approximately $1.5 billion to bring a drug to market (from discovery to approval). This is why an antiviral for Ebola virus was not available. Vaccines are also only considered if there is a perceived global threat. So, to answer your question: diseases prevalent in resource-poor regions will not attract pharma to either develop diagnostics or treatments … unless there is the potential for these diseases to cause global outbreaks for which there will be a market.
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