Is India ready for controlled human infection studies? A narrative review of stakeholders' perceptions & regulatory preparedness

Abstract

Background

Controlled Human Infection Studies (CHIS) involve the introduction of standardized, attenuated or wild type microorganisms into healthy volunteers to further advance understanding of disease pathophysiology, response to treatment and accelerate the development of vaccines and therapeutics. Although CHIS are established in many countries, India has only begun to explore their possibility. This study aims to examine the prevailing stakeholder perceptions and regulatory preparedness for CHIS in India.

Methods

A structured literature search was conducted in PubMed, Scopus, and Embase using terms related to CHIS and India. Qualitative studies, surveys, viewpoints, and review articles addressing stakeholder perspectives and regulatory issues were screened. Three empirical studies met the inclusion criteria.

Results

Available evidence indicates that Indian stakeholders acknowledge the potential of CHIS for accelerating vaccine development, particularly for endemic diseases and public health emergencies whilst trying to address different research questions such as concerns regarding participant safety, informed consent, public trust, regulatory oversight, biosafety infrastructure, compensation, and protection against exploitation of vulnerable populations. Public awareness of CHIS was mostly marginal with focus on the time it would take for benefits to reach the public, while ethics committee members emphasized the need for more development in the technical and legal aspects. The 2023 Indian Council of Medical Research policy statement for CHIS provides an important ethical framework, but certain operational and regulatory challenges persist.

Conclusion

India demonstrates conceptual readiness however sustained public awareness, ethics committee training, and comprehensive participant safeguards are essential to ensure that CHIS are conducted responsibly, while upholding the principles of beneficence, non-maleficence, and participant autonomy.

1. Background

Controlled Human Infection Studies (CHIS) or human challenge studies, involve controlled and measured introduction of a standardized attenuated or wild type infectious organism (bacteria, virus or protozoa), into healthy consenting adults, to elicit infection for understanding of disease pathophysiology, response to treatment and prevention strategies such as vaccines. [1] This unique research design warrants additional safeguards and precautions for all stakeholders including sponsors, researchers, institutions, ethics committee members and most importantly the study participants and public. While such studies are being conducted elsewhere in the world, including developing nations like Kenya, Gambia, Uganda, Malawi andThailand [2], [3], [4], [5], India has also begun to explore their possibility of conduct. Indian Council of Medical Research (ICMR) recently released the policy statement for the ethical conduct of CHIS in India in 2023 for which several deliberations on the ethical aspects of such studies, involving biomedical researchers, clinicians, policy makers, regulators, ethics and legal experts from the country, as well as international experts with previous experience of doing such studies, have been held since 2017 [6]. Even though CHIS can aid substantially in early drug and vaccine development, it continues to raise multiple ethical, legal and feasibility concerns. These issues warrant a multi-dimensional approach, keeping into account the regional and cultural relevance, and acceptance among the public, while formulating the necessary legal and ethical frameworks to maximize benefit and minimize harm to study volunteers. [7], [8] This narrative review aims to collate the concerns and preparedness of various stakeholders, namely ethics committees and more importantly the general population, specifically in the Indian setting.

2. Methodology

A structured literature search was performed to identify published articles on controlled human infection studies (CHIS) in the Indian context. The inclusion criteria comprised of qualitative and/or questionnaire-based surveys conducted in India in the last 10 years, seeking the perspectives or viewpoints of major stakeholders in the context of CHIS, namely, the general population, ethics committee members, medical institutions, industry sponsors and regulatory bodies.

The electronic databases PubMed, Scopus and Embase were searched, and additional manual screening was done with reference lists of included articles. The principal search strategy combined free-text terms related to controlled studies and India. The search string included, (controlled human infection study OR controlled human infection studies OR controlled human infection model OR controlled human challenge OR human challenge study OR human challenge studies OR controlled human infection OR CHIS OR CHIM OR human infection study) AND (India) ((CHIS terms) AND (ethics OR regulation OR governance OR LMIC OR low middle income countries OR stakeholder OR perception). Our literature search was restricted to articles published in English. Review articles, conference abstracts, editorials without substantive discussion, and publications unrelated to the Indian context were excluded. The primary electronic search using the abovementioned keywords identified 14,483 searches on PUBMED, 35 on SCOPUS and 27 on EMBASE. After removal of duplicates and screening for relevance, 98 full-text articles were assessed, of which 3 empirical studies met the eligibility criteria.

3. Results

Based on the literature search we found two qualitative studies (using grounded theory and inductive approach), exploring the perceptions of ethics committee (EC) members and public of rural and urban Bangalore, conducted in 2022 and 2020 respectively, and one cross-sectional systematic survey conducted in 2025 by JIPMER Puducherry, with the purpose of providing the foundation for future capacity-building initiative among the ethics board [7], [8], [9] (Fig. 1). Since this review limits itself to the perspectives of Indian population, the available empirical literature and/or studies conducted on controlled human infection studies (CHIS) in India remains limited. Three primary studies were identified, comprising of two qualitative studies and one cross-sectional survey (Table 1). We would like to acknowledge that two of these studies (Sharma et al. [9] and Lakshminarayan et al. [8]), were conducted through collaborative research networks, and in overlapping academic institutions, with several shared investigators, albeit at different time points. Nevertheless, they address different research questions and participant perspectives. Sharma et al. explored ethics committee members' perceptions using qualitative methods (inductive approach and focused group discussions in 2022, whereas Lakshminarayan et al. employed a systematic cross-sectional survey following a sensitization workshop to evaluate ethics committee members' perspectives on challenges in CHIS review in 2025. The third study by Vaz et al. [7], conducted in 2020, examined public perceptions and community attitudes toward CHIS and therefore contributes with a complementary perspective. Accordingly, the findings presented in this review have been summarized under some commonly identified themes across these studies, and should be interpreted as the best available evidence on an upcoming research tool, through the lens of the pertinent stakeholders while keeping in mind the concerns and additional safeguards necessary to actually conduct CHIS in India in the near future. The overall findings of the EC members and public perceptions have been classified under three themes namely, perceived need or acceptance of CHIS, apprehensions about conduct of CHIS and possible risk mitigation strategies (Table 2).

Fig. 1.

overview of study selection based on inclusion criteria.

Table 1.

Summary of studies included.

Study / Year	Study Site(s)	Study Perspective	Study Design	Study Participants
Perceptions of members of ethics committees of medical institutions in India on CHIS following a sensitization workshop (2025)[8].	1.Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry. 2. Post Graduate Institute of Medical Education And Research (PGIMER) Chandigarh. 3. Christian Medical College (CMC) Vellore 4. Translational Health Sciences and Training Institute (Faridabad)	Ethics committee members	Cross-sectional systematic survey Semi-structured questionnaire	n = 43 Clinicians (10) Basic scientists (14) Chairpersons (4) Social scientists (4) Legal experts (2) Lay persons (2)
Perceptions about Controlled Human Infection Model studies among members of ethics committees of Indian medical institutions (2022)[9].	1.KEM Hospital Research Centre (KEMHRC), Pune 2.St. John's Research Institute (SJRI), Bengaluru 3.Yenepoya University, Mangalore 4.Centre for Chronic Disease Control (CCDC), Delhi 5.Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 6.Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh	Ethics committee members	Qualitative study: Grounded Theory and Inductive approach FGDs = 11 IDIs = 31	n = 72 Clinicians (29) Basic scientists (21) Lay persons (9) Legal experts (6) Social scientists (7)
Public perceptions on Controlled Human Infection Model (CHIM) studies – a qualitative pilot study from South India (2020)[7]	1.Urban site: Bengaluru city (urban metropolis) 2.Rural site: Mugalur village	General public & key informants	Qualitative study: Grounded Theory and Inductive approach FGDs = 11 IDIs = 18	n = 110 Urban (49): students, IT workers, teachers, slum residents, daily wage laborers Rural (36): farmers, youth, women groups, community health workers Key informants (18): clinicians, scientists, lawyers, journalists

Table 2.

Summary of the various themes and subthemes identified in studies conducted by Vaz M et al. and Sharma et al. [7], [9].

Theme 1: Perceived need/acceptance for CHIS in India
Ethics Committees' Perspectives
1.For endemic illnesses and special relevance 2.Lack of animal models or not reliably applicable to human pathogens 3.To identify early leads in emergencies or pandemics 4.For early phase vaccine trials 5.With clear and favorable risk-benefit ratio with rescue treatment readily available 6.Reducing dependence on foreign studies 7.When benefits can reach public quickly
Public's Perspectives
1. Understanding of Research	•Research perceived as a long process before benefits reach public, with clear socio-economic and geographical divide •Urban participants- associated research with clinical trials and pharmaceutical companies •Rural participants- showed limited awareness
2. Understanding of Ethics in Research	•Broadly understood in local language, related to beneficence, non-maleficence, autonomy of choice, respect, and dignity •Imperative to avoid harm and guide responsible research conduct; necessary to regulate research processes •Some distrust due to perceived commercialization and unethical trials
3. Understanding of CHIS Concept	•Most participants had no prior knowledge •CHIS understood as infecting healthy volunteers with pathogen •Participants questioned why naturally infected individuals could not be studied instead •Doubts about whether infection can truly be “controlled” due to unpredictable responses
Theme 2: Apprehensions about conduct of CHIS
Ethics Committees' Perspectives
1.Limited specialized research infrastructure and trained trial workforce 2.Risk of public exploitation 3.Challenge of attenuated viral strain standardization 4.Risk of infection to community and/or study team 5.Lack of proper regulatory framework 6.Unfamiliarity about CHIS among IEC members 7.Varied culture context including mistrust & lack of public support
Public's Perspectives
1. Ethical concerns	•Infecting a healthy volunteer perceived as ethically questionable •Acceptability increased if study had clear public health benefits •Participation should be voluntary with full understanding of risks
2. Fears & Concerns	•Major fear was risk of death or serious health consequences •Concerns about unknown long-term effects and mutation of pathogens •Fear of transmission to family or community •Mistrust due to weak health systems and past unethical research
3. Perceived benefit vs risks	•Potential benefits for vaccine and treatment to prevent diseases and save lives •Some compared it to vaccination or controlled testing •However, benefits needed to clearly outweigh risks for acceptance
Theme 3: Proposed strategies for risk mitigation in CHIS
Ethics Committees' Perspectives
1. Need for specialized infrastructure- •Laboratory and waste management facilities appropriate for biosafety level of pathogen involved •Infrastructure and protocols for PEP (post-exposure prophylaxis) •Establish a standalone set-up with 24 × 7 access to healthcare, and living facilities 2.Specific regulatory guidelines- •Monitoring periodically in different phases of CHIS, including strategies used for participant recruitment, consenting, data safety and post-trial phases •Specialized training of researchers & IEC members in scientific and ethical aspects •New formula for compensation of CHIS participants •Clearly defined participant enrolment strategies •Insurance coverage and indemnification for all stakeholders •Augmented power of IECs in decision making and suggesting substantial changes in 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
Public's Perspectives
Possible volunteers	•Risk-takers, financially needy, or those without dependents •Belief that altruistic individuals motivated by social good may participate •Tendency of “othering” was observed- participants felt others, not themselves, would volunteer •Trust in researchers, institutions, and government oversight influenced willingness to participate
Compensation and Financial Incentives	•Mixed opinions on monetary incentives for participation •Concerns that high payments may exploit economically vulnerable groups •Compensation considered acceptable for time, inconvenience, and lost wages •Suggestions for insurance or long-term care in case of adverse effects
Regulatory and Ethical Safeguards	•Need for clear regulatory frameworks and government oversight •Importance of informed consent with full understanding of risks •Emphasis on participant safety, medical care, and long-term monitoring •Call for public engagement, awareness, and transparent research practices

4. Discussion

4.1. India is conceptually ready but operationally getting there

The Human Infection Challenge – Vaccine network (HIC-Vac), established in 2017 to support and promote CHIS, conducted their fifth annual meeting [10], focusing on ‘Human challenge models for vaccines’, with emphasis on their utility, strengths and limitations in endemic settings. Eighty-five experts and representatives from various countries including India attended the meeting to deliberate on the lessons learnt from challenge models on vaccines and respiratory antivirals, along with strategies for public involvement, ethics. Industry perspectives and GMP challenges for agent manufacture. Indian scenario was presented by JIPMER, discussing the perspectives from different stakeholders and public, as mentioned in this review [8], [9]. It was highlighted that while CHIS in India is yet to be attempted, the need for risk mitigation and sustained public involvement is imperative. In this regard suggestions were taken regarding public engagement in designing trials, giving autonomy to participants and tailoring informed consent processes to risks as per pathogen and endemic or non-endemic setting. Industry representatives stated an increased utility of CHIS in quicker decision making and investment, while also answering questions on biomarker development which may not be feasible in larger field trials. However, an opposing viewpoint with respect to growing reliance on CHIS for go or no-go decision in vaccine development was also considered.

The release of the ICMR policy statement for ethical conduct of CHIS (2023) [6] marks a pivotal shift from conceptual discourse to policy acknowledgment, positioning India among LMICs formally recognizing CHIS as a potential research tool [6]. However, multiple analyses highlight that this framework is largely normative rather than regulatory, lacking statutory backing under the existing New Drugs and Clinical Trials Rules (2019) [11].

Studies by Lakshminarayan et al. (2025) [8] and Sharma et al. (2023) [9] consistently report that ethics committee members perceive absence of clear regulatory pathways, ambiguity in approval hierarchies, and lack of CHIS-specific review expertise as major barriers.

In the systematic survey conducted by Lakshminarayan et al. [8], several challenges were identified by the EC members particularly pertaining to the ethics review of CHIS. The most important challenge perceived by about 98% of the members was the need for intensive, periodic monitoring of CHIS including the consenting process. This was followed by challenges in assessing risk minimization strategies, post-trial responsibilities of researchers and performing adequate risk-benefit analysis, as expressed by 95%, 95% and 93% of EC members respectively [7]. Other challenges noted included acceptance of a lack of expertise and training of EC members to review CHIS, lack of proper national guidelines, lack of adequate infrastructure and issues regarding determining compensation, re-imbursement and insurance for the prospective study participants [8].

Further, Eberts et al. (2024) [12], emphasize that LMIC settings including India face challenges in aligning global CHIS standards (GMP-grade challenge strains, biosafety containment, and indemnity structures) with domestic regulatory systems, creating a disconnect between ethical acceptability and legal enforceability. Thus, while India has initiated high-level ethical positioning, translation into enforceable, harmonized regulatory processes remains incomplete. Dholakia & Dholakia [13] argue that without robust regulation, CHIS risks ethical vulnerability despite potential public health benefits, reinforcing the need for dual-layer review systems (institutional and national), real-time monitoring, and explicit liability frameworks.

4.2. Lessons from LMICs with experience of CHIS

CHIS for vaccines such as malaria and influenza have significantly advanced the timeline for development of effective candidates in the recent past. Typically, such framework and standard operating procedures (SOPs) for such studies are formulated in developed or high-income countries (HIC) such as UK or USA, who have successfully utilized these studies for pathogens like cholera, hepatitis C, malaria, typhoid, dengue [14], [15], [16], [17], [18], [19], [20], [21]^, to name a few. Among LMICs, CHIS has been successfully conducted in Thailand and multiple African countries such as Tanzania, Uganda, Kenya, Malawi, Gambia, Gabon and Zambia, for organisms like malaria, shigella, pneumonia and schistosomiasis. [2], [3], [4], [22], [23]

Like India, in African countries qualitative studies have been conducted to survey the perceptions of previously volunteered and possible volunteers for CHIS with respect to their experiences, concerns, suggestions and recruitment strategies followed. CHIS conducted across these countries have addressed some key issues which mirror India's concerns irrespective of the pathogen in question. First being scientific justification to conduct these studies in LMICs when prior data is available on similar organisms in HMICs – the need has been justified based on the endemicity, different genetic predisposition and variable host-pathogen interaction of the local population rendering the drugs or vaccines developed elsewhere inadequate or ineffective. Second concern being – creating equivocal international standards for CHIS conduct, including proper infrastructure, laboratories, improved clinical and emergency facilities, and the generation or importation of strains developed through good manufacturing practices (GMP). Also providing adequate compensation using standard formulae, considering all aspects such as time, daily wages lost and risks to physical and mental health are imperative. In the study conducted by Nsomba et al. [23] in 2025 in Malawi, lessons and experiences about recruitment strategies for Pneumococcal vaccine (PCV13) study were assessed. It was found that out of 299 participants, most participants were recruited via snowballing or word of mouth spread of information (71.9%). This was accredited to proper dispersion of knowledge, along with assurance from others who had gone through the same process. Other strategies employed were in-person sensitization, poster and audio-visual communication. In another qualitative study conducted by Nazziwa et al. [24] in Ugandan public, perceptions of the participants regarding CHI methods were taken. While altruism and faster drug approvals were seen as motivating factors for participation, some concerns included long term and/or serious side effects, religious and cultural beliefs disfavoring CHIS, dilemma that the Western countries may have ulterior motives to infect the African race, mistrust of researchers and government, and lack of legal framework to support CHIS. Some key proposals by the public included intensive engagement, awareness sessions, capacity building of scientists and regulators, increased government funding and adopting CHIS as the last resort study method, once all avenues are exhausted. Similar studies were conducted in Kenya and Gambia about malaria CHIS [2], [3]. While the key motivating factors included financial compensation, comprehensive health checkups and meaningful contribution to malaria research, their concerns included repeated blood sampling and the volume of blood collected. Involvement was also driven based on trust built by the implementing organization or the central health facilities as many participants revealed that well-studied pathogenesis of the disease was a key factor in taking the decision to enroll in the study. [25]

4.3. Recommendations for the Responsible and Ethical Conduct of CHIS in India [1], [6], [11], [12], [25]

CHIS should be conducted with the highest level of scientific, legal and ethical standards. This involves careful planning, coordination, monitoring and collaboration between various stakeholders.

• 1.CHIS regulations & guidelines: The need for a regulatory framework is imperative for the conduct of CHIS in India. EC members have suggested a dual review system, wherein CHIS protocols may be reviewed by both institutional EC and Central EC, prior to approval. While ICMR India released Ethical Conduct of CHIS Policy statement in 2023, CHIS-specific training of EC members in conjunction with infectious disease and epidemiology experts has been suggested by majority of EC members.
• 2.Pathogen-specific Risk Stratification for CHIS: the ICMR- CHIS policy document recognizes the need for disease specific CHIS considerations, particularly for malaria, dengue, tuberculosis and typhoid. Specifically with respect to vector bourne diseases such as malaria, the need for studies to be conducted in a secure facility to prevent exposure of participants to mosquitoes becomes imperative. Also, if vectors are being used then proper procedure for rearing and infecting the vectors needs to be in place. In dengue infection, there exists the possibility of severe infection if an individual has had previous exposure, therefore adequate history taking is must prior to participant enrolment. In tuberculosis CHIS there exists the risk for recurrent infection after treatment since the infection may not be reliably eradicated from the infected participant, with chances of community transmission and environmental contamination as well. Also, prolonged treatment poses risk for serious adverse events, with inadequate treatment modalities. For typhoid CHIS the chances of prolonged bacterial shedding in stool have been identified, which requires continued follow up of participants and proper effluent treatment in poor resource settings. Also, genetically modified challenge strains require extra caution, especially pertaining to the participant quarantine measures to avoid community transmission.
• 3.Responsibilities of institutions: Academic institutes or centers where CHIS can be conducted will require all the necessary resources, infrastructure, budget and research expertise to handle the complexities of such studies. If the study requires an enclosed setting in situations where significant clinical symptoms are expected, the facility must be well equipped with emergency and critical care provisions for quick response to prevent spread of infection. This must be facilitated with periodic checks and audits to ensure patient safety is not compromised at any stage. Additionally, ICMR recommends that CHIS should only be conducted in clinical settings with accredited and robust quality assurance programs, after obtaining due approvals from Institutional Scientific Review, Institutional Ethics Committee, Institutional Biosafety Committee (IBSC) (including infrastructure/ environment surveillance) and other relevant authorities as applicable.
• 4.Responsibilities of researchers: the entire study team must be well versed and updated on Good Clinical Practice (GCP) guidelines and ICMR ethical standards. They should also have prior experience and skills in conducting clinical studies and trials. Administration of the challenge microbe strain must be carried out by trained professionals. All adverse events should be recorded and handled promptly by the study physicians. Also, before discharging the participants it is mandatory to ensure complete resolution of the infection. A declaration or certificate of ‘complete resolution of infection’ or ‘participation in CHIS’ may be given to the participants for future reference.
• 5.Robust informed consent: informed consent is one of the most crucial processes of CHIS, which must involve a continuous dialogue between participants and investigators. Consenting may be audio-visual and in the presence of on-site monitoring by IEC sub-committee. Participants must be encouraged to undergo a test of understanding, comprising of open-ended questions, to make sure participants completely understand the study procedure and only those who demonstrate an adequate understanding of the study may be recruited. Also, clear communication regarding quarantine period and the consequences of study withdrawal to be specified, such as probability of disease transmission to third parties.
• 6.CHIS monitoring: IEC subcommittee for continuous and active study monitoring is required, right from selection of challenge strain, procedure of participant selection, informed consent process, compensation and standard of care given. Also, availability of Basic life support (BLS), trained nurses, doctors and psychologists should be appointed as part of 24 × 7 study support team.
• 7.Choice of study participants: selection of CHIS participants must be fair, ensuring that they are not vulnerable and understand the risks and benefits of the study to the fullest. The ICMR policy statement for CHIS suggests healthy adults, aged between 21 and 60 years of age, both males and females may be selected. It also emphasizes that participants should be at least graduates or those who have completed a degree program from college or university. The survey conducted by Lakshminarayan et al., saw 71.4% EC members suggesting healthcare professionals as initial CHIS participants. However, this view contrasted with the public's perceptions in the study conducted by Vaz et al., where both the rural and urban participants perceive that those in need of monetary benefits, risk takers, those with altruistic bend of mind and without family responsibilities, are the most likely to participate in CHIS (Fig. 2).
• 8.Compensation & Reimbursement: various strategies are being deliberated upon to decide the quantum of compensation for CHIS. Some EC members have also suggested alternatives that go beyond financial compensation such insurance for participants and family or compassionate employment opportunities to dependent family members. It has been suggested to use additional clauses and criteria to set compensation, apart from those mentioned in schedule seven of New Drugs and Cosmetics Act (NDCT) 2019 (Fig. 1).

Fig. 2.

Who should be allowed to volunteer for CHIS and what should the Compensation model in India might entail [8], [11], [26], [27].

5. Limitations & Conclusion

This review must be interpreted considering several limitations. First, the empirical evidence on stakeholders' perception on CHIS in India remains limited, with only three primary studies identified. Two of these studies originated from overlapping institutional collaborations and research networks, which may reduce the diversity of available evidence. Second, the included studies were conducted in few select academic institutions across India and public perception of only South Indian (Bangalore rural and urban) community was taken, limiting the generalizability of the findings to the broader Indian population. Third, stakeholder perspectives were unevenly represented, with predominant representation of ethics committee members than that of potential participants, community representatives, regulators, and policymakers. Fourth, this narrative review did not conduct a formal methodological quality appraisal of the included studies, making the synthesis descriptive rather than quantitative. Finally, regulatory preparedness is inferred primarily from the ICMR CHIS policy statement and published expert analyses, rather than from direct empirical studies of regulators or policymakers.

In conclusion, CHIS in India calls for global collaboration, guidance, expertise and training. Through this article, the opinions of different stakeholders and feasibility of CHIS in India have been explored. There is a felt need for sustained public engagement, while building awareness and advocacy in the presence of strong regulatory compliance, and keeping the principles of beneficence and non-maleficence intact.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

CRediT authorship contribution statement

Shreya Gupta: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Priyanka Mishra: Writing – original draft, Methodology, Data curation. K. Niveditha: Writing – review & editing, Supervision.

Consent for publication

NA

Ethics approval and consent to participate

NA.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the authors used ChatGPT to improve the readability and language clarity of the manuscript. These tools were not used for interpretation or drawing conclusions. The authors reviewed and edited all AI-assisted content and take full responsibility for the integrity of the work. No figures, images, maps, or graphical abstracts were created or altered using generative AI tools.

Funding

None.

Declaration of competing interest

The authors declare no conflict of interest in writing this manuscript.