In July, the Indian Council of Medical Research introduced a policy document on controlled human infection studies – a first step in introducing a controversial mode of research that India has so far stayed away from.
Controlled human infection studies involve exposing healthy individuals to germs and pathogens in a controlled setting. This allows researchers to study a disease’s physiology and the body’s immune response faster than by observing the course of a natural infection.
Such studies are used to develop vaccines or treatment for the disease. If allowed in India, controlled human infection studies will find application in tuberculosis, cholera, typhoid, malaria, dengue, Japanese encephalitis infections.
Dr Roli Mathur, scientist in ICMR’s bioethics unit, told Scroll that in the last few years many developing countries have been considering infection studies to accelerate research for diseases endemic to low- and middle-income countries. “However, this is yet to begin in India due to the unique ethical issues and our socio-cultural context,” Mathur said.
So far practised in Western countries, controlled human infection studies come with several ethical risks. Several health activists have raised an alarm over its possible misuse in India, especially when underprivileged and vulnerable sections are involved. They have urged the regulatory body to make norms around informed consent and inducement stricter.
In 2021, the World Health Organisation came up with ethical guidelines to conduct controlled human infection studies, or CHIS.
The ICMR policy document was drafted by an expert group which looked at various international publications before arriving at guidelines for an Indian context. It was opened to public feedback and suggestions till August 16. Mathur said the ICMR has received over 600 responses, which are now being examined.
“India may be the first country in the world to prepare a policy document on ethical aspects of CHIS,” she said.
But experts believe the document lacks clarity on compensation, and does not ensure stringent protocol and high biomedical standards.
The western cautionary tale
Concerns over infection studies stem from the record of such experiments in the West, which, at times, exposed vulnerable and poor populations to great harm.
One of the most controversial experiments on syphilis was carried out in America between 1932 and 1972. For over four decades, 600 African-American men in Alabama – of them, 399 had syphilis – were a part of a controlled human infection study carried out by the United States Public Health Service.
Their consent for participation was taken on the promise of free meals, free transport and free burial.
In the 1940s, penicillin was available as a known treatment for syphilis, but the participants were not offered the treatment, resulting in the deaths of 100 men. The study was stopped in 1972 on ethical grounds. In 1997, the US president issued a formal apology to the survivors and families.
Between 1946 and 1948, USA led another study into sexually transmitted diseases such as gonorrhoea, chancroid and syphilis by experimenting on 5,128 Guatemalans.
This included including sex workers, orphans, inmates at mental hospitals, and soldiers. In all, 1,308 people were injected with pathogens that caused the infections without their informed consent. The study was not carried out in a sterile environment. In 2010, US resident Barack Obama apologised for the experiments.
In the 18th century, England had experimented with the smallpox vaccine by infecting healthy adults and children with it. In 1897, an Italian physician, Giuseppe Sanarelli, isolated the yellow fever pathogen and injected five hospital patients with it in Uruguay. No consent was taken. Three of them died later.
Not all such studies have broken ethical rules. In Maryland, USA, 118 volunteers were exposed to infected mosquitoes to study the progression of malaria infection after consent. The study was conducted between 1985 and 1992 and all participants recovered.
The question of consent
Experts argue that the ICMR guidelines on consent leave scope for improvement.
In its document, the ICMR has asked for an audio-visual consent from a participant in such a study, though it does not elaborate further.
The policy document mandates that researchers need to fully explain the deliberate harm caused by the germ, the possible consequences, the risks and benefits of such studies. The document also mandates that researchers must only select participants with “altruistic motives”, implying that financial motivation must not be offered.
Several experts, however, have warned that it will be difficult to ascertain whether a participant has been offered financial incentives as motivation to join the study.
Public health researcher Dr Vijay Gopichandra said the current policy document is weak on informed consent. “India has low literacy levels and it is important that participants are informed about the deliberate harm caused by exposure to infectious agents,” Gopichandran said.
The policy document also needs to elaborate upon the legal entitlement of participants and the legal obligations of researchers, he added.
Dr Amar Jesani, an independent consultant in bioethics, said the experiments in the West are proof that introducing controlled human infection studies could open the door for smaller labs to unethically conduct trials in India where regulation is lax. “The policy document is also vague on punishment in case anything goes wrong, or on paying compensation to the participant,” Jesani said.
Jesani said if the government intends to permit such studies, there should be long-term and medium-term follow up to look at residual effects of the infection. “The current policy document does not really specify prolonged follow-up,” he said.
Gopichandran said to ensure the highest level of standards, only institutes that follow strict biosafety measures and stringent regulatory oversight must be permitted to conduct infection studies. “We have to ensure the infection does not spread to others,” he said.
Mathur, from ICMR, said they have elaborated upon the informed consent process, third party risks, additional safety for vulnerable persons and on the issue of disproportionate payments in the policy.
It suggests compensation for medical harm caused by the study, and to provide insurance to participants. It also says that researchers should make budgetary provisions for compensation.
The case for controlled human infection studies
According to ICMR, infectious diseases contribute 30% of the disease burden in the country.
The most common types of controlled human infection studies are vaccine development trials, challenge studies, and treatment studies.
In a vaccine development trial, a vaccine is given to a group of participants while another group is given a placebo.
An attenuated bug will be exposed to both groups to compare their immunological responses. “The bug itself will be mild and not cause harm,” said epidemiologist Dr Jayaprakash Muliyil. “But it will help measure the response in both groups, the ones vaccinated versus those who didn’t receive any vaccine.”
A challenge study involves intentional exposure of a healthy volunteer to an attenuated bug to study the host pathogen interaction and disease progression.
In a treatment study, a bug will be exposed to a group of persons and an experimental or new treatment will be given to assess whether it can neutralise the bug. This will be compared to a group that is exposed to the bug but provided no treatment or the existing treatment.
These studies are different from the current clinical trials undertaken in India, which do not involve an intentional exposure of a person to an infection.
For instance, if a clinical trial for a vaccine is undertaken – such as those undertaken during the development of a Covid-19 vaccine – a group is administered the vaccine and their antibody levels and other medical conditions are measured after regular intervals. This group is compared to a control group that is not given a vaccine or given a placebo. Both groups are not deliberately exposed to the pathogen to see how their body responds.
Muliyil said if trained specialists conduct human infection studies in a highly monitored setting, it can “give extremely valuable results”. If the infection is controlled and mild, it is unlikely to lead to severe health consequences, he said.
But he warned that there would be few takers for such a method. “This kind of experimentation can create anxiety in ordinary human beings. No one would want to participate in it,” he told Scroll.
Experts ask for more
Gopichandran said the ICMR policy allows international collaborators to partner with Indian researchers and study Indian participants. “In that case, if the study is for a vaccine or treatment, will that be available to Indian patients at a cost that they can afford or will the international agency finish the study and exit from India without providing any benefit? The ICMR has to specify this,” Gopichandran said.
He added that infection studies need more safety settings than routine trials. Ethics committees will have to be trained and criteria for such studies will need to be more stringent.
A group of researchers and advocates from Bhopal, Pune, Ahmedabad and Mumbai have also written to ICMR urging them to provide clarity on which diseases can be studied in India and which cannot.
“This is necessary to ensure that there is no ethics dumping with controlled infection studies being carried out in India on diseases of concern in high-income countries,” the group said in a collective statement.