Perceptions about controlled human infection model (CHIM) studies among members of ethics committees of Indian medical institutions: A qualitative exploration

Introduction: Controlled Human Infection Model (CHIM) studies provide a unique platform for studying the pathophysiology of infectious diseases and accelerated testing of vaccines and drugs in controlled settings. However, ethical issues shroud them as the disease-causing pathogen is intentionally inoculated into healthy consenting volunteers, and effective treatment may or may not be available. We explored the perceptions of the members of institutional ethics committees (IECs) in India about CHIM studies. Methods: This qualitative exploratory study, conducted across seven sites in India, included 11 focused group discussions (FGD) and 31 in-depth interviews (IDI). A flexible approach was used with the aid of a topic guide. The data were thematically analyzed using grounded theory and an inductive approach. Emerging themes and sub-themes were analyzed, and major emergent themes were elucidated. Results: Seventy-two IEC members participated in the study including 21 basic medical scientists, 29 clinicians, 9 lay people, 6 legal experts and 7 social scientists. Three major themes emerged from this analysis—apprehensions about conduct of CHIM studies in India, a perceived need for CHIM studies in India and risk mitigation measures needed to protect research participants and minimize the associated risks. Conclusion: Development of a specific regulatory and ethical framework, training of research staff and ethics committee members, and ensuring specialized research infrastructure along with adequate community sensitization were considered essential before initiation of CHIM studies in India.


Introduction
Controlled human infection model (CHIM) studies, also known as human challenge studies, involves a calculated and measured introduction of an infectious organism into consenting healthy adult study participants. These studies can help understand the pathophysiology of a particular infectious disease in response to different doses of an infectious agent, the development and nature of immunological responses in humans to a pathogen, and the response of infection to the vaccines and therapeutic agents 1,2 . As CHIM studies have less variability of disease than in natural infection, it allows rapid testing of vaccines and drugs, making the process of their development more efficient and cost-effective. In recent years, CHIM studies have facilitated the development of vaccines against several diseases, such as typhoid, yellow fever and cholera 3 . In the ongoing pandemic of coronavirus disease 2019 (COVID-19), the use of CHIM studies for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection had been proposed 4 and initial studies to establish the inoculum dose needed to produce a reproducible infection have begun in the United Kingdom 5 . In low or middle-income countries (LMICs), despite high burden of infectious disease, CHIM studies have been carried out infrequently 6,7 , in Kenya 8 , Malawi 9,10 and Thailand 11 for diseases such as malaria, shigella, and streptococcal pneumonia.

Conduct of CHIM studies raises important ethical issues.
A disease-causing pathogen for the purpose of the study is intentionally inoculated into healthy, consenting adult volunteers, with no individual benefit to them 1 a possible violation of the principle of non-maleficence. The degree of it could vary depending on the pathogenicity of the virulent introduced, the dosage and the preparedness to manage its onslaught on the body and the effectiveness of the treatment available This issue of non-maleficence is heightened further when there is no treatment available for the infection. Is it justifiable to infect a volunteer and place them at risk for the benefit of humankind even with their consent? In the LMIC setting, there is an additional risk of exploitation of study participants due to their lower educational status and extreme poverty 12 . These are ethically contentious issues which require further exploration. Hence, CHIM studies, particularly for COVID-19, have been a subject of much debate and disagreement in scientific circles as well as the lay community 13,14 . To address these issues, the World Health Organization (WHO) set up a Working Group to assess the ethical acceptability of CHIM studies in COVID-19 vaccine development 15 and has also published a guidance on ethical conduct of CHIM studies 16 .
Although CHIM studies have not commenced in India, several deliberations on the ethical aspects of such studies, involving biomedical researchers, clinicians, policy makers, regulators, and ethics and legal experts from the country, as well as international experts with previous experience of doing such studies, have been held since 2017. There have also been several publications on various aspects of CHIM studies by Indian researchers [17][18][19] . More recently, Indian Council of Medical Research convened a meeting on the issue of CHIM studies in the context of the ongoing COVID-19 pandemic with several international experts 20 . These consultations have led to the realization that it is important to understand the perspectives of various stakeholders in CHIM studies. While a previous study has captured the perspective of the community on CHIM studies 18 , the need to understand the perspectives of members of institutional ethics committees (IECs), whose main objective is to protect the ethical rights of the research participants, was considered important. The present study explored the views of members of ethics committees about CHIM studies in their context. It was carried out amongst consenting members of IECs from multiple health care research institutes in India with experience in conducting clinical trials

Study sites and investigators
As indicated above, the participating sites were selected from among institutions with experience in conducting clinical trials and whose IECs are registered with the Drug Controller General of India and the Department of Health Research, Ministry of Health and Family Welfare. The study sites included both government and private-owned institutions: KEM Hospital Research Centre (KEMHRC), Pune (site 1); St. John Research Institute (SJRI), Bengaluru (site 2); Yenepoya University (YU-deemed to be University), Mangalore (site 3); Centre for Chronic Disease Control (CCDC), Delhi (site 4); Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry (site 5); Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh (site 6). All the site investigators had a doctoral or postgraduate degree in a biomedical field, and experience of conducting qualitative research and serving on an ethics committee. They were also familiar with the IEC members at their sites through their prior interactions. The investigators included a mix of both genders.

Study design
This was a multi-centric qualitative exploratory research study, conducted between February 2021 to July 2021 involving IEC members of six institutions. The present study employed a grounded theory method and an inductive approach which involved 21 gathering data through focus group discussions (FGD) and in-depth interviews (IDI). This exploration is referred to

Amendments from Version 1
In this revised version we have addressed all the queries of both reviewers by providing justification wherever necessary and revising the text based on their comments. To reiterate the rationale the study we have added text in the introduction paragraph and other parts where it was required. Use of particular data collection methods and analytical process has been explained in the response section, also added required text in the revised manuscript. Details and justification about the opted theoretical approach has been provided in the response section and text added in the revised edition.
Any further responses from the reviewers can be found at the end of the article REVISED as 'grounded' since they are based on the participants' own explanations or interpretations. An inductive approach ensures that the researcher begins with an almost blank slate and considers the opinions of the participants rather than imposing one's own. This was important as CHIM studies are new and de novo rather than a priori ethical responses to them were being sought. Figure 1 and Figure 2 summarizes the methodology of this study.

Participants
At each site, all the IEC members were invited to participate in the study-either in FGD and/or IDI. The study participants belonged to diverse fields, covering the range of expertise of mandated IEC members-clinicians (CN), biomedical scientists (BM), social scientists (SS), legal experts (LE) and lay persons (LP), with rich experience and expertise in their respective roles. Site-wise details of participants are provided in Table 1. IEC members who were not able to participate cited reasons such as lack of time due to increased institutional responsibilities during the COVID-19 pandemic, poor health and COVID-19 illness.

Data collection
The data were collected using FGDs that mirrored the deliberative process of decision-making in IEC meetings, and semi-structured IDIs to get more in-depth understanding of perceptions of individual IEC members. In all, 11 FGDs and 31 IDIs were conducted across all the sites. The site-wise details regarding the FGDs and IDIs are provided in Table 2 During the FGD as well as IDIs, the enquiry focused on possible challenges in the conduct of CHIM studies in India-for IECs as well as the investigators, eligibility criteria for unbiased selection of study participants, need for modifications in the ethics committee review process for CHIM studies, need for training, compensation or reimbursement for participation, involvement of social media, community engagement activities and need for CHIM studies for COVID-19. Additionally, demographic details and information about qualification, years of experience as an ethics committee member were also collected. The IEC members were assured that there were no right or wrong answers to the questions, and that the FGDs and IDIs were being done solely to understand views and perceptions on the ethical aspects of doing CHIM studies in India. FGDs and IDI played a complementing role. While FGDs provided the dynamic process of discussion and deliberation similar to the real world functioning of IECs in reviewing research proposals, the IDIs helped to provide a more in-depth perspective of individual members. Provision of allowing IDI also allowed views of a member who could not make it on the day of the FGD to express his/her views separately.
The details of study methods are depicted in Figure 1.

Data analysis
The data at each site were subjected to thematic analysis using grounded theory and an inductive approach 25 . FGDs and IDIs were conducted till data saturation or redundancy criteria were reached. The transcripts were rechecked and verified by researchers within the site team. These were de-identified and then shared with the core-team. Transcripts were critically assessed to identify and construct the emergent themes. Coding was an iterative process done at individual sites (either manually or using a qualitative analysis software [NVivo 12]) and across sites using the methods of constant comparison to arrive at mutually-agreed, comprehensive codes without duplication. As IDIs were meant to explore the issues discussed in the FGDs, data from both FGDs and IDIs were analyzed together, and were not compared with each other. Thereafter, in a workshop conducted across sites, presentations were made where codes were discussed and de novo codes arrived at to establish patterns or relationships in the data. Emerging themes from sub-themes were deliberated upon, differences resolved, and consensus arrived at. The process of generating themes is depicted in Figure 2. The quotes were labelled with the role of the IEC member and the site number. e.g. BM01 indicates basic medical scientist from site 1.

Demographic characteristics of IEC members
A total of 72 IEC members participated in the study that included 34 men and 38 women members with an age range of 30-79 years [ Table 2]. The participants included 29 CN, 21 BM, 7 SS, 6 LE and 9 LP. The characteristics of the participating IEC members is shown in Table 3.

Findings
Across all sites, IEC members were extremely articulate and freely expressed their views and counterpoints during the FGDs and IDIs. There was active listening and respectful interjections, openness to each other's perspectives, and a willingness to reconsider early positions and move to a practical problem-solving mode. Members engaged actively with the subject and there was always more than one hand up in an FGD, asking to speak. They took notes to help keep track of the discussion points, and each person shared multiple points on each question raised. This shows that group members knew each other well and possibly follow similar processes in their working as an IEC. The topic, though unfamiliar to most, was refreshed with every probing question. Perceptions were insightful and well considered.
The thought processes expressed had three major emergent themes. The first theme was "Apprehensions towards the conduct of CHIM studies in India", given that CHIM studies involve complexity, expertise, and possible ethical challenges and risks particularly in the social and economic context of India, with a scope for misuse and volunteer coercion. The second theme was "Perceived need for CHIM studies in India" with apparent scientific and public health benefits. This was especially in the context of an urgent need for a vaccine in a health emergency such as COVID-19. The third theme, "Proposed measures for risk mitigation in CHIM studies", covered methods, structures, processes and regulations which would prevent untoward incidents, and minimize harm and risk to the study participants.

Theme 1 -Apprehensions towards conduct of CHIM studies in India
The participating IEC members across sites, hereafter referred to as 'members', shared that CHIM studies were to be considered as 'highly specialized' studies, requiring specialized dedicated facilities, competent and qualified research teams and medical professionals. In CHIM studies, infection is deliberately introduced, and participants may not fully comprehend the risks associated with this. Given that CHIM studies were new to healthcare professionals as well as IECs, the members expressed uncertainty about the lay public being sufficiently aware, much less comprehending CHIM studies.
A particular concern expressed with CHIM studies was the risk of infection causing possible long-term consequences which may not be fully known, e.g. the risk of long-COVID following CHIM studies on COVID-19 26 , necessitating stringent monitoring and long-term follow-up. There was also apprehension regarding IEC members' added responsibility since the diseases being studied may not have a treatment and may pose a serious threat to the study participants. This was of greater concern to the legal experts serving on IECs. The scope for misuse and volunteer exploitation was considered high for the following reasons: CHIM studies could attract lucrative funding, which could induce medical professionals and institutions without adequate expertise and structures for oversight and volunteer safeguards, to undertake these studies. Members continuously reiterated the context of India's socio-economic deprivation, where such studies could lead to coercion of vulnerable individuals to participate. Impoverished men and women may enroll to tide over extreme poverty and provide for their families.
Institutions and investigators conducting CHIM studies need special expertise, advanced medical care facilities and quality multidisciplinary specialists. There is a high chance of institutions and professionals without the required and requisite expertise and facilities jumping in to do CHIM studies. The other apprehensions expressed included risk of infection to the study team and the community at large, possible stigmatization of participants, lack of support from the general public and concerns of human right activists. Standardisation of the infectious strain used was a further concern.
Table 4 provides details of apprehensions expressed by the members, in the form of sub-themes with supporting illustrative quotes.

Theme 2 -Perceived need for CHIM studies in India
Despite the apprehensions, given that animal models are either not available or not reliably applicable to all human pathogens, ..."not always but only during such times (public health burden)" -SS03 "In the emergency situation, it is very much needed" -LP03 As for the role of CHIM studies in the Indian context, members opined that despite a high burden of infectious diseases in India, CHIM studies have not been conducted in India, leading to our dependence on research conducted elsewhere for vaccine and drug development.

Theme 3 -Proposed strategies for risk mitigation in CHIM studies
The members felt that appropriate structures, and regulations required to protect study participants and to prevent abuse and misuse of CHIM studies are presently not available in India. Such guidelines are urgently needed to set standards for eligibility of institutions and investigators for CHIM studies.
Additionally, stricter systems of participant selection; stringent consent procedures involving counselling and ensuring comprehension by not only the participant but also their family members; reduction of risk of infection of others, e.g. family members and/or workers in the research facility by ensuring proper infection control and safety measures in the facility through strict biosafety and follow-up systems; and, specific insurance safeguards and specific compensation structures are needed.
It was suggested that this could be done by a central body (such as the Indian Council of Medical Research) bringing in strict regulations on the conditions and requirements of institutions who could do these studies, the participant protection needed and the responsibilities of IECs. Several members insisted that conduct of such studies could be restricted to only those institutions that have the required facilities and expertise, and experienced IECs.
The members further added that for CHIM studies on viral disease, because of absence of drug treatment and the wide spectrum of clinical consequences, a separate and tighter regulatory framework is required. Details of the sub-themes under required safeguards and suggestions are as follows: Specialized infrastructure: Members stressed the need for physical, laboratory and waste management facilities appropriate for the biosafety level of the pathogen involved, and infrastructure and protocols for post-exposure prophylaxis. It was considered important to establish a standalone set-up with 24 × 7 access to healthcare, and living facilities. Informed consent: The predominant view was that the informed consent process should be simpler but more interactive and rigorous than the current procedure and audio-visual recording should be done to ensure adequate comprehension and documentation. The patient information sheet should provide a thorough explanation about the nature and purpose of the research. There was a suggestion to include counselling by a psychologist to ensure that the participant comprehends the information and that there is no social pressure. Giving participants the opportunity and even encouragement to discuss their participation with their family members and /or family physician prior to consent was suggested. It was also proposed that a third party be involved in the process of obtaining consent to make it more transparent. Joint counselling sessions with volunteers and their families regarding the procedures, risks and follow up requirement was needed to ensure that consent is well informed and well understood.
''I believe that the consent should be more in depth [and] in length. "I think extra benefits should be given because the amount of risk involved and the amount of psychological stress they may have during the study period, may be 10-20% more than whatever already involved to be approved by the Ethics committee to make sure that there is no inducement" -BM05 These members also felt that the reimbursement and compensation amount in CHIM studies could be higher than in regulatory clinical trials and suggested that the authorities devise a new formula for compensation of CHIM participants. It would need to address all events that might occur during and after the study.

Insurance coverage and indemnification:
As CHIM studies run the risk of spreading infection to the study team and the community, the members suggested that there should be a comprehensive insurance policy that covers third parties, such as the family members. They were however skeptical about insurance companies being willing to provide comprehensive insurance coverage and felt that pharmaceutical companies or the study sponsors may have to provide the necessary coverage. An additional point raised was regarding risks beyond the immediate third parties e.g. risk to the unborn fetus in case of a Zika virus CHIM, might have to be taken into consideration.
"See the Insurance in India will not cover for the next generation...the insurance companies have to come up with some plans for CHIM...in this ability, I don't think the insurance companies are going to cover them (family/third party affected by the study)" -LP03 The members suggested that the entire study team as well as the IEC members involved in the review process should be indemnified considering the risk involved.

''Investigator has to have a stronger indemnification because he is at the helm of everything.'' -LE01
Stakeholder engagement and community dissemination: The members felt that engagement activities were required to sensitize various stakeholders, such as the government partners, health care personnel and the general public. Methods suggested included educational campaigns such as public meetings, advertisements, discussions, and social media. Two-way communication with the community members was preferred, to provide clarity and build the community's trust in research teams. Once trust is established, dealing with misinformation and erroneous perceptions about CHIM studies would possibly be easier.

"Build trust among the community members. There is a common perception that such kinds of studies may have some hidden motive and common people are being used to achieve that motive" -SS06
The members felt that collaboration with government bodies could increase the credibility of CHIM studies from the public perspective. The use of social media was proposed to disseminate positive information and to engage with misinformation about CHIM studies. However, they shared experiences about how false or negative information could get disseminated through social media networks and suggested responsible involvement of social media by the researchers right from the inception of the study to avoid this problem.

Empowerment of ethics committees:
Considering the perceived high risk involved in CHIM studies, the members were clear that such studies would need very close monitoring by the IEC. IECs should be empowered with close oversight of the investigator team. Specific suggestions included frequent monitoring, real-time monitoring of participant recruitment by an IEC subcommittee, and monitoring beyond study completion for any (un)anticipated adverse events. Augmented authority or power of IECs in terms of decision making in suggesting substantial changes in the study design, recruitment and other procedures, site inspections, site closures, rigidity of competence of research teams, and long term follow up of facility, volunteers and family communities was suggested, to ensure the well-being of stakeholders. It was emphasized that the contribution of every IEC member was critical for decision making.
"The monitoring will have to continue beyond the end of study dates here for whatever period, so all kinds of auditing need to be taken care of and periodic review has to be submitted if there is any other committee it has to be informed too.'' -LE01 A summary of the proposed risk mitigation measures from the perspective of regulatory bodies, research institutes, institutional ethics committees and general population is depicted in Figure 3.
Finally, the readiness of the country for CHIM studies was captured metaphorically as being a "Lamborghini on Indian roads" indicating that the advanced level of expertise needed for the conduct of CHIM studies is much higher than that of existing clinical research in India.

Discussion
Vaccines are important tools in the armamentarium of public health systems and with the advent of COVID-19 pandemic, the world has witnessed a desperate need for fast tracking vaccine development. CHIM studies provide a disease model for testing of vaccine candidates during early stages of clinical development and thus reduce the time to pivotal clinical studies 27 . However, CHIM studies raise difficult ethical questions, in particular whether it is justified and permissible to infect a healthy volunteer with an infectious agent 28 . Considering the burden of infectious diseases in India, introduction of CHIM studies may be needed in future and IEC members will be important stakeholders in ensuring the ethical conduct of CHIM studies and protecting the rights and wellbeing of study participants.
The results of our multicentric study indicate that IEC members from Indian healthcare and research institutions have several apprehensions regarding CHIM studies, such as vulnerability of our population due to poor socioeconomic status, lack of specialized research infrastructure, lack of specific training amongst researchers and IEC members, lack of stringent regulatory framework and public mistrust. The apprehensions extended to the possible risk of transmission of the experimental pathogen to family members of study participants and the wider community, as also the risk of progression towards severe disease; these were concerns of CN and BM members of the IECs, reflecting their real-life experience. A critical current concern in India is the breach of trust between the medical community and the general public, especially if there was any study-related death. Some of these concerns, such as the risk of infection and likelihood of exploitation of study participants, were also identified in a previous study conducted by Vaz et al. amongst lay public and key opinion leaders 17 . These concerns are realistic considering ethical violations in the history of human clinical trials 29 and the fact that a clinician has an ethical commitment to benefit and protect the participant/patient 30 . CHIM studies are different from first in human studies as these studies don't just involve exposure to new drug but include establishment of a disease model in healthy humans using a standardized pathogen and then evaluating the effects of drugs and vaccines within the established disease model. This is in the context where people outside the study have already suffered from the pathogen as against a new drug which has never been used before. Overall, in the present scenario, implementation and acceptance of CHIM studies is challenging in an LMIC such as India, given the limited understanding of biomedical research and high vulnerability amongst lay public, and lack of readiness at the level of researchers, regulators and IEC members.
Despite the apprehensions, most of the IEC members agreed that such studies should be conducted in India as they offer benefits over animal studies and help to fast-track vaccine development especially in a pandemic situation. This is in line with a recent public consultation on SARS-CoV2 conducted in the United Kingdom where the participants believed that a controlled infection is better than infection with a wild virus 31 . However, the risks in terms of pathogenicity of the controlled viral strain, severity of the disease, public health priority of the disease and availability of rescue treatment will have to be closely evaluated before agreeing to any specific study proposal on CHIM study 32 . Further, as pointed out by Gordon et al, CHIM studies in LMICs such as India need to maintain standards equivalent to those prevalent internationally, and the risk to study participants should not be more than those elsewhere in the world.
The risk mitigation measures suggested by the members include strengthening of the regulatory, monitoring and ethical frameworks, and engagement of stakeholders to increase the credibility and understanding of CHIM studies. Some of the salient points included stringent selection criteria, a two-way consent process (including counselling wherever needed) to ensure comprehension (with adequate documentation and recording), reduction of risk of infection to family and society at large by ensuring proper infection control and appropriate biomedical waste disposal, strict post-study follow-up of volunteers, revised reimbursement and compensation guidelines and comprehensive insurance coverage for volunteers research team and IEC members. Other measures for risk reduction include capacity building and training of research team and IECs, which will approve such studies including experience sharing from CHIM-experienced research teams and IECs abroad.
Our study confirms these gaps which have been identified in previous published literature on CHIM studies in India 1,33 . Our results also emphasize the previous recommendations that CHIM studies should not be started before adequate community engagement has been done and public trust has been built 34 . This is the first systematic multi-centric study amongst IEC members in the Indian setting to understand their perceptions about CHIM studies and their possible conduct in India.
The study provides useful insights into the apprehensions about as well as the acceptance of CHIM studies by these key stakeholders. Theirs is a conditional acceptance, provided the required regulatory and ethical framework were in place in India. It was heartening to find in our qualitative exploration that IEC members were receptive, and engaged openly with the topic of CHIM studies, despite it being a new field to most of them and one with several layers of complexity and challenges. Within the duration of the FGDs, the tone of the discussions changed from trepidation to conditional acceptance as new thoughts and suggestions emerged on how to limit risks. There was a dynamic weighing of pros and cons with benefits and critical conditions needed for CHIMs in India evolving organically. This is reflective of the consideration of benefit and evaluating risk, when determining the justification of research protocols by IECs 38 . However, the study included IEC members from only select research institutions (both government and private) in India, which are well-known for expertise in conducting clinical research and having well-established, accredited IECs. These opinions may not therefore be representative of other IECs in other research institutions or teaching hospitals in the country. Secondly, all the interviews were conducted during the COVID-19 pandemic and this might have influenced the perceptions compared to if the study had been done at another time. This was the first exploratory study amongst IEC members and did not focus on CHIM study for any particular disease. Future studies may look into risk and benefits of specific CHIM models of diseases of public health importance from the point of view of general public, IEC members or researchers.
Many of the concerns identified during this study have been addressed in the recently published WHO guidance on ethical conduct of CHIM studies, and that document will hopefully act as a roadmap for providing country specific guidance or regulations 16 . A need for the harmonization of guidelines for CHIM studies across the world has been expressed 39 . However, such international initiatives do not take away from the imperative of having our own guidelines in India, specific to our societal conditions and medical research milieu. Our study findings from a key stakeholder perspective of members of Indian IECs could pave the way in preparing the regulatory and ethical guidelines for implementation of CHIM studies in India.
Finally, much training, infrastructure development and strengthening of processes need to be in place before the introduction of CHIM studies in India can be considered safe and ethical. Public engagement and clear regulatory guidelines based on basic ethical principles can aid in creating a sustainable model for CHIM research. The establishment of required infrastructure with mandatory clinical units and residential facilities for the participants would be a key step, since the participants need to spend an average of 10-15 days in the facility. Rigorous safety standards are needed for CHIM studies especially owing to the infectious nature of the pathogens. These include mechanisms to ensure that participants do not come into direct contact with others and there is appropriate bio-medical waste disposal in the facility. It is suggested that both public and private institutions can be involved in conducting CHIM studies, and that such studies be funded by government bodies, to prevent allurement of institutions and investigations by commercial firms.

Conclusion
In conclusion, members of IECs believe that it is important to conduct CHIM studies in India; however, before this is done, we would need to develop a specific regulatory and ethical framework for such studies, train research staff and IEC members, and put in place specialized research infrastructure, besides ensuring adequate community sensitization. Clinical infrastructure in terms of equipment, personllem and facilities are a nonnegotiable basic as medical safety of the research participants is non-negotiabe. Our findings directs us towards a realization that preparedness for something as new and challenging as CHIM studies in a context such as India, requires readiness of multiple stakeholders, not sequentially but in parallel with each one of the constituent stakeholders having an influence over the other. Is it regulations that need to come first or public advocacy? Clinical and research infrastructure or training of all personnel involved? These are chicken and egg situations with no answer to be even attempted. This study has been critical in influencing a bottom up understanding of readiness of Ethics Committees not in isolation but with a number of other conditions in play. The conditions of the road, the skills of the driver, the availability of the Police, the functioning of the traffic lights and the agency and civic sense of the general public are all essential for a smooth ride!.

Data availability
Underlying data The authors confirm that, for ethical and security reasons, they are unable to make interview transcripts and internal administrative documents publicly available. As outlined in the consent forms, interview respondents were informed that the data would be shared without revealing individual identities and with other researchers after approval by relevant local and national review committees. Requests for these data can be sent to the corresponding author [abhishekanthropu@gmail.com]. Access to these restricted data will be granted where deidentification can be adequately achieved to protect the privacy and confidentiality of the respondents and any mentioned individuals and institutions, and where the proposed use is seen as relevant to the nature of the data. This project contains the following extended data: -ANNEXURE-I FGD GUIDE.pdf (Topic guide for FGD (focus group discussion)).

Open Peer Review
This manuscript provides timely and important insights into key stakeholders' perceptions, views, and readiness to review research involving controlled human infection model (CHIM) studies in India. I strongly recommend its approval. This study makes a significant contribution to the academic literature and will be of great use to policymakers and others hoping to introduce CHIM studies in new settings.
The following points are suggestions intended to strengthen the quality and contents of the submission. They should be viewed as "food for thought" but not as requirements for publication. The principle of 'non-maleficence' is a fundamental principle of medical ethics and involves a duty that a physician has toward their patients. When this principle is extended and adopted to a research ethics context, especially for non-therapeutic research, it is unclearand a matter of vigorous academic debate -whether asking participants to partake in a study involving minimal risk (or risk slightly above minimal risk) violates the principle of non-maleficence. Here, I'd encourage the authors to rethink stating without qualification that CHIM studies violate the principle of non-maleficence. If this is the view of the authors, perhaps further substantiation could be provided.

1.
It would be good to know whether participants' views, perceptions, and readiness to review CHIM studies depends on the level of risk or the kind of CHIM study. Some of the feedback shared clearly have to do with CHIM studies involving more than a slight increase above minimal risk, where rescue treatments are needed, and where there is a risk of long-term harm or disease. However, views, perceptions and readiness may change if the CHIM studies under consideration were deemed to be slightly above minimal risk. If such information could be provided, that would be helpful.

2.
Some discussion on what it is about CHIM studies that warrants special ethics and regulatory attention would be helpful to situate the paper, and guide readers in their understanding of how, for example, a CHIM study is different than a first-in-human phase 1 drug trial.

3.
I would encourage the authors to build upon this important work. One possible route they may take is to draw a distinction among the various themes and challenges raised and determine whether such themes and challenges are (i) ethics/research ethics issues or (ii) practical issues, and then come up with remedies and solutions to adequately address them. Given the potential social and societal benefit of conducting CHIM studies in India this seems to be one potential next step. Another possible route the authors might take is to conduct a similar study where they engage research ethics committee members' perceptions, views and readiness to review specific CHIM studies for particular diseases and pathogens that have a high burden of disease in India, and where CHIM studies may provide significant scientific and social value. This kind of more specific feedback may be particularly helpful with the introduction of CHIM studies that investigate particular diseases/pathogens in India.

4.
To reiterate, the four comments above are simply suggestions. Overall, this is an excellent manuscript that makes a significant contribution to the academic literature. While community engagement in India on the introduction of CHIM studies has been going on for some time, this is the first study of its kind to systematically engage research ethics committee members directlyi.e., the individuals who have special responsibilities to safeguard the rights, safety, and welfare of research participants.
individual benefit to them1, a possible violation of the principle of non-maleficence. The degree of it could vary depending on the pathogenicity of the virulent introduced, the dosage and the preparedness to manage its onslaught on the body and the effectiveness of the treatment available. This issue of non-maleficence is heightened further when there is no treatment available for the infection.
2. It would be good to know whether participants' views, perceptions, and readiness to review CHIM studies depends on the level of risk or the kind of CHIM study. Some of the feedback shared clearly have to do with CHIM studies involving more than a slight increase above minimal risk, where rescue treatments are needed, and where there is a risk of longterm harm or disease. However, views, perceptions and readiness may change if the CHIM studies under consideration were deemed to be slightly above minimal risk. If such information could be provided, that would be helpful. Response-You are absolutely right in asking this as to how the participant's views changed based on the level of the risk. This makes for an excellent research question for a follow-up study with larger sample sizes, and multiple vignettes with scales developed. Since this was the first exploration in India, we were unable to assess this in this study. We have to note that this study was looking at IEC members' perceptions of hypothetical CHIM scenarios and was being cautious and looking at worst case situations to protect research subjects. Future studies could look at specific comparisons of 'high risk' and 'low risk' CHIM studies and the differences in responses.
3. Some discussion on what it is about CHIM studies that warrants special ethics and regulatory attention would be helpful to situate the paper, and guide readers in their understanding of how, for example, a CHIM study is different than a first-in-human phase 1 drug trial. Response-Thank you. We have added the following sentence in the discussion: CHIM studies are different from first in human studies as these studies don't just involve exposure to new drug but include establishment of a disease model in healthy humans using a standardized pathogen and then evaluating the effects of drugs and vaccines within the established disease model. This is in the context where people outside the study have already suffered from the pathogen as against a new drug which has never been used before.
4. I would encourage the authors to build upon this important work. One possible route they may take is to draw a distinction among the various themes and challenges raised and determine whether such themes and challenges are (i) ethics/research ethics issues or (ii) practical issues, and then come up with remedies and solutions to adequately address them. Given the potential social and societal benefit of conducting CHIM studies in India this seems to be one potential next step. Another possible route the authors might take is to conduct a similar study where they engage research ethics committee members' perceptions, views and readiness to review specific CHIM studies for particular diseases and pathogens that have a high burden of disease in India, and where CHIM studies may provide significant scientific and social value. This kind of more specific feedback may be particularly helpful with the introduction of CHIM studies that investigate particular diseases/pathogens in India. Response-Thank you for this comment and your positive feedback. We will definitely take up these suggestions for the next phase of studies. We have added the following sentence in the discussion section: This was the first exploratory study amongst IEC members and did not focus on CHIM study for any particular disease. Future studies may look into risk and benefits of specific CHIM models of diseases of public health importance from the point of view of general public, IEC members or researchers.
of data of IDI considering that perceptions are subjective and would vary with the educational background and expertise.
Themes are not properly constructed; they are broad and moreover are like headings of the paragraphs.

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There is no category development, and there is an absence of a coding framework (should have a table explaining the process from code-categories-themes).

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Triangulation of data from different sources/participants is not attempted.
○ A substantive theory is produced in order to present the findings of a Grounded Theory -as a collection of concepts connected to one another in an interconnected whole. The absence of a theoretical framework/theory is the biggest lacuna of the study.

Are sufficient details of methods and analysis provided to allow replication by others? Partly
If applicable, is the statistical analysis and its interpretation appropriate? Not applicable 1. Introduction requires strengthening of the rationale for study. The Introduction states the ethical challenges in CHIM studies, namely the possible intentional harm of introducing a pathogen into a healthy consenting study volunteer, the vulnerability of study volunteers especially considering the socio-economic situation of India and hence the important role played by the Institutional Ethics Committee, the key functionary in the protection of human volunteers as mandated by all ethical regulatory bodies and also the Indian Council of Medical Research. To reiterate the rationale the following line has been added to the end of the Introduction: The present study has been carried out amongst consenting members of IECs from multiple health care research institutes in India with experience in conducting clinical trials to elicit their views on the ethics of conducting CHIM studies in India. Following text has been added to the introduction section: A disease-causing pathogen is for the purpose of study, intentionally inoculated into healthy, consenting adult volunteers, with no individual benefit to them1, a possible violation of the principle of non-maleficence. The degree of it could vary depending on the pathogenicity of the virulent introduced, the dosage and the preparedness to manage its onslaught on the body and the effectiveness of the treatment available. This issue of non-maleficence is heightened further when there is no treatment available for the infection.
2. Overlapping of methods (FGD-IDI) needs to be justified. Thank you for this comments. FGDs and IDI, played a complementing role. While FGDs provided the dynamic process of discussion and deliberation similar to the real world functioning of IECs in reviewing research proposals, the IDIs helped to provide a more indepth perspective of individual members. Provision of allowing IDI also allowed views of a member who could not make it on the day of the FGD to express his/her views. One method helped the other and hence the need to have these overlapping methods. We have added the above text to the methods. analysis of the data. As there was no theoretical framework for this research question, we had to start by a thematic analysis and building it from the data. The work of Strauss A, Corbin JM: Basics of qualitative research: Grounded theory procedures and techniques. Thousand Oaks, CA, US: Sage Publications, Inc; 1990; 270 has been used to guide the GT approach followed and has been explained with this line This exploration is referred to as 'grounded' since they are based on the participants' own explanations or interpretations. An inductive approach ensures that the researcher begins with an almost blank slate and considers the opinions of the participants rather than imposing one's own. The following line has been added: This was important as CHIM studies are new and de novo rather than a priori ethical responses to them were being sought. Response: Thank you for the suggestions. We deliberated on this same matter and concluded that we did not want to draw inferences state wise or make comparisons across institutions but rather look at emerging viewpoints across all sites across India. All ethics committees adopt the same principles of thinking and functioning as all international ethics regulatory bodies and principles which are also aligned to the rules and regulations of the ICMR National Ethical Guidelines for Biomedical and Health Research involving human participants. We were keen to bring in views from different disciplinary backgrounds such as basic scientists, lawyers, clinicians etc. Also another consideration was confidentiality. Any further details -site specific would break the code of confidentiality, which we had signed on when seeking consent from the members of the ethics committees at each site. We did not want a any site specific disclosure or individual identities. We did not want to jeopardise the ethical premise of the confidentiality of data and processes.
8. For such type of research expect a detailed conclusion with recommendations. Response: This study was not powered to be normative or prescriptive but to be descriptive and provide direction for future work -research, training, development stringent code of conducts to suit CHIM studies , or fine tuning of guidelines and public engagement. This has been spelt out in Figure 3. Proposed risk mitigation measures for CHIM studies. A line summarising the above figure has been brought into the paragraph on Conclusions. In conclusion, our grounded theory approach to our findings directs us towards a realisation that preparedness for something as new and challenging as CHIM studies in a context such as India, requires readiness of multiple stakeholders, not sequentially but in parallel with each one of the constituent stakeholders having an influence over the other. Is it regulations that need to come first or public advocacy? Clinical and research infrastructure or training of all personnel involved? This study has been critical in influencing a bottom up understanding of readiness of Ethics Committees not in isolation but with a number of other conditions in play. For example introducing formula racing -one has to also consider the conditions of the road, the skills of the driver, the availability of the Police, the functioning of the traffic lights and the agency and civic sense of the general public are all essential for a smooth ride! Abhishek Sharma Response to Additional comments: • The study mentions that FGDs were conducted to understand the deliberative process of decision-making in IEC meetings and IDI to understand perceptions about CHIM-analysis could have been done independently for both sources.
Response: This has been addressed earlier " FGDs and IDI, played a complementing role. While FGDs provided the dynamic process of discussion and deliberation similar to the real world functioning of IECs in reviewing research proposals, the IDIs helped to provide a more in-depth perspective of individual members. Provision of allowing IDI also allowed views of a member who could not make it on the day of the FGD to express his/her views. One method helped the other and hence the need to have these overlapping methods." As mentioned earlier, these were overlapping methods. The codes and themes were generated using iterative methods.
• Heterogeneity among the participants as clinicians (CN), biomedical scientists (BM), social scientists (SS), legal experts (LE), and lay persons (LP). Context-specific analysis with respect to the expertise of the IEC members could have been done rather than a common analysis of data of IDI considering that perceptions are subjective and would vary with the educational background and expertise. Response: As mentioned earlier, while participants appear heterogeneous in terms of their individual backgrounds and domains of expertise, they are homogenous in terms of the purpose of coming together and being selected as IEC members … ie. the protection of human volunteers participating in biomedical research and the upholding of ethical standards in human participant research. We had to also be sensitive to maintaining the confidentiality of the sites and study participants. Ethics committee composition is pubic knowledge, so any more details would be breaking the code of confidentiality about who has said what from which committee.
• Themes are not properly constructed; they are broad and moreover are like headings of the paragraphs. Response: Being the first exploratory study from India, the themes were built from bottom up.
• There is no category development, and there is an absence of a coding framework (should have a table explaining the process from code-categories-themes). Response: Subthemes used in the analysis are analogous to categories as they have emerged from the codes and feed into emerging themes. Please refer to figure 1 and 2 of the manuscript that explain the methods in details.
• Triangulation of data from different sources/participants is not attempted. Response: We have used overlapping methods i.e. in-depth interviews and focused group discussion for this purpose. Also, data has been collected from different members of the IEC that play distinct roles in the decision making while conducting ethical review.
• A substantive theory is produced in order to present the findings of a Grounded Theory -as a collection of concepts connected to one another in an interconnected whole. The absence of a theoretical framework/theory is the biggest lacuna of the study.

Response:
We have used the principles of grounded theory to guide the process of iterative analysis of the data. As there was no theoretical framework for this research question, we had to start with a thematic analysis and building from the data.

Competing Interests:
No competing interests were disclosed.