The story so far:
On July 17, the ICMR Bioethics Unit posted the consensus policy statement for the ethical conduct of controlled human infection studies (CHIS), also known as human challenge studies, in India. The consensus policy statement has been posted on the Indian Council of Medical Research (ICMR) website for public consultation for a period of one month, from July 17 to August 16, 2023.
Why is India venturing into undertaking human challenge studies?
Human challenge studies, in which human beings are exposed to diseases to learn more about it, have been carried out for hundreds of years; the yellow fever study in the early 1900s, for instance, established that mosquitoes transmitted the yellow fever virus. However, India has not undertaken such trials before and will be collaborating with scientists and institutions outside India who have been conducting such studies.
Human challenge studies are almost always conducted to understand the various facets of infectious microbes and the diseases or conditions caused by such pathogens. The disease burden and mortality from infectious diseases is significantly high at around 30% in India. Though traditional human clinical trials have been carried out in the country for a very long time, the inclusion of human challenge studies will help supplement traditional clinical studies and speed up the process of finding safe and effective interventions in the form of drugs and/or vaccines.
Most importantly, human challenge studies will vastly help in providing better insight into multiple aspects of even well-studied pathogens, infection, transmission, disease pathogenesis and prevention. Since many infectious diseases are endemic in several developing countries, and resistance to existing drugs is increasing, there is a pressing need to find more effective medical interventions; human challenge studies may offer more benefits to people in these countries. Many countries, including low-and middle-income countries such as Colombia, Kenya, Tanzania and Thailand, have carried out human challenge studies.
What is the fundamental difference between human clinical trials and human challenge studies?
The fundamental difference between the two scientific methods is the nature of exposure to pathogens by participants during the conduct of the studies. While participants in traditional clinical trials are strongly advised to adopt and adhere to safety measures to avoid getting infected and any exposure to the microbes and infection arising in the participants from such an exposure is left to chance and infection is left to chance, the opposite is the case with human challenge studies. Volunteers in a human challenge study, as the name indicates, are deliberately exposed to disease-causing pathogens.
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The second major difference is that traditional clinical trials are undertaken to study the safety and efficacy of drugs and vaccines, whereas human challenge studies are carried out to understand the various facets of infection and disease pathogenesis besides selecting the best candidate drug or vaccine. The third difference is that while the adverse effects of the candidate drugs or vaccines are not known in both the studies (safety is evaluated for the first time in humans during the phase-1 stage of a traditional trial), volunteers in a human challenge trial face an additional risk when deliberately exposed to the pathogen. Finally, human challenge studies are often undertaken to study “less deadly diseases” such as influenza, dengue, typhoid, cholera and malaria, unlike in traditional clinical studies.
What special safeguards are followed to reduce harm to participants?
Except in very rare cases, as in the SARS-CoV-2 virus that causes COVID-19, the infectious agents that are tested in human challenge studies are well-known and studied. To reduce harm to the participants, a weaker or less virulent form of the pathogen is used. The other important requirement is the availability of a ‘rescue remedy’ to prevent the disease from progressing to its severe form. An exception was the reliance on remdesivir as a rescue remedy for participants in the studies involving SARS-CoV-2 virus even when the substantial mortality benefit of remdesivir was not known.
What makes human challenge studies ethically more challenging vis-à-vis traditional clinical trials?
That participants in a human challenge trial are deliberately exposed to a disease-causing pathogen makes it ethically more challenging. The ICMR consensus statement has clearly mentioned that only healthy individuals in the 18-45 years age bracket are to be enrolled. Children and women who are pregnant, lactating or planning to conceive within the study period will not be enrolled; children will be included when “deemed appropriate”, says the statement. Participants with pre-existing medical conditions are to be excluded but very often people are unaware of many medical conditions. This makes it essential to carry out detailed medical examination of the participants before enrolment. According to the consensus statement, information on payment for participation should be mentioned in the consent form but the exact amount of payment for participation is to be revealed “only after the volunteer has consented to participate”. It is left to the investigators to not reveal the payment before the participant gives his or her informed consent. Assured payment (even when the amount is not revealed) over and above reimbursement of the expenses may serve as an inducement and, in turn, to exploitation. Enticing people to participate by advertising the amount of money that volunteers will be paid is quite common in traditional clinical trials, as was seen in the Covaxin trial conducted in Bhopal.
Like the SARS-CoV-2 virus infection that remains asymptomatic in some people while leading to death in others, the disease state in an individual cannot be 100% predicted even when a less infectious agent is used. This makes the availability of an effective rescue remedy important. It remains to be seen how “informed” will be the informed consent, especially when the pathogen is studied in specific age groups such as children or disadvantaged groups, given the riskier nature of human challenge trials and the compulsion to get people enrolled in the new research methodology. The HPV vaccine trial in 2010 became notorious as informed consent requirements were flagrantly violated, as also during the Covaxin trial in Bhopal in 2020-2021.