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The Global Burden of Disease study estimates 63 400 (95% CI 38 900 to 78 600) snakebite deaths for 2019, with about 80% in India and Pakistan. In 2019, the WHO set the target to halve the burden of snakebite by 2030 and recognised the need for fostering research on snakebite treatment as a strategy towards ‘ensuring safe, effective treatment of snakebite’. Major funders, such as Wellcome Trust, have committed investments for developing better treatments for snakebite. A 2022 landscape analysis found that, since 2015, 196 candidate therapeutics (drugs and biologics) and 127 available immunoglobulin products (animal plasma/serum derived) had been researched for snakebite treatment. With a pipeline of candidate therapeutics, more intervention research on snakebite is imminent. Interest from snake antivenom (SAV) manufacturers might also be expected to increase to comply with Target Product Profiles (TPPs) for SAV being developed by the WHO.

To the best of our knowledge, and published research at that time, our research group, in 2020, first identified the need for developing a core outcome set (COS) for snakebite. A COS is a consensus-derived, minimal list of outcomes that should be measured in research or practice for a particular health condition. Apart from standardisation, which enables comparison, a COS also ensures that outcomes which are measured in research are relevant to not only researchers but also to healthcare workers, patients and other stakeholders, thus, enabling research efficiency. We aimed to develop a COS for studies on snakebite management in South Asia (Bangladesh, Bhutan, India, Nepal, Pakistan and Sri Lanka) for interventions that: Are for management of the bitten part, for example, for the management of wounds, bacterial infections and or swelling of the limbs and compartment syndrome. Are specific to management of neurotoxic manifestations, for example, ventilation-different modalities and neostigmine edrophonium. Are specific to management of haematological manifestations, for example, blood products—different types, plasma exchange, heparin and recombinant factors.

We focused on South Asia due to its high burden of snakebites and similarities in the distribution of medically important snakes, health systems structure and a shared cultural history. Unlike other health conditions, which are clinically similar globally (and thus a global COS has high usability), snakebite envenomation is a heterogeneous clinical condition. The clinical presentation and interventions for its management are dependent on snake species in a particular geographical area. It is for this reason that WHO develops region-specific practice guidelines and TPPs, rather than global ones. By setting the scope of the COS to a region (South Asia), we aimed to develop a more contextually relevant and better-suited tool for use in future research to facilitate safe and effective treatment in the region. The categorisation of interventions into five different groups (in the aforementioned objectives) is in alignment with WHO-SEARO (South-East Asia Regional Office) guidelines for the management of snakebites. The study was set up to develop a COS for each intervention category, allowing researchers and trialists to choose one that is appropriate to the intervention they are evaluating in their study.

We registered the study in the COMET database ( https://comet-initiative.org/Studies/Details/1849 ) and developed the study protocol a priori. We report our compliance with the Core Outcome Set-STAndards for Reporting (COS-STAR) reporting guideline in . There were no protocol deviations.

A steering committee for the study included representatives of the COMET Initiative, healthcare workers and researchers from Bangladesh, India, and Nepal and a community practitioner from India, leading snakebite mitigation and prevention programmes (see the ‘Acknowledgements’ section). This committee members played an advisory role, providing inputs through emails and virtual meetings, and the members did not participate in the Delphi survey.

We generated the initial list of outcomes from a systematic review of outcomes (separately published), which categorised outcomes as per a standard outcome taxonomy. Based on the results, we confirmed, with the steering committee, the scope of the project to exclude the development of a COS for mental health interventions for snakebite, although it is an important area of concern. For the reasons stated, we did not include the following types of outcomes, identified from the systematic review, in the Delphi survey: Psychiatric outcomes: deemed out of scope. Immunological or serology related (eg, venom concentration or antibody measurement): deemed as proxy, not relevant to clinical decision-making and not feasible. Composite outcomes: varied combinations, not validated in South Asia, impedes patient and public understanding and are difficult for healthcare communication.

We reviewed all remaining outcomes and merged those that are sufficiently similar, into a single item. We did this with the intent of limiting survey time to 30 min per round and avoiding confusion around similar outcomes (particularly in non-clinician health workers, patients and the public). Survey time is a key factor for participation, completion and retention in Delphi surveys. Delphi participants could see details of each outcome entity by clicking on it. During the pilot phase, we conducted multiple rounds of testing on the survey tool to avoid ambiguity in language for the outcomes and to acquire feedback on instructions, presentation and time of completion (see the ‘Acknowledgements’ section).

Three groups of participants (18 years and above) participated in the Delphi survey: Healthcare providers (clinicians, nurses, community health workers and social workers) involved in snakebite care. Patients and the public (snakebite survivors, family members of a person who has experienced snakebite and representatives of communities affected by snakebite). Potential COS users (researchers including trialists, venom researchers, systematic reviewers, journal editors, research funders and guideline developers). All participants were from South Asia. For the ‘potential COS user’ category, those with an international scope of work related to snakebite also participated. The study was designed to be multilingual with options in Bangla, English and Hindi, primarily to enable participation of patients and the public. We recruited participants through email (authors of published studies and trial registry records), recruitment posters (for patients and the public), email lists of snakebite-related organisations/networks and institutional social media accounts. All potential participants were introduced to the COS concept through a plain language summary and a COMET Initiative video. Those who expressed interest were sent the participant information sheet and a link for registering in Delphi Manager, a web-based online system, through which the two-stage electronic Delphi survey was instituted.

In both rounds, participants rated outcomes on a Likert scale of 1–9 (wherein a rating of 1–3 corresponds to ‘limited importance for decision-making’; 4–6 to ‘important for decision-making, but not critical’ and 7–9 to ‘critical for decision-making’) for five different modules, corresponding to the five interventions groups for which the COS was developed. During the Delphi voting, intervention modules appeared at random, with no fixed order. In the first Delphi round, participants could suggest additional outcomes, for consideration of inclusion in the second round. We carried all outcomes from the first round and relevant additional outcomes (reviewed by the research team and steering committee member) to the second Delphi round. In the second round, participants saw their own ratings as well as group ratings for the three stakeholder groups and were asked to consider rescoring the outcomes. We defined consensus for the Delphi a priori as: Consensus of classification as a core outcome (consensus in): ≥70% of participants in all three stakeholder groups give a score between 7 and 9 (critical for decision-making) and ≤15% of participants in all three stakeholder groups give a score between 1 and 3 (of limited importance for decision-making).

Consensus of classification as not being a core outcome (consensus out): ≥70% of participants in all three stakeholder groups give a score between 1 and 3 (of limited importance for decision-making) and ≤15% of participants in all three stakeholder groups give a score between 7 and 9 (critical for decision-making). If a participant skipped rating a particular outcome, we used the actual number of responses for each outcome to calculate the proportions. We invited those who participated in both the rounds of the Delphi to attend an online consensus meeting. For outcomes on which there was ‘no consensus’ after two rounds, the participants deliberated and voted to achieve consensus as per the following a priori criteria: Consensus in: >70% of meeting attendees marked it as critical for decision-making. Consensus out: ≤70% of meeting attendees marked it as critical for decision-making.

We were guided by the principles of the COnsensus-based Standards for the selection of health Measurement Instruments guidance to develop consensus recommendations on how outcomes in COS should be measured. The minimum criteria for choice were to have good content validity (including face validity), good internal consistency (if applicable) and be feasible in the South Asian Context. In addition, we also considered reliability and responsiveness (if applicable). We listed options for ‘how’ outcomes in the COS should be measured (including different definitions available and relevant time points for each included outcome) in a tabular manner noting details about its content validity, internal consistency, feasibility and reliability and responsiveness of each tool. For this purpose, we use information from the systematic review conducted in phase I, and additionally conducted focused literature searches, as relevant. We shared the document with participants online, for consultation for 15 days giving them time to comment, modify and edit our document on any aspect. Subsequently, an online workshop was organised where the COS with measurement recommendations (definitions and time points) was finalised. We had planned to do voting should there be no consensus, among participants, but this was not necessary.

The Delphi survey took place during August–October 2022. A total of 81 participants registered in the Delphi Manager platform, out of which 9 did not participate in the survey (ie, did not rate any outcome). Overall, 72 participants completed the first round, and 61 participants (84.7% of the 72) completed the second round. In the first round, four (5.5% of 72) participants did not rate outcomes in all five intervention modules. The corresponding number in the second round was two (3.2% of 61). Characteristics of Delphi participants are presented in .

After the first round, consensus was achieved on the inclusion of one outcome in the intervention specific to the neurological manifestations module, and two outcomes in the interventions that target snake venom module. For all other outcomes, no consensus was attained. We reviewed 16 free-text responses from 8 participants with regard to additional outcomes and included 1 for rating in the second round which was—outcomes specific to viper bites (capillary leak syndrome, thrombotic microangiopathy and adrenal/pituitary insufficiency). Details on suggestions received and reasons for their inclusion or exclusion in the next round are presented in . After the second Delphi round, a ‘consensus in’ status was obtained for two outcomes in the preventing adverse reaction intervention module, four outcomes in intervention specific to neurological manifestations module, two outcomes in intervention specific to haematological manifestations module, and five outcomes in interventions that target snake venom. In both the rounds, no consensus attained ‘consensus out’ status.

The results of the Delphi rounds with scores were sent to all participants who completed both rounds, before the online consensus meeting. A total of 13 (10 male and 3 female) participants from Bhutan (1), India (9), Sri Lanka (1), Malaysia (1) and Australia (1) attended the consensus meeting. No patient or public stakeholder joined the meeting. All outcomes in the ‘no consensus’ category were discussed and voted on to achieve the final decision regarding inclusion or exclusion for the COS. A summary of different consensus decisions in the two rounds of Delphi, with detailed scoring is presented in .

In this phase of the project, 16 people (including 3 who expressed intent to join the consensus meeting on ‘what’ outcomes should be part of COS but were unable to attend the meeting at the last minute) participated. In the online consultation, the participants reviewed and discussed ‘how’ the outcomes included in the COS should be measured. Overall, we received 203 responses during this consultation, including suggested edits, notes on agreement and disagreements, discussion on preference parameters, definitions and time points of measurement. After the online consultation, there was unanimous consensus on outcome definitions for: All three outcomes in preventing adverse reaction intervention COS. All, but two, outcomes in intervention specific to neurological manifestations COS. All five outcomes in intervention specific to haematological manifestations COS. All, but one, outcome in interventions that target snake venom COS. In the final online workshop, the participants discussed all pending issues to arrive at a consensus on all aspects of how the core outcomes should be measured in future intervention studies. The final COS for intervention research for different intervention groups, along with recommendations for measurement, is presented in .

In this study, we developed a COS of what and how outcomes should be measured in future intervention research on snakebite in South Asia in four domains. The COSs are on interventions that prevent adverse reaction to SAV (three outcomes), specifically for the management of neurotoxic manifestations (five outcomes), specifically for the management of the haematological manifestations (five outcomes) and on interventions that act against snake venom (seven outcomes).

Setting the scope for COS for snakebite is challenging. Snakebite is a heterogeneous condition, dependent on the varying distribution of species geographically and consequent variability in interventions. A very narrow geographical scope of COS would have a very well-defined context, with few conflicting opinions on what should and should not be part of the COS. However, the relevance of such a COS might be limited to trials in the specific geographical area or population only. On the other hand, a very wide geographical COS would be contextually less relevant, with challenges in achieving consensus (leading to agreement on the inclusion of too many or too few outcomes), thus hampering its utility and applicability. We contend that a regional scope based on similarity in geographical species, health systems and shared sociocultural history, as was done in our COS, achieves the right balance. For snakebite, another research group has developed a global COS but this is might not be ‘fit for purpose’ in specific regions, such as South Asia. A global COS is conceptually problematic for snakebite. It is not in alignment with other ecosystem initiatives that seek to balance between heterogeneity and standardisation, through a regional basis of work. For example, standards around clinical practice or production of therapeutics are developed on a regional basis by the WHO. Furthermore, in contrast to the global COS, which focuses on therapeutics against snake venom alone, our COS includes several types of interventions, thus enhancing its utility.

In interpreting and using the findings of the COS on interventions for the management of the bitten part, it is worthwhile noting that the intervention group consists of three distinct aspects: wound management, bacterial infections and swelling of the limbs. We reflect that this broad scope might have prevented achieving consensus. For the future, we recommend development of separate COS for the three aspects separately. In the interim, trialists and systematic reviewers working in this area might consider inclusion of the three outcomes that would have been included if we had lowered the threshold from 70% to 50%. These are oedema or swelling (localised around the area/extremity in which the bite has occurred), requirement of any type of surgery and impact on life after snakebite (functional impact, disability, quality of life, extremity function and recovery).

We followed standard methods of COS development and reported in accordance with the COS-STAR guidelines.Involvement of stakeholders was in alignment with the scope, relevancy of COS for multiple types of interventions and provision of clear recommendations on how to measure outcomes enhanced the utility of our COS. The number of outcomes in each intervention module in our COS is relevant and reasonable.

We faced considerable challenge in achieving greater involvement of patients and the public. We did anticipate the challenge, and therefore, designed our study to be multilingual, with options to participate in Bangla, English or Hindi. However, despite the multilingual option, extensive promotion through recruitment posters in multiple communities in India (we did not do so in other countries), and social media acceleration, we could recruit only 12 participants in this group. There was no patient participation in phase 3. While the Delphi approach does not depend on statistical power, a minimum number of 10 participants are considered necessary to give reliable results. We did achieve this number for all intervention modules except one, which the participation of patient and public group was suboptimal. Four participants skipped the module on interventions that are specific for management of haematological manifestations, in entirety. Two of these participants noted that this was because they did not experience haematological manifestations. We believe participation in the patient and public group was impeded overall because of multiple reasons: absence of lived experience around outcomes or intervention groups, digital nature of the Delphi and the low levels of education in people who are most affected by snakebite. Four snakebite survivors who expressed interest could not differentiate between ratings for the importance of outcomes versus ratings for the severity of outcomes. Despite our endeavours, we were unsuccessful in communicating that importance and severity, although related, are not the same. For the future, we recommend methodological research to support and improve patient and public participation in COS development for conditions, such as snakebite, which primarily affects those with little or no education and people deprived of health literacy.

Other methods that can be tested are—interviewer-administered Delphi, the use of graphical visual cards and interactive animation with native language audio to support the Delphi survey. There is also a need for providing more guidance for the patients and public group on deciding how to measure outcomes, where discussions are highly technical in nature. We tried to mitigate this by asking a member of our steering committee, who is a community practitioner leading a snakebite mitigation and prevention programme, to join the consensus meeting. We acknowledge gender imbalance in terms of less participation of female health workers. We also note the limited participation of nursing staff.

The COS-STAD sets the minimum standards for COS developers to follow and COS users to evaluate methodological rigour. We suggest that future iterations of COS-STAD should consider adding a standard around geographical region within the scope specification domain. Such a specification is not only important for conditions like snakebite which have clear geographical variation, but also for other health conditions where variation in cultural preferences and health systems is important. The COS-STAD guideline might also be revised to have more nuanced standards to ensure that COS development happens through the meaningful involvement of stakeholders from high burden and endemic nations. A recent systematic review found that only 20% of COS included LMIC participants. It is known that non-involvement or tokenistic involvement of appropriate stakeholders decreases the utility, acceptance and uptake of COS. Setting a standard for representative participation will fill this gap and contribute towards the larger challenge of poor stakeholder engagement and low uptake of COS in most research areas.

For many neglected tropical diseases and acute medical emergencies (not linked to chronic disease), such as snakebite, there are no organised survivor groups that can support recruitment in COS development. This is also true for many chronic conditions in low-income and middle-income countries. The current strategy of the COMET People and Patient Participation, Involvement and Engagement (PoPPIE) Working Group for involvement and engagement is predominantly focused on patient organisations. Guidance and tools for community engagement might be developed by the COMET-POPPIE group to enable future COS development.

To enhance the uptake of our COS, the core study team will develop a strategy to increase awareness, engage with potential users and promote the adoption of COS in the wider evidence ecosystem, as recent work on the area of COS uptake has suggested. We will engage with national research funders (such as Bangladesh Medical Research Council, Indian Council of Medical Research, Nepal Health Research Council, Pakistan Health Research Council), professional bodies, medical journals and clinical trial registries (Indian and Sri Lankan) in South Asia to endorse and promote the uptake of this COS for future intervention research on snakebite. During our phase III discussions, numerous challenges and issues around the measurement of outcomes in intervention research on snakebite were raised. A by-product of this study is the formulation of an epistemic community of clinicians and COS users, who hope to work together on a position statement noting challenges and a research agenda on outcome measurement for snakebite trials. We will audit clinical trials conducted on snakebites in South Asia, 3 years after publication of the COS to evaluate the effect of the COS we developed and adjust strategies for its uptake.

The Delphi process resulted in the development of a COS for snakebite research in South Asia, which would enable standardisation of outcomes, facilitate meaningful comparisons and improve efficiency in research in the South-Asian region. Our research has also led to methodological insights, particularly around development standards of COS, and patient and public engagement.