Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 13 October 2020
Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 13 October 2020 Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases, 13 October 2020 ISBN 978-92-4-002404-5 (electronic version) ISBN 978-92-4-002405-2 (print version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases, 13 October 2020. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. iii Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Contents 1. Introduction 1 2. Background 1 3. Progress reports from disease-specific subgroups 2 3.1 Soil-transmitted helminthiases 2 3.2 Schistosomiasis 3 3.3 Onchocerciasis 5 3.4 Lymphatic filariasis 5 3.5 Human African trypanosomiasis 7 3.6 Skin NTDs 7 4. Update on cross-cutting subgroups 9 5. General discussion and round-up 10 6. Closing remarks 12 7. Next steps 12 8. Conclusions, recommendations and further considerations 13 References 14 Annex . List of participants 15
1Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 1. Introduction Owing to the ongoing COVID-19 pandemic, the second meeting of the Diagnostic Technical Advisory Group for Neglected Tropical Diseases (DTAG), an advisory group to the World Health Organization’s (WHO’s) Department of Control of Neglected Tropical Diseases, was held virtually on 13 October 2020. The meeting was opened by Dr Daniel Argaw Dagne, Unit Head, Prevention, Treatment and Care, WHO Department of Control of Neglected Tropical Diseases, who noted the progress made since the last meet- ing (30–31 October 2019). He congratulated all the members of the subgroups and commented on their considerable progress in developing target product profiles (TPPs). He also noted that DTAG members and observers would receive an update on the status of the subgroups and discuss next steps. Professor Patrick Lammie. Director, Neglected Tropical Diseases Support Center (a programme of The Task Force for Global Health), and DTAG chair, made additional opening remarks. He referred to the reports that were to be made on the progress of each disease-specific subgroup, and noted that these sub- groups were formed in response to recommendations made at the last meeting that such groups be asked to generate landscape analyses and TPPs. He thanked the chairs and subgroup members for their signifi- cant time commitments and efforts during the summer in instituting the TPP process. He also noted that towards the end of the meeting the DTAG would review what had been done to date and consider what has not yet been accomplished; the DTAG would re-evaluate the prioritization exercise undertaken at its first meeting to identify if there were new use cases or diseases for which work should be accelerated. Professor Lammie ended by noting that it was important to mention that the generation of TPPs would not be the end of the DTAG’s work and that TPPs do not in themselves create new diagnostics. The pur- pose of the DTAG is to bridge the gap between WHO and test developers and to encourage the process of bringing in new partners who will be able to help transform TPPs into tools that truly fit programme needs. The list of participants is annexed to the report. 1.1 Declarations of interest All the invited experts and observers were asked to declare any conflict of interest before the meeting. The declarations were returned to and reviewed by WHO in line with the procedures set for WHO ex- perts and advisory group members, namely: • a counter-signed copy of the invitation letter; • a signed copy of the Memorandum of Agreement; • the Confidentiality Undertaking; and • the Declaration of Interest form together with a “Code of Conduct for WHO Experts”. 2. Background The WHO Department of Control of Neglected Tropical Diseases manages a diverse portfolio of 20 diseases and disease groups, each with its own unique epidemiology and diagnostic challenges. Pro- grammes to address each of these diseases have different goals according to a particular disease’s profile – disease control, elimination as a public health problem, elimination of transmission, or eradication. These programmatic goals may also change over time as new tools are developed and global attention attracts increased support. 2Virtual meeting, 13 October 2020 In spite of the diversity of disease programme goals, it was felt that there were common areas across programmes that would benefit from the establishment of a single working group for diagnostics. Therefore, a WHO working group was formed to help ensure a unified approach for identifying and prioritizing diagnostic needs, and to inform WHO strategies and guidance on the subject. At its first meeting in 2019, the DTAG reviewed the status of diagnostics across the 20 diseases and disease groups, with input from WHO focal points around programmatic and diagnostic needs. Mem- bers discussed priorities for the year ahead as well as ways of managing the complexity of supporting the diagnostics agenda across the entirety of the WHO portfolio of NTDs. The recommendations are available in the meeting report (1). The objectives of the second DTAG meeting were: • to discuss the progress made by the disease-specific subgroups; • to discuss the progress made by the cross-cutting groups and the resource mobilization group; and • to review the recommendations from the disease-specific subgroups. 3. Progress reports from disease-specific subgroups In the sessions that followed, the disease-specific subgroups presented feedback on the TPP develop- ment process. 3.1 Soil-transmitted helminthiases The feedback from the subgroup on soil-transmitted helminthiases was presented by its chair, Professor Bruno Levecke. Professor Levecke explained that all use cases discussed were based on a 1% prevalence threshold. Since the community of experts or people interested in and working on research and control programmes for soil-transmitted helminthiases has not yet finalized thresholds, it was decided to aim for the most strin- gent threshold under discussion. He also noted that the draft zero TPP would be reviewed on 21 October 2020. The draft zero TPP is based on the programmatic need for a monitoring and evaluation tool. Key features include: • sensitivity: ≥ 60–76%; and • specificity: ≥ 99%. The ideal format is a test that can be performed at the point of sampling; however, a laboratory-based test is also acceptable. The challenge, according to Professor Levecke, had been in defining a diagnostic threshold in the ab- sence of an established monitoring and evaluation framework. Strongyloidiasis was discussed during the previous DTAG meeting, but the subgroup had excluded it because it is not currently in the portfolio of soil-transmitted helminthiases; they thought it should be considered for a future TPP. It was also noted that high specificity will represent a particular challenge for the serological assays and that there would have to be creativity in the way that testing strategies were designed. It was further noted that the sensi- tivity of a diagnostic test may vary according to prevalence in a given area. 3Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Discussion Professor Levecke stated that the TPP is “disease-agnostic”, so it is applicable to single or multiple tar- get testing. The diagnostic performance defined will be similar for any diagnostic for soil-transmitted helminthiases. It was also noted that a comment should be added to the TPP to indicate that the 1% threshold was selected to be the most stringent, but that a higher threshold might still be defined and that performance characteristics have also been defined for higher thresholds. 3.2 Schistosomiasis The feedback on schistosomiasis was presented by the subgroup chair, Dr Evan Secor. The subgroup presentation stated the following principal points: • The group is aiming to submit a publicly available TPP document for consultation by December 2020. [NB: Between the date of the meeting and the compiling of this report, TPPs were submitted to WHO for review on 12 November 2020.] • There are two priority use cases: • Monitoring and evaluation – a field-applicable test capable of measuring a 10% prevalence threshold: – sensitivity: ≥ 60–78%; and – specificity: ≥ 95–98.5%. – Sensitivity, specificity and sample size are balanced to obtain the appropriate performance characteristics. – Test and survey costs should be lower than doing 2–3 rounds of mass drug administration • Existing data demonstrate that a survey after two rounds of treatment is able to reveal whether a particular area is a hotspot area requiring additional intervention. – Ideally, there would be one test that can detect Schistosoma mansoni and S. haematobium, but the group would be willing to accept a single target test. • Interruption of transmission/surveillance: – sensitivity: ≥ 88%; and – specificity: ≥ 99.5%. – Achieving such high specificity is likely impractical, necessitating a combined testing approach with a screening test followed by a confirmatory test. Ideally, the tests can be done in parallel on the same sample, although it is not required – Even with a two-test approach, the lowest prevalence threshold that can be measured is 3%. Schistosomiasis is known to be a highly focal disease; therefore a standard stratified random sampling approach risks prompting decisions that lead to over- or under-treating. That means that there needs to be confidence that the threshold has been met in every part of the implementation unit. To accomplish this, it was assumed that lot quality-assurance sampling would provide a Yes/No answer for each location tested. Specificity will also be critical, it was noted, to maximize results. 4Virtual meeting, 13 October 2020 Discussion In the discussion that followed the subgroup presentations, a question was asked about sampling and average village size. That is, if one is to sample the whole village, this would not amount to lot quali- ty-assurance sampling, but would approximate a measure of true prevalence, depending on the rate of non-response and test performance characteristics. It was agreed that village size would vary, and that it was possible that adjacent villages may need to be included. There followed a question about transmission, surveillance and thresholds in relation to elimination of transmission of schistosomiasis and small geographical sampling: how practical would it be over time, in an area that met the threshold, to go back and retest with high frequency, especially when those areas might be close to areas with ongoing transmission? Dr Secor responded that the cut-off used in the ex- ample provided was 25% prevalence. It was unlikely that one might have a very high prevalence in one area and be close to the cut off in a nearby location. In most of Africa, the goal of eliminating transmis- sion is a long way off; therefore, as long as there is some indication in a general zone that transmission is ongoing, treatment will continue to be provided. Dr Michael Marks commented that, with regard to cost–effectiveness, there is a trade-off between treat- ing lots of people (a single set of costs) and carrying out many surveys (a different set of costs). A further question addressed the possibility of testing intermediate hosts (snails) as a diagnostic to test interruption of transmission, to which the subgroup replied that even in areas with high transmission, the tendency is to see only a small proportion of snails that are shedding. Tests of this kind are therefore unlikely to be sensitive enough to be useful in low prevalence settings. Additional general comments and considerations were then invited from participants. Dr Marks stated his belief that the discussion highlighted the need to take TPPs forward into actual op- erational research about impact. The group then considered sensitivities and specificities for characterization of individuals and commu- nities, and the point was raised that with trachoma, for example, there have been cluster randomized controlled trials comparing “continuing” versus “diagnostic driven decisions” (2). Dr Amadou Garba Djirmay stated that interruption of transmission refers to countries that have not reported autochthonous cases of schistosomiasis for five consecutive years. This, however, is not the case with African countries in general where, due to insufficient WASH coverage and continued high levels of human water contact, transmission will still continue for years. Dr Judit Rius Sanjuan asked the subgroup whether options for TPPs for multiplex diagnostics had been explored, to which the respondents stated that the skin NTD groups and cross-cutting DTAG subgroups were looking at precisely that issue. The discussion on schistosomiasis concluded with Dr Marks’s statement, in line with Professor Lammie’s comments about actions after TPP development, emphasizing the need for tests that lead to (i) pro- gramme change and (ii) change that is beneficial from both a health and cost–effectiveness standpoint. 5Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 3.3 Onchocerciasis The onchocerciasis subgroup findings were presented by its chair, Dr Marco Biamonte. The group considered two use cases: • Mapping • prevalence threshold: > 2%; • sensitivity: ≥ 60%; and • specificity: ≥ 99.8%. • A rapid diagnostic test is strongly preferred; a laboratory test is difficult to implement but acceptable. • Stopping • prevalence threshold: < 1%; • sensitivity: ≥ 89%; and • specificity: ≥ 99.8%. • A rapid diagnostic test preferred; a laboratory test is acceptable. • The thresholds were selected based on the recommendations of the Onchocerciasis Technical Subcommittee, which are constituted in terms of seroprevalence. Dr Biamonte confirmed that the onchocerciasis TPPs were nearly finalized and are due to be posted for public comment in the near future. [NB: As of 1 December 2020, TPPs had been translated into French by WHO and posted on its website.] 3.4 Lymphatic filariasis The work on lymphatic filariasis was presented by the subgroup chair, Dr Kimberly Won. The use cases for which TPPs were drafted and posted on the web for public consultation included: • Stopping triple drug (IDA) therapy (ivermectin, diethylcarbamazine, albendazole) • Threshold: 1% • Sensitivity* – Single test: > 60% (ideal); > 40% (minimum) – Decision confirmatory test: > 85% (ideal); > 78% (minimum) • Specificity* – Single test: > 99.7% (ideal); > 99.5% (minimum) – Decision confirmatory test: > 96% (ideal); > 82% (minimum) • The group recognized the environmental conditions in which the tests are typically used. To accommodate these conditions, preferred shelf-life and test stability characteristics were established as such: – Ideal: ≥ 24 months, 4–40 °C, 50% relative humidity (no cold chain required); temperature excursion/prolonged deviation of 50 °C for two weeks acceptable. – Minimum: ≥ 18 months, 4–37 °C; temperature excursion/prolonged deviation of 40 °C for two weeks acceptable. * Sensitivity and specificity calculations were based on testing the 1% threshold and considering two potential scenarios: (i) a “single test” approach in which a new assay replaces the current tools (i.e. filariasis test strip/Brugia rapid test); and (ii) a “de- cision confirmatory test” approach in which individuals are screened with both tests first; the new diagnostic is used as a con- firmatory assay on individuals testing positive by filariasis test strip/Brugia rapid test. Results of the confirmatory test are used to make a programme decision at a population level as opposed to an individual clinical treatment decision or confirmation of the first test result. 6Virtual meeting, 13 October 2020 • Surveillance • Threshold: 5% • Sensitivity: > 99% (ideal); > 85% (minimum) • Specificity: > 99.8% (ideal); > 98.8% (minimum) • The group recognized challenges in determining sensitivity and specificity requirements in the absence of an established monitoring and evaluation platform. Performance characteristics for this TPP were determined assuming a population-based cluster survey at the village level will be conducted. The group recognized the possible need to change parameters if a different monitoring and evaluation platform is recommended by WHO. The period of public consultation came to an end shortly before the date of the meeting. The next step, therefore, is to review the limited feedback that was received. [NB: Since the meeting, TPPs have been finalized, submitted to and approved by the WHO Science Division.] An important point of feedback received was the need to clearly state what the reference test is and how specificity is to be defined. This, along with other requested detail, has been included with the TPPs. Discussion The discussion centred on lymphatic filariasis that followed the presentation of subgroup activity began by considering more complex statistical methods, such as latent class analysis, in order to deal with an imperfect gold standard. This issue, it was stated, is recognized as a challenge for lymphatic filariasis and other NTD infections, and there was openness to considering options for the evaluation of a new test. An important part of future discussions, it was stated, will involve defining performance characteristics, as these, currently, are not defined. The Loa loa use case TPP was cited as a useful support for the global programme, as raised at the first DTAG meeting. However, it is as yet unclear whether a new TPP is needed for that specific use case or if the IDA TPP will result in the production of a test that can be used in settings where lymphatic filariasis and loaiasis are co-endemic because the high specificity requirement may limit cross reactivity. Xenomonitoring was also a topic flagged for further discussion. Comment: The onchocerciasis subgroup also discussed the programme platform. If we need a labora- tory-based test, there is some capacity available, but additional capacity is needed. The group discussed therefore whether a rapid test or a laboratory test is more desirable. The argument for the laboratory test is that it will build capacity over time. The DTAG may consider whether a recommendation in this regard would be appropriate. Dr Wendy van de Sande was of the opinion that it would be worthwhile to opt for similar testing meth- odologies in case laboratory tests are to be used. If the assays to be developed use different technologies, there will still be a need for relatively well-equipped endemic laboratories and highly trained personnel. 7Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 3.5 Human African trypanosomiasis Dr Enock Matovu led the presentation of the human African trypanosomiasis subgroup’s deliberations. He stated that the group had considered the following use-case criteria, for rhodesiense and gambiense human African trypanosomiasis respectively, and provided the following information/considerations. • Use cases • rhodesiense human African trypanosomiasis – Test for use in peripheral health facilities – Version 1 of the TPP will be available soon – Sensitivity – Specificity – The group will accept a two-step testing strategy with a screening test followed by a confirmatory test. • gambiense human African trypanosomiasis (TPPs under review) – A test is needed to decide on treatment for infections that cannot be confirmed via microscopy – Individual testing in low prevalence settings – A high throughput test for gambiense human African trypanosomiasis is also needed for verification of elimination. Discussion In the discussion that followed the presentation, Dr Marks stated his opinion that this was an area in which medicines may significantly change the TPPs: as the toxicity profile changes, so the acceptability of over-/under-treating will change radically. 3.6 Skin NTDs The findings of the subgroup on skin NTDs were presented by the group chair, Dr Isra Cruz. The diseases covered included Buruli ulcer, cutaneous leishmaniasis, post kala-azar dermal leishmaniasis, leprosy, mycetoma, scabies and yaws. • Dermal leishmaniasis (cutaneous leishmaniasis and post kala-azar dermal leishmaniasis – Priority use case: point-of-care test for confirmation of suspected cutaneous leishmaniasis or post kala-azar dermal leishmaniasis – Status: Published in 2019 and now being adapted to WHO format for public consultation (3). • Buruli ulcer – Use case 1: Confirmation of suspected Buruli ulcer at point of care to trigger treatment Use case 2: Confirmation of suspected Buruli ulcer (early and advanced), test of cure, differential diagnosis at district hospital or reference laboratory – TPPs for both use cases were published in 2018 (4) and are now being reviewed and adapted according to WHO guidance for public consultation – Performance should be comparable to microscopy at a minimum or, ideally, polymerase chain reaction – Buruli ulcer has no gold standard, so the group is discussing statistical methods or other strategies for the reference test. 8Virtual meeting, 13 October 2020 • Leprosy • The diagnostics working group of the Global Partnership for Zero Leprosy is working together with members of the DTAG skin NTD subgroup and the secretariat (Global leprosy programme) to define TPPs for leprosy • Work began in September 2020 and aims to finalize TPPs and wrap up in May 2021 • Activities to be conducted: – use case characterization – develop first draft TPP – review TPP – publish final TPP • Mycetoma • Additional support needed for TPP development, especially in the guidance of the process itself. • Landscape analysis is ongoing; the discussion group members have been identified and reviews are available on the current diagnostic tools. • Previous TPPs have been developed; however, not in the requisite WHO format. • Scabies • Identification of priority use cases is pending • There are no previous TPPs for scabies • Discussion group has been identified • Yaws • No previous TPPs Priority use cases have been identified: – use case 1 – use case 2 • Discussion group has been identified • Multiplexing • Multiplexing would be useful for differential diagnosis. • Other challenges • Access/logistics/supply chain • There is a need to be diligent in considering ethics with regard to stigmatizing diseases. If a community level test is being promoted, consideration must be given to the implications for patients. Discussion Comments and questions on the presentation came from a number of meeting participants. It was stated that an overarching aim of the road map is to set up a harmonized skin NTD focus. How- ever, it is important to bear in mind that there are targets too for the individual diseases. There are also diseases for which programmes are yet to be developed and for which there currently exist no targets. This would need to be considered when prioritizing. 9Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases In response to a question about the human African trypanosomiasis and skin NTDs subgroups’ ap- proach to identifying the performance characteristics by use case, Dr Marks replied that for the skin NTDs, the detailed TPPs for cutaneous leishmaniasis/post kala-azar dermal leishmaniasis and Buruli ulcer cover these points. Dr Gerardo Priotto further pointed out that, for human African trypanosomia- sis, performance characteristics are covered thus far only for the rhodesiense test, still at draft stage. The approach consists mainly of expert discussion based on what is currently available and what it would be desirable to see. In response to a question about the prioritization of use cases, Dr Marks replied that in the case of Buruli ulcer/cutaneous leishmaniasis, these are already under way, and that leprosy is relatively well supported. It was noted also that yaws/mycetoma have clear needs, are heavily dependent on diagnostics and are therefore a high priority. Scabies has less clear needs and a clearer role for clinical diagnosis, and can therefore be considered a lower priority. The subgroup respondents stated that individual subgroups would be in charge of workflow. Products will appear one by one as they become available. The TPP development process requires that it start with a use case definition, especially given the new road map targets. Diagnostics should be developed to support the new targets. Therefore, the starting point should be the use case to address specific program- matic needs. For those diseases where TPPs have already been developed, there will need to be a review of these to determine whether those TPPs will support the new 2030 targets. Again, with regard to diseases suitable for preventive chemotherapy, the group then considered other use cases or activities that need to be undertaken by the disease-specific subgroups. Discussion centred on the following principles, by disease. • Soil-transmitted helminthiases: TPPs on strongyloidiasis and stopping/surveillance are required. • Schistosomiasis: A TPP on female genital schistosomiasis is required. • Onchocerciasis: Monitoring tools are required between the mapping and stopping stages. It is very difficult to get a consensus understanding of the Ov16 serology. Depending on who you ask, those tools may or may not already meet some of our programme needs. Consideration of this is required. The group noted a need to be thoughtful in developing work plans to address these and other needs. Use cases, especially for the diseases amenable to preventive chemotherapy, are thoroughly grounded in the monitoring and evaluation for a particular disease. Therefore, the group noted the need to be deliberate about linkage with the new WHO Working Group on Monitoring, Evaluation and Reporting. This work ought not to be considered in isolation, it was stated, either by use case or by disease. 4. Update on cross-cutting subgroups Dr Argaw Dagne then presented updates about the development of the cross-cutting subgroups to the assembled participants. The call for nominations to the group has been closed, and the process of selecting members and observers is ongoing. A resource mobilization group is also being set up. With regard to testing platforms, the point was made that it might be beneficial to think outside of the “NTD box”. If the aim is to increase capacity for laboratory-based tests, there needs to be an alignment with other programmes beyond the NTD world. It would be desirable, for example, for the cross-cut- ting group to establish links with other WHO programmes that are trying to push laboratory develop- ment for low- and middle-income countries. 10 Virtual meeting, 13 October 2020 Discussion then turned to ways in which donors might contribute to or participate in the work of the cross-cutting subgroups, and the DTAG resource mobilization group’s likely expectations with regard to donors. The group noted that donors would be invited to the cross-cutting subgroups, although resource mobilization may not fall under the purview of the DTAG. Currently, very few donors support NTD programmes and they each have their own disease focus. It would therefore be desirable, it was noted, to create a forum where donors can come together and map the areas currently supported by existing donors. This would be done to ensure no significant overlap and also to identify gaps where new donors are needed. Some TPPs may not have any donors to support tool development, which is where an advo- cacy function could play an important role – i.e. targeted advocacy with specific, defined tasks. It was stated also that in diagnostics development, there are still manufacturing issues that donors may be able to play a role in. There may also be innovative mechanisms that donors can support to overcome manu- facturing challenges. 5. General discussion and round-up In a general discussion after the presentations made by individual subgroups, meeting participants touched on a variety of issues, further to the content of the specialized subgroup discussions. Discussion began with an invitation to specify other topics not covered thus far which might benefit from being considered by the DTAG. Dr Marks stated his belief that operational research platforms might be built in order to assess whether new diagnostics and their implementation are truly able to change programme behaviours/outcomes/ costs. Specifically, he enquired how evidence of this happening might be brought out, further enquiring as to the role of the DTAG in developing/steering those research agenda items and platforms. Dr Isra Cruz agreed with Dr Marks’s comment with regard to operational research, suggesting a similarity with developing and using impact assessment frameworks to show to policy-makers and potential donors. Dr Veerle Lejon noted that access and availability of NTD diagnostics would seem to be a cross-cutting issue and may become particularly relevant now. Discussion then focused on some specifics. Dr Wendy van de Sande enquired about the presence of commercial partners in donor groups, to which it was stated that bigger companies are perhaps the ones most likely to produce tests in greater capacities. This led to Dr Hayato Urabe pointing out a need for a database of all the opportunities for funders so as to better coordinate activity. Professor Levecke then revisited some previous cross-cutting issues, mentioning the need to determine sensitivity and specificity in the absence of a gold standard. He also brought to the fore the idea of setting up a well-defined biobank for samples to ensure that the community are able to assess charac- teristics. There was agreement from the group in this regard; guidance on how to proceed in the absence of a clear gold standard is very important for diagnostics developers. Building on this, Dr Biamonte stated his belief that biobanks would be needed to cross-evaluate dif- ferent diagnostics for the same indication. Dr Marks stated his belief that the issue might be addressed not only through biobanks; just as a standard methodology for TPPs is agreed, so it would be useful to think about standard methodology for addressing the absence of gold standards, i.e. the statistical or other techniques that the DTAG might recommend. Both these approaches in combination would con- stitute a powerful response, namely a standardized well-described panel of samples with a standardized approach to analysis. The DTAG, it was noted, might benefit from hearing from a health economist in this specific regard. 11 Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases The meeting referenced a pilot project by the Foundation for Innovative New Diagnostics to set up a virtual biobank for requesting access to well-characterized specimens by investigators undertaking bio- marker discovery and assay validation before going to the field for validation. This virtual biobank will move from pilot to operational in 2021, beginning with specimens relevant to diagnostic development for lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted helminthiases, as these are the first NTDs for which TPPs have been developed in the current tranche of work. The virtual bio- bank will be a virtual repository that provides information about samples stored physically in various locations. It will be a database that will link available, well-characterized samples with clinical data and information on storage site and contact points. It has been suggested that the absence of such a resource is viewed as a barrier to bringing in new donors/manufacturers. Participants drew attention to the importance of access to well-characterized sample collections for validation and cross-evaluations, and to the availability of reference standards for diagnostic batch and laboratory performance evaluation. Some parameters in the TPPs, Professor Noordin noted, should be standardized across rapid diagnostic tests – these would include factors such as stability at a certain temperature for a certain period of time, length of time for stability, cost and quality control issues/indicators. Dr Cruz, in response, noted that these parameters may be different for some diseases, depending on the areas in which they are endemic. Cost is also likely to be context-specific. Professor Noordin then enquired about the possibility of major diagnostic manufacturers such as Ab- bot, and other companies with the latest rapid diagnostic test technology (DCN, GE), being invited to help in filling some gaps if needed. Dr Marks stated the importance of knowing that testing translates into use at the programme level. There is a need to be able to quantify value in many ways, he noted, including at the health economic levels. There is a need to show that this approach is more cost-effective than continuing with the status quo, in order to demonstrate to donors that it is worth their investment. He encouraged the DTAG to consider the operational research setting that might be able to show that TPPs will result in real-world changes. It was further noted that there is a need to standardize the validation pathway for laboratory and field validation, and that operational research would have a role in that process. New tools would need to undergo objective laboratory-based evaluation before being taken to the field, it was stated, through a clear stage-gating process, to ensure that they are delivering the intended performance and are likely to meet programme needs. Professor Levecke then turned again to the question of gold standards, stating that many diseases are struggling with the lack of a gold standard when evaluating new tools. There may also be a need, therefore, to consider in what settings assays are evaluated. If certain levels of sensitivity and specificity are defined, it may be necessary to define the population or populations in which this will be evaluated. In a high prevalence area, for example, it may be very simple to demonstrate the required performance characteristics. Dr Emily Wainwright stated that, from the donor perspective, there was a real need for a mapping exer- cise to show where investments are located and where there is currently no investment. This, however, would need to be translated into an evaluation of support for the 2021-2030 NTD road map goals. If there is a desire to start reaching out to new donors, she stated, it is crucial to show clearly where there is investment currently and where there are gaps. This has to do with prioritization within and across disease programmes. A “landscaping and communications” piece of work might lay out the problem and develop a strategy for outreach, she commented. 12 Virtual meeting, 13 October 2020 • Dr Argaw Dagne suggested that the WHO team follow up on this recommendation. Dr Hayato Urabe welcomed Dr Wainwright’s suggestion, stating that from the standpoint of the Global Health Innovative Technology Fund, the coordination of donors is very important and that such land- scaping work was essential, given that each donor will have different strengths, restrictions and sched- ules. If donors are able to share that information in a database, it would be helpful for other donors as they consider releasing requests for proposals. This section of the meeting concluded with a discussion about securing the equivalent of a priority review voucher for diagnostics. 6. Closing remarks Dr Malecela, Director, WHO Department of Control of Neglected Tropical Diseases, then gave an overview of the situation with regard to diagnostics and their importance within the 2021–2030 NTD road map, stating that during the road map’s development process, diagnostics had been cited as a ma- jor hindrance to achieving the 2030 targets. The DTAG has an essential role to play in addressing this issue. Dr Malecela thanked members for their time and efforts and their commitment to developing the new TPPs, remarking particularly on the number of complex issues presented during the discussion on skin NTDs. She reiterated her belief that this group would be critical in terms of supporting the new road map, adding that the landscape analysis of funding needs will be very important from WHO’s point of view. The cross-cutting groups, for their part, provide much-needed broad perspective. Laboratory capacity is also crucial, said Dr Malecela, and a pressing issue. Existing networks need to be brought together, and this group needs to be aligned with activity in the field. One important question in this regard concerns ensuring that work remains quality-assured and quality-controlled. A vital con- sideration concerns global interplay with existing laboratory resources, including hardware and human resources. Dr Malecela then drew attention to the need for global engagement, noting that there are partners be- yond the NTD community who have not yet been fully engaged. The landscaping document, she noted, would be a great aid in this respect. Engaging with manufacturers was also identified as an issue that needs to be considered now. She assured the meeting that the DTAG will have the necessary platform and support to advocate to ensure this. Dr Malecela ended her remarks by stating her opinion that Professor Lammie would be a welcome addition to the WHO Working Group on Monitoring, Evaluation and Reporting, in order to make sure that both groups were aligned. 7. Next steps In his remarks, Professor Lammie noted that, with the TPPs well under way, it might be time for the DTAG to pivot more towards the advocacy, engagement and communication work mentioned by previ- ous contributors, to ensure that the TPPs develop into real, workable tools. In the future, he stated, the DTAG could make use of the virtual setting to ensure an ongoing pro- gramme of work that can proceed in the absence of in-person meetings. 13 Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 8. Conclusions, recommendations and further considerations • Owing to the current situation, it may be difficult to conduct meetings for the DTAG to review TPPs. The DTAG requests that the Secretariat send TPPs to members of the DTAG for a two- week period of review before posting them online for public comment. • The DTAG would welcome the establishment of a donor group. • WHO should consider forming subgroups on zoonotic diseases and visceral leishmaniasis, tak- ing into consideration and creating mechanisms for cross interactions and exchange of informa- tion across related subgroups. • WHO should consider developing a framework for translating TPPs into operational diagnostic assays, to include considerations such as minimum standard requirements for laboratory and field validation, and, potentially, reports or position statements of recommendations from the DTAG. (Access and Regulatory working groups to play a role in this also.) • WHO should engage as wide a group of developers as possible, including both academic and industry partners, in the diagnostic development process, to ensure independent evaluation and to lessen any potential deterrent for developing tests. • Current research initiatives on NTDs can have a role in ensuring a pathway for at least the pre- ventive chemotherapy diseases to be appropriately tested in the field. The more clarity that can be provided on validation requirements, the easier it will be to justify and build test evaluation into annual work plans. For case management diseases, it is less clear how these processes will be managed. The Secretariat is requested to be of assistance in brokering those discussions. • As TPPs are released, feedback should be requested directly, especially from national pro- grammes. – WHO to inform their list of programme managers through established channels or mechanisms. • Strategies for engagement and advocacy – DTAG with support of WHO to expressly reach out to National Institutes of Health in different countries – Secretariat to develop a standard set of slides for members to take with them to various conferences and network meetings to describe diagnostic needs across the NTDs. References 1. Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases, Geneva, 30–31 October 2019. Geneva: World Health Organization; 2020 (https://apps.who. int/iris/bitstream/handle/10665/331954/9789240003590-eng.pdf, accessed 17 February 2021). 2. Harding-Esch E, Jofre-Bonet M, Dhanjal JK, Burr S, Edwards T, Holland M, et al. Costs of testing for ocular Chlamydia trachomatis infection compared to mass drug administration for trachoma in the Gambia: application of results from the PRET study. PLoS Negl Trop Dis. 2015;9(4):e0003670 (https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003670). 14 Virtual meeting, 13 October 2020 3. Cruz I, Albertini A, Barbeitas M, Arana B, Picado A, Ruiz-Postigo JA, et al. Target product profile for a point-of-care diagnostic test for dermal leishmaniasis. Parasit Epidemol Control. 2019:e00103 (https:// pdf.sciencedirectassets.com/313542/1-s2.0-S2405673118X00063/1-s2.0-S2405673119300017/main. pdf, accessed 17 February 2021). 4. Report of a WHO–FIND meeting on diagnostics for Buruli ulcer, Geneva, 26–27 March 2018. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/bitstream/handle/10665/274607/WHO- CDS-NTD-IDM-2018.09-eng.pdf, accessed 17 February 2021). Annex. List of participants MEMBERS Dr M.A. Biamonte, Drugs and Diagnostics for Tropical Diseases, San Diego, United States of America Dr R.N. Coler, Seattle Children’s Research Institute, University of Washington, Seattle, United States of America Dr I. Cruz, National School of Public Health, Instituto de Salud Carlos III, Madrid, Spain 15 Second meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Professor P. Lammie, NTD Support Center, Task Force for Global Health, Decatur, United States of America (Chair) Dr V. Lejon, Institut de Recherche pour le Développement, Montpellier, France Professor B. Levecke, Ghent University, Merelbeke, Belgium Dr F.K. Marchini, Carlos Chagas Institute – Fiocruz Parana, Curitiba, Brazil Dr M. Marks, London School of Hygiene and Tropical Medicine, London, United Kingdom Dr P. Millet, Université de Bordeaux, Bordeaux, France Professor S.M. Njenga, Kenya Medical Research Scientist, Nairobi, Kenya Professor R. Noordin, Universiti Sains Malaysia, Penang, Malaysia Dr R. Paulussen, Mondial Diagnostics, Amsterdam, The Netherlands Dr E. Sreekumar, Rajiv Gandhi for Biotechnology, Kerala, India SUBGROUP CHAIRS AND VICE-CHAIRS Professor J. Kamgno, Vice-Chair, subgroup on onchocerciasis Dr E. Matovu, Chair, subgroup on human African trypanosomiasis Dr M. Odiere, Vice-Chair, subgroup on schistosomiasis Dr W. von de Sande, Vice-Chair, subgroup on skin NTDs Dr K. Won, Chair, subgroup on lymphatic filariasis OBSERVERS AND WHO COLLABORATING CENTRES Dr F. Alves, Drugs for Neglected Diseases initiative, Geneva, Switzerland Dr S.R. Bialek, Centers for Disease Control and Prevention, Atlanta, United States of America Dr D. Evans, United States Agency for International Development, Washington, United States of America Dr A. Golden, PATH, Seattle, United States of America Dr C. Hanson, Bill & Melinda Gates Foundation, Seattle, United States of America Dr M. Helinski, The European & Developing Countries, The Hague, The Netherlands Professor S. Kaneko, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan Dr F.J. Moreno Nuncio, Instituto de Salud Carlos III, Majadahonda, Spain Dr T. Moriyasu, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan Professor J. Ndung’u, Foundation for Innovative New Diagnostics, Geneva, Switzerland Dr S. Nogaro, Foundation for Innovative New Diagnostics, Geneva, Switzerland Dr R. Peck, PATH, Seattle, United States of America Dr J. Rius Sanjuan, United Nations Development Programme, New York, United States of America Dr W.E. Secor, Centers for Disease Control and Prevention, Atlanta, United States of America Dr J. Shott, United States Agency for International Development, Washington, United States of America 16 Virtual meeting, 13 October 2020 Dr J. Tappero, Global Health Program, Seattle, United States of America Dr H. Urabe, Global Health Innovative Technology Fund, Minato-ku, Japan Dr E. Wainwright, United States Agency for International Development, Washington, United States of America SECRETARIAT Dr B. Abela-Ridder, Veterinary Public Health, Vector Control and Environment, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr P. Albajar Vinãs, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr D. Argaw Dagne, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr K. Asiedu, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr A. Aseffa, Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland Dr E. Cooreman, Global Leprosy Programme, World Health Organization Regional Office for South-East Asia, New Delhi, India Dr C. Ducker, Consultant (diagnostics), United Kingdom Dr J.R. Franco Minguell, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr A. Garba Djirmay, Strategic Operations, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr S. Jain, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr J. King, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr A. Kuesel, Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland Dr M.N. Malecela, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr P.S. Mbabazi, Strategic Operations and Analytics, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr A. Montresor, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr V. Pemmaraju, Global Leprosy Programme, World Health Organization Regional Office for South-East Asia, New Delhi, India Dr G. Priotto, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr J. Ruiz Postigo, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr D. Sankara, Prevention, Treatment and Care, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr A. Solomon, Office of the Director, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr A. Tekle, Strategic Operations, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Dr R. Velayudhan, Veterinary Public Health, Vector Control and Environment, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland