Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Geneva, 30–31 October 2019
Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Geneva, 30–31 October 2019 Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases, Geneva, Switzerland, 30–31 October 2019 ISBN 978-92-4-000359-0 (electronic version) ISBN 978-92-4-000360-6 (print version) © World Health Organization 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareA- like 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, pro- vided 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. 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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. How- ever, 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 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Contents 1. Introduction 1 1.1 Declarations of interest 1 2. Background 1 3. Sessions 2 3.1 Terms of reference, structure and objectives of the Working Group 2 3.2 Introduction to WHO target product profiles 3 3.3 The road map for 2030 4 3.4 Diagnostic gaps for specific diseases 5 3.5 WHO Model List of Essential In Vitro Diagnostics and prequalification process 12 3.5.1 Prequalification 12 3.5.2 WHO Model List of Essential In Vitro Diagnostics 12 4. Discussion 13 4.1 Managing complexity 13 4.1.1 Revised approach 13 4.1.2 Preventive chemotherapy diseases 14 4.1.3 Case management diseases 15 4.2 Overview of discussion 16 5. Recommendations 20 5.1 Tasks 20 5.1.1 Conduct a formal landscape analysis, including biomarker discovery 20 5.1.2 Expand the technical expertise that DTAG can call upon 20 5.1.3 Formulate a process to bring existing TPPs under development into the DTAG structure 20 5.1.4 Develop a repository of TPPs 20 5.2 Sub-groups 21 5.2.1 Case management diseases 21 5.2.2 Preventive chemotherapy diseases 21 Annex 1. List of participants 23 1WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 1. Introduction The first meeting of the Diagnostic Technical Advisory Group (DTAG), an advisory group to the WHO Department of Control of Neglected Tropical Diseases, was held at the Inter-Parliamentary Union in Geneva, Switzerland, on 30–31 October 2019. The meeting was opened by Dr Mwele Malecela, Director, WHO Department of Control of Neglected Tropical Diseases, who welcomed participants. She noted the importance of this inaugural meeting given that, during the process of developing the road map on neglected tropical diseases 2021–2030, it became apparent that failing to give adequate consideration to critical diagnostic needs would lead not only to the NTD community missing new targets that were being set but also to losing or compromising the gains made during the past decade. Dr Malecela also noted that the Department currently manages a diverse portfolio of 20 diseases and disease groups, each with its own unique epidemiology and diagnostic challenges. The goals associated with individual disease programmes are disease-specific – whether for control, elimination as a public health problem, elimination of transmission or eradication – but each disease poses a unique diagnostic challenge that must be addressed in order to reach the 2030 road map targets. Dr Patrick Lammie, Director, Neglected Tropical Diseases Support Center, a programme of the Task Force for Global Health, was appointed Chair of the Working Group and Dr Veerle Lejon, Director of Research at Institut de Recherche pour le Développement, as vice chair. Dr Rhea Coler, Senior Vice Pres- ident of Preclinical and Translational Research, Infectious Disease Research Institute, was nominated rapporteur. The meeting was attended by 10 invited experts, 17 observers and 15 staff from the WHO Secretariat (Annex 1: List of participants). The Working Group met in both plenary and breakout sessions. 1.1 Declarations of interest All the members 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 experts 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 disease categories, each with its own unique epidemiological and diagnostic challenges. Programmes to address each of these diseases have different goals according to the targets set for a particular dis- ease: control, elimination as a public health problem, elimination of transmission, or eradication. These programmatic goals may also change over time as programmes achieve success and disease prevalence declines, as new tools are developed or as global attention attracts increased support and commitment. Accurate and reliable diagnostic tools are necessary for all of these programmes. While classical clinical and parasitological techniques are often adequate for mapping the distribution of disease and monitoring 2Report of the first meeting. Geneva, 30–31 October 2019 the progress of interventions against neglected tropical diseases (NTDs), the need for improved diagnos- tics becomes critical as infection prevalence declines and elimination becomes a possibility. For NTDs that require case management, diagnostics are essential to achieve the goals of control, elim- ination or eradication, as the intervention for this group of diseases relies on detecting individual cases and conducting surveillance. The addition of new diseases to the portfolio has highlighted the require- ment for improved diagnostic tools. For diseases targeted by preventive chemotherapy, diagnostic tests are required to support programmatic decisions on changing the frequency of treatment or stopping mass treatment, or on conducting surveillance and validating or verifying elimination. Reports from the field indicate that NTD programmes are facing a number of problems that require urgent solutions. Recognition of the achievements accomplished on the road to 2020, and the enthusiasm generated by the Sustainable Development Goals for 2030, have renewed momentum for consolidating programme gains and accelerating progress towards programme end-points, as reflected in the new road map, which identifies critical gaps in diagnostics in order to meet the ambitious targets for 2030. In view of the need to support programmes to deliver much-needed health interventions to vulnerable populations, and in order to demonstrate and maintain the health gains achieved so far, the Depart- ment has determined, in accordance with the recommendations of the Strategic and Technical Advisory Group for Neglected Tropical Diseases, that it is necessary to reassess needs and access-related issues around diagnostics for all the diseases in its portfolio. Despite the diversity of the programme goals, common areas exist across programmes that lend them- selves well to consideration by a single working group for diagnostics. Individual programmes, depend- ing on their goals, may need diagnostics for case detection, diagnosis, prognosis, mapping of endemicity, monitoring and evaluation, test of cure and whether to stop mass treatment, determination of infectivity and/or post-treatment surveillance. A single WHO working group will ensure a unified approach to identifying and prioritizing diagnostic needs and to informing WHO strategies and guidance on the subject. In accordance, the objectives of the first meeting of the DTAG were: • to review the terms of reference, structure and working modalities of the group; • to introduce the WHO process for developing target product profiles (TPPs) development and including TPPs in the WHO Model List of Essential In Vitro Diagnostics; and • to discuss critical gaps in and prioritization of NTD diagnostics and the use cases for these tools. 3. Sessions 3.1 Terms of reference, structure and objectives of the Working Group Dr Daniel Argaw Dagne, Coordinator, Innovative and Intensified Disease Management, WHO Depart- ment of Control of Neglected Tropical Diseases, summarized the terms of reference, structure and work- ing procedures of the DTAG. He reiterated that planning for the 2030 road map required a reassessment of diagnostic needs and links with partners to redefine priorities for new and in-development diagnostics and other platforms. Dr Dagne reviewed the responsibilities of the DTAG members. He noted that all of the NTDs in the road map require diagnostics and that limited resources will require the group to prioritize urgent needs, rec- ognizing that all such needs will have to be addressed over time in a phased manner. He noted also the need to define test characteristics – use case, target population, ideal performance and ease of use – in order to support WHO in ensuring a harmonized TPP and establishing standards that the wider com- munity can agree upon and endorse. 3WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Reflecting on the membership of the DTAG (12 members and one alternate member, to serve in a per- sonal capacity and represent a range of disciplines), Dr Dagne commented that maximum effort must be exerted to ensure representation by geographical WHO regions and various areas of NTDs and of the importance in securing a balanced perspective. He reminded the group that experts were present in the fields of epidemiology, public health, infectious diseases health systems and management, as well as reg- ulatory authorities. He reiterated that all members would serve for a 4-year term and may subsequently be invited for a further 3 years. Dr Dagne reminded the group that experts should not bring their institutional positions or interests to the discussions and that members should attend all meetings, if possible. Members who were not able to attend two consecutive meetings would be asked to step down. The DTAG would meet once a year, with additional meetings and teleconferences to be scheduled as agreed upon by the Chair and the Depart- ment. Furthermore, only DTAG members could participate in voting or decisions by consensus, and in the formulation of final recommendations. The report on the meeting will be written by the rapporteur and the WHO secretariat, approved by mem- bers of the DTAG and posted on the WHO website. The role of the DTAG is to define priority gaps, coordinate the creation of a TPP for each priority use case, including synopses of position/policy statements, and to advise on strategy and access to NTD diag- nostics. The DTAG will also advise the Department on the establishment of ad-hoc use-cases or disease specific sub-groups in order to deliver on specific tasks and target product characteristics. Discussion turned then to the scale of the task facing the DTAG and the need for its processes to be nimble. Dr Malecela reflected on the need for tests that could be used in the most remote areas, not just in primary care centres; she agreed with the group that feasibility and production are real issues that should be addressed via a rapid but rigorous TPP process. There was general agreement from the group that the practical end-use should be considered from the outset, especially as there are few resources for diagnostics. 3.2 Introduction to WHO target product profiles Dr Vaseeharan Sathiyamoorthy, Team Lead, Data Sharing and Target Product Profile workstreams of the R&D Blueprint, and Coordinator, Research, Ethics, Knowledge Uptake at the WHO Department of Information, Evidence and Research – summarized the new WHO process for TPPs. He explained that the existence of a WHO TPP in a given area should be taken as a strong indication that products meeting the criteria are highly desirable for public health, and that critical gaps exist in the current landscape of available products. WHO TPPs should be considered as guidance from an end-to- end perspective, linking product development, access and affordability, as well as regulatory, policy and financing considerations, in order to enable line-of-sight so that product development can proceed with public health goals in mind. Dr Sathiyamoorthy then explained the eight steps within the process. Step one consists of determining whether a WHO TPP is needed. The proposed TPP should focus on a public health issue or disease that is prioritized by WHO through the World Health Assembly or another documented WHO process for setting priorities that includes (i) a review of the available literature and (ii) external consultative processes. An analysis of the available products and of the development pipeline should be conducted before the TPP is developed, to indicate that existing products in development do not meet critical public health needs in settings where that need is greatest. This may be because products do not exist, or licensed prod- ucts are not suitable or accessible for relevant populations. 4Report of the first meeting. Geneva, 30–31 October 2019 Step two is the drafting of a one-page scope and purpose document with regard to the specific TPP, for planning clearance within the relevant WHO technical unit. An entry would also be added to the Intranet information sharing portal for WHO’s TPPs (once this is established). This portal will provide transparency across WHO about which TPPs are available or in development. Step three consists of engaging in external consultations with relevant audiences, including the product development audience for the technical area, to determine whether a need exists for such a TPP outside WHO. Step four involves constituting a scientific TPP development group including, where appropriate, lead- ing scientists and experts, public health officials, regulators (in liaison with the regulatory unit at WHO/ MVP cluster) and, as a minimum, some in-country end-user representatives. End-user representatives should include disease control programmes in health ministries and, where possible, patient represen- tatives and/or civil society. For the TPP development group, the standard WHO declaration of interest procedures should be followed and experts with declared interests that cannot be managed adequately should be excluded. The group should not include current members of staff at for-profit industry entities. Step five consists of developing a zero draft version of the TPP document and consulting on the draft with the TPP development group (via phone or face-to-face) to produce a 0.1 version. Step six is to post version 0.1 with a proforma comment form for public consultation for a period of 28 days, to disseminate news of the public consultation widely and, specifically, to seek comments from industry, funders, scientists and end-users. Step seven is to share the comments received with the TPP development group, along with a proposed next version of the TPP. Depending on agreement by the TPP development group, this version may then undergo further consultation with relevant audiences, or may be labelled as version 1.0, dated and posted on WHO’s website as the first non-draft TPP for use in the technical area. WHO TPPs should be widely disseminated and in particular be made available to groups involved in the development of WHO policy recommendations for use later on in the development process, when data on products are being reviewed for their public health value. Step eight is to consider all WHO TPPs as living documents that may require modification if the status of the associated science or the pipeline in the area changes. The status of active/archive should be changed in the Product Profile Directory. It is also part of the TPP process that 5 years from the initial publication date, TPPs should be considered expired unless they have undergone a formal review and been updated appropriately with versioning and dating to indicate changes made. Dr Sathiyamoorthy emphasized that throughout the process, each version of the TPP should be recorded and dated and kept current on the WHO intranet portal for transparency. 3.3 The road map for 2030 Dr Malecela presented the new road map for NTDs for 2021–2030, which had been prepared with her team at WHO over the previous 6 months through a global consultative process of the wider NTD community, national programme managers and various WHO departments. The road map will be a key guiding document for the global response to NTDs over the next decade and serve as a critical strategic document to assist in the delivery of programmes that span the 20 diseases and disease groups; it will also serve as a policy and advocacy document that draws attention to the key challenges in the NTD space and encourages continued commitment from the global community of partners. The WHO Department of Control of Neglected Tropical Diseases used a consultative approach to develop the road map, focused on cross-cutting themes and strategies that span multiple NTDs. Grateful thanks were expressed to those 5WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases who took part in developing the document, with the aim of ensuring that the road map itself reflects the views of all stakeholders who contribute to the fight against NTDs. The road map was submitted to the Executive Board for approval in September 2019 and will be officially launched in 2020. The road map has four chapters: • Chapter 1, on the context and purpose, including the landscape of NTDs and the progress made to date globally; • Chapter 2, on the overarching, cross-cutting and disease-specific targets and milestones; • Chapter 3, on the strategies and actions required to achieve the 2030 targets, structured accord- ing to a strategic framework; and • Chapter 4, on guidance for countries in developing their national NTD plans, including key components that should form part of this plan, and the process and steps required. Dr Malecela then presented the “heatmap” component of the road map, which reflects the program- matic progress made for each disease, and the following headings: scientific understanding; diagnostics; effective intervention; operational and normative guidance; planning, governance and programme man- agement; monitoring and evaluation; access and logistics; and health care infrastructure and workforce. The heatmap identifies areas of common need. Diagnostics was clearly shown as an area of critical need for many NTDs to reach their 2030 goals. Better diagnostics can accelerate progress towards elimination, reduce morbidity, minimize programme costs and support monitoring and evaluation. 3.4 Diagnostic gaps for specific diseases Each of the NTD focal points presented two slides describing the current status of diagnostics and the diagnostic needs identified by the technical focal point and team. The presentation is summarized in the table below. 6Report of the first meeting. Geneva, 30–31 October 2019 Disease Current diagnostics Diagnostic needs Dracunculiasis • Clinical with epidemiological link • Microscopy for individual clinical diag- nosis • PCR test – confirmatory for individual clinical diagnosis Serological tests to detect pre-patent Guin- ea worm: • to anticipate interventions to stop transmission in endemic areas; would also ultimately help in the certification process. • for humans, dogs and other animals to detect pre-patent Guinea worm; • field pond-side test for detecting D. medinensis DNA in copepods • to identify water sources that are con- taminated with D. medinensis to facilitate interventions Yaws • Clinical – unreliable, lesions similar to other causes • Dark field microscopy • POC test (SD Bioline) – individual diag- nosis and screening; very high sensitivity and specificity • Treponemal serological test (DPP) – diagnosis and screening • PCR – confirmation, identify subspecies, can be used for AZT resistance monitor- ing; cannot distinguish/determine latent from seropositive cases • Detection of azithromycin resistance at the health facility/district • Automated high-throughput non-trepo- nemal test for certification of elimi- nation; large-scale serosurveillance of asymptomatic persons • Serological differentiation of yaws and syphilis – for individual diagnosis espe- cially of adults Human African trypanosomiasis (gambiense) • CATT (Ab serology) – screening of T. b. gambiense, community; low prevalence during surveillance limits its use • RDT (SD Bioline HAT and Coris HAT Sero-K-SeT) – screening, community and peripheral health facility • Immune trypanolysis test (TL) – referral test for surveillance, feasible on dried- blood spots; cumbersome • ELISA serological test – test for surveil- lance (reference laboratories) • Microscopy of blood, lymph fluid or CSF – parasitological confirmation, low sensitivity • mAECT and HCT (Woo) • PCR; LAMP – to reinforce serological suspicion, lack of accuracy for confirma- tion (PCR-reference laboratories; LAMP – district hospitals • Confirmatory tests for gHAT to be used in peripheral health systems – for screen- ing of population at risk of gHAT and confirmation of cases • More sensitive and specific serological test, cheaper – for screening of popula- tion at risk of HAT • High throughput test on blood dried spots in filter paper – for surveillance in low prevalence or post-elimination settings; for validation/verification of elimination • Algorithm combining different tests – to improve specificity of current tests • Test of cure – to reduce long-term fol- low-up and replace the invasive lumbar puncture, depending on efficacy of treat- ment available • Availability of existing tests – to ensure that the production of currently available tests is continued and affordable … • Serological rHAT – no screening test currently available 7WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Disease Current diagnostics Diagnostic needs Leprosy • No test available for diagnosis of infec- tion • Microscopy (demonstration of acid-fast bacilli in slit-skin smear) • Individual clinical diagnosis (some forms only); disease classification (some forms of MB leprosy); follow up and diagnosis of relapse • ELISA, lateral flow assays – individual clinical diagnosis for PB leprosy; low accuracy • PCR – individual clinical diagnosis; higher sensitivity and specificity than ELISA and lateral flow assays; lack of standardization; not commercially avail- able; requires technical and laboratory expertise • Diagnosis of infection – to provide pro- phylaxis to those most at risk • Screening for potential disease – to bet- ter identify suspected leprosy patients • Diagnosis of disease – to confirm diag- nosis of all forms of leprosy (especially indeterminate and PB leprosy) • Prediction of future disease - to identify those at risk of disability • Diagnosis of nerve function loss – to rec- ognize early nerve function loss (before it becomes irreversible) Onchocerciasis • Ov16 IgG4 – mapping and stopping; commonly used version: in low preva- lence settings, low sensitivity and very high specificity; newer versions more sensitive but concerns about specificity • Ov16 IgG4 RDT – maybe mapping, M&E; not specific enough for stopping, issues with reading in field, much lower sensitivity in low prevalence areas; good quality assurance • O-150 PCR – entomology needed for stopping MDA and transitioning to post-treatment surveillance; being tweaked to enhance performance • Serological test – for mapping low prev- alence areas; have a bridge solution but may need new tools • Serological test – for stopping MDA; higher sensitivity • Serological test (ideally multiplex) – for post-transmission surveillance; need sensitive test of early recrudescence: possibly replace entomology long-term Chagas disease • Microscopy – screening and diagnosis • Blood concentration methods – screen- ing and diagnosis • Serology (including chemiluminescence and other related tests) – screening and diagnosis • Molecular biology – Screening, diagno- sis, discrete typing unit of T. cruzi • Diagnostics – to detect current infection and assess treatment response • RDT – for early detection of infection in neonates (congenital transmission) • RDT – to identify the discrete typing unit of T. cruzi Visceral leishmaniasis • Clinical plus epidemiological link – indi- vidual clinical diagnosis • Microscopy – individual clinical diagno- sis • RDT rK39; RDT rk28 – individual clini- cal diagnosis; epidemiological surveys • IFAT, ELISA – individual clinical diag- nosis • Loopamp™ Leishmania detection kit (LAMP) • PCR – individual clinical diagnosis, species typing • Rapid test – more sensitive and specific especially for eastern Africa and Latin America regions • Test (serological or other preferably rapid test) – to monitor treatment response or test of cure • Rapid test for PKDL – to distinguish PKDL from other skin conditions 8Report of the first meeting. Geneva, 30–31 October 2019 Disease Current diagnostics Diagnostic needs Lymphatic filariasis • Microscopy (microfilaria in blood) – mapping and monitoring; low sensitivity, particularly after MDA • Filariasis Test Strip – for mapping, mon- itoring, stopping and transitioning to surveillance in areas endemic for W. bancrofti; recently identified as cross-reactive in patients with high Loa loa mf; operational issues; recent reliabil- ity issues on “failure to flow” • Brugia Rapid Test (BmR1 IgG4 RDT) – for stopping MDA and transitioning to post-MDA surveillance in areas endemic for Brugia spp.; point-of-care complex- ity – takes several steps, requires buffer, results after 30 min; some previous issues of reliability • Serology – for areas co-endemic with Loa loa and for mapping and stopping MDA • Serology – for stopping triple-therapy (IVM-DEC-ALB) MDA; need specific marker of worm viability to better assess impact of IDA on transmission potential • Post-MDA and post-validation sur- veillance – need biomarker specific of early exposure to confirm elimination of transmission and/or detect early recru- descence Schistosomiasis • Urine filtration – for S. haematobium; morbidity control/elimination as a PHP • Haematuria – for S. haematobium; mor- bidity control/elimination as a PHP, lacks specificity • Kato–Katz – for intestinal schistosomi- asis; morbidity control/elimination as a PHP; lacks sensitivity in low prevalence settings • CCA – morbidity control/elimination as a PHP; recommended for S. mansoni only; used for mapping and surveillance • Serology tests – interruption of transmis- sion (high sensitivity); moderate to low specificity • Molecular (PCR, LAMP) – interruption of transmission with high sensitivity and specificity • Hatching tests – interruption of trans- mission with high specificity; mainly for cercaria; time-consuming • RDT – for monitoring and evaluation of S. haematobium, S. mekongi and S. japon- icum transmission; and of humans and animals in low transmission areas • RDT – for verification of interruption of transmission for verification surveys; human, animals, snails • RDT – to assess treatment/drug efficacy Soil-transmitted helminthiases in- cluding strongyloidiasis • Kato–Katz/microscopy – Ascariasis, trichuriasis, hookworm infection; poor sensitivity for infection of low intensi- ty; gold standard, widely used; samples should be examined in a few hours • Mini-FLOTAC/microscopy – Ascariasis, trichuriasis, hookworm infection; poor sensitivity for infection of low intensity • Baermann/microscopy – for strongyloi- diasis, good sensitivity; gold standard but long and complex procedure • ELISA – for strongyloidiasis, good sensitivity and good performance when prevalence > 20% • RDT or artificial intelligence slide reader • The method should be capable of differ- entiating among the causative species and quantifying the intensity of infec- tions 9WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Disease Current diagnostics Diagnostic needs Trachoma • Clinical examination for TT and active trachoma (WHO-recommended) • NAAT – detection of infection; for re- search use only • Antibody detection test – for post-vali- dation surveillance; potential application for excluding trachoma at baseline Buruli ulcer • PCR (IS2404) – individual diagnosis; sensitivity and specificity > 90%; used in reference laboratories only; some quality issues • F-TLC – individual diagnosis; sensitivity < 70%; under evaluation in four coun- tries. • Microscopy (standard Ziehl–Neelsen light microscopy) – sensitivity 60%; rarely done • Culture – only method to identify viable AFB; identifies clinically suspected relapses after antimicrobial treatment; unsuitable for quick laboratory confir- mation. • Rapid point-of-care tests targeting my- colactone – for individual diagnosis at PHC/community level • LAMP – design locked test could replace home-brewed PCR methods; RPA – for individual diagnosis; design locked test could replace home-brewed PCR meth- ods Dengue and chikungunya • RDT + ELISA–NS1 antigen – screening, individual clinical diagnosis; sensitivity range 49–90%; specificity range 91– 100%; low performance • RDT + ELISA–IgM antigen – screening, individual clinical diagnosis; sensitivity range 21–98%; specificity range 77–91%; low performance • NAT-PCR screening, individual clinical diagnosis; sensitivity range 83–93%; specificity range 99–100%; irregular and low performance • RDT + ELISA–IgG – for screening; high sensitivity, low specificity; cross-reactivi- ty with flaviviruses and certain vaccines • High performance dual IgM+NS1 – for screening and individual clinical diagno- sis Echinococcosis • Imaging: X-ray, ultrasound, computer- ized tomography, MRI – for individual diagnosis, classification and staging and for monitoring treatment response • Serology: indirect haemagglutination test, ELISA, latex agglutination, immu- noblotting – for individual diagnosis but must be used with imaging • Histopathology – definitive individual diagnosis • Molecular assays – conventional and real-time PCR; individual diagnosis and definitive after imaging • Screening – antigen assay needed for communities endemic for echinococco- sis; POC Ag detection • Staging – biomarker antigen needed for suspected individuals, POC Ag detection • Treatment follow up – Ab assay or NAT needed for suspected individuals; high throughput antibody assay or POC NAT 10 Report of the first meeting. Geneva, 30–31 October 2019 Disease Current diagnostics Diagnostic needs Foodborne trematodiases • Imaging: X-ray, ultrasound, computer- ized tomography, MRI – for individual diagnosis, classification and staging and for monitoring treatment response • Serology: indirect haemagglutination test, ELISA, latex agglutination, immu- noblotting – for individual diagnosis but must be used with imaging • Histopathology – definitive individual diagnosis • Molecular assays (conventional and re- al-time PCR) – individual diagnosis and definitive after imaging • Screening – antigen assay needed for communities endemic for echinococco- sis; POC Ag detection • Staging – biomarker antigen needed for suspected individuals, POC Ag detection • Treatment follow up – Ab assay or NAT needed for suspected individuals; high throughput antibody assay or POC NAT Taeniasis/(neuro) cysticercosis • Microscopy (Kato–Katz) – taeniasis indi- vidual diagnosis, low sensitivity • Copro-Ag ELISA (taeniasis) – screening, clinical diagnosis, validation; sensitivity in field lower than published; not com- mercially available. • Copro-PCR (taeniasis) – confirmatory, test of cure; no test independently vali- dated • EITB assay – for screening but verify positives with other methods • Serology: Ag-ELISA, Ab-ELISA (neu- rocysticercosis) – to support clinical diagnosis • Serology: Ag ELISA, Ab ELISA (porcine cysticercosis) – for selecting pigs for necropsy • Screening, track and treat (taeniasis) – biomarker not available; Copro Ag under evaluation; POC antigen detection or POC NAT (e.g. PCR or LAMP) • Test for selection of patients in need of brain scan (neurocysticercosis); treat- ment follow up – POC antigen detection or POC NAT (e.g. PCR or LAMP) • Porcine cysticercosis – screening, valida- tion • Determination of cure and surveillance – biomarker not available; POC NAT (e.g. PCR or LAMP) Cutaneous leishmaniasis • Clinical and epidemiological link • Microscopy – smear, biopsy, gold stan- dard but variable sensitivity • Immunological (ELISA, LST) and molec- ular (PCR, qPCR, LAMP) tests – occa- sionally used in reference laboratories, field surveys (LST) • Detect rapid test – not validated inde- pendently • Rapid test – for confirmation of sus- pected cases that at peripheral health facilities Mycetoma • Clinical diagnosis – triad of a subcutane- ous mass, sinuses and granular discharge • Microscopy – smear, biopsy, gold stan- dard but variable sensitivity • Culture • Histopathology, aspiration cytology • Serological tests • Molecular – PCR, LAMP • (1→3)-β-D glucan assay • Early (subclinical) case detection – to identify early (subclinical) cases in the general population • Treatment response – test to determine when to stop treatment • Culture – to determine optimum treat- ment; may require species identification • Susceptibility testing – to determine optimal therapy 11 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Disease Current diagnostics Diagnostic needs Chromoblastomy- cosis and sporotrichiosis Chromoblastomycosis: • Clinical – itching nodulo-verrucous chronic skin lesion depicting a “black dot” surface usually after cutaneous trau- ma • Microscopy – direct exam skin scrapings, crusts, secretions, biopsied tissues • Histopathology • Culture • Immunodiagnosis – immunodiffusion and ELISA • Molecular Sporotrichiosis: • Commercially available lateral flow test in distinguishing cases from leishman- iasis, cutaneous NTM infection and chromoblastomycosis • Extracutaneous clinical form • Sensitive, specific molecular and POC tests Snakebite envenoming • Diagnostic algorithms and checklists • Clinical signs aided by aided by a 20-min whole-blood clotting test (20WBCT) • Currently only one diagnostic test is commercially available to confirm the type of snake venom present in the body of an envenomed patient. • Diagnostic for envenoming • POC diagnostic – to confirm envenom- ing through detection of two or more of a group of ubiquitous venom compo- nents • Test to confirm envenoming by detection of two or more toxins present in almost all venoms • Bioclimatic analysis of venomous snake distributions • Risk mapping to improve prevention and control of snakebite envenoming Ab, antibody; Ag, antigen; AZT, azithromycin; CATT, card agglutination test for trypanosomiasis; CCA, circulating cathodic antigen; DPP, dual path platform; ELISA, enzyme-linked immunosorbent assay; EITB, enzyme-linked immunoelectrotransfer blot; HCT, micro-haematocrit centrifugation test; IFAT, immunofluorescence antibody test; IVM-DEC-ALB, albendazole–diethylcarbamazine (citrate)–albendazole; LAMP, loop-mediated isothermal amplification; LST, Leishmania skin test MB, multibacillary; M&E, monitoring and evaluation; MDA, mass drug ad- ministration; mAECT, mini-anion exchange centrifugation technique; mf, microfilaraemia; MRI, magnetic resonance imaging; NAAT, nucleic acid amplification test; NAT, nucleic acid test; NTM, nontuberculous mycobacteria; PB, paucibacillary; PCR, polymerase chain reaction; PHC, primary health care; PHP, public health problem; qPCR, quantitative PCR; PKDL, post kala-azar dermal leishmaniasis; POC, point of care; RDT, rapid diagnostic test; RPA, recombinase polymerase amplification; TT, trachomatous trichiasis 12 Report of the first meeting. Geneva, 30–31 October 2019 3.5 WHO Model List of Essential In Vitro Diagnostics and prequalification process 3.5.1 Prequalification The Prequalification Programme, set up in 2001, is a service provided by WHO to facilitate access to med- icines that meet unified standards of quality, safety and efficacy for treatment of HIV/AIDS, malaria and tuberculosis. From the outset, the Programme was supported by the Joint United Nations Programme on HIV/AIDS (UNAIDS), the United Nations Children’s Fund (UNICEF), the United Nations Population Fund (UNFPA) and the World Bank as a measurable contribution to the United Nations’ priority goal of addressing widespread diseases in countries with limited access to quality-assured medicines. Its mis- sion is to work in close cooperation with national regulatory agencies and partner organizations to make quality-assured priority medicines available for those who urgently need them by conducting assessment and inspection activities, building national capacity for manufacture, regulation and monitoring of med- icines and working with regulators to register those medicines quickly. WHO has been assessing the performance and operational characteristics of in-vitro diagnostics (IVDs) since 1988; however, the Prequalification Programme for IVDs was introduced in 2008. Although diag- nostics for NTDs are currently not included in the process, discussions are under way with the WHO Department of Control of Neglected Tropical Diseases to include selected diseases based on needs. The aim of prequalification of diagnostics (PQDx) is to promote and facilitate access to safe, appropriate and affordable IVDs of good quality. Focus is placed on IVDs for priority diseases and their suitability for use in resource-limited settings. The findings of PQDx generate independent technical information on safety, quality and performance of IVDs, principally used by other United Nations agencies, WHO Member States and other interested organizations to guide their procurement of IVDs. The prequalification assessment process includes three components: • review of a product dossier; • inspection of manufacturing site(s); and • performance evaluation (that is, independent verification of the performance of IVDs submitted for prequalification assessment). 3.5.2 WHO Model List of Essential In Vitro Diagnostics (EDL) The EDL provides evidence-based guidance and sets a reference for developing or updating national lists of essential in vitro diagnostic tests. National lists of essential medicines have been successful in raising awareness and political will, guiding procurement and regulation policies and facilitating ac- cess to affordable medicines, particularly in low-resourced countries, by prioritizing the most important medicines all countries need to make available to their populations. It is expected that such national lists will provide similar benefits and improve access to essential in vitro diagnostic tests, as well as contribute towards health system strengthening and realizing universal health coverage, which is central to Goal 3 of the Sustainable Development Goals (“Ensure healthy lives and promote well-being for all at all ages”). The second EDL, published in 2019, includes a section on disease-specific IVDs (dengue, schistosomiasis and visceral leishmaniasis) for use in clinical laboratories. The third meeting of the Strategic Advisory Group of Experts on In Vitro Diagnostics will take place at WHO headquarters in Geneva on 23–27 March 2020 and is currently accepting submissions for discus- sion. 13 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 4. Discussion 4.1 Managing complexity The Chair, Dr Lammie, opened the discussion. Prior to the meeting the group had been sent a prioritiza- tion exercise the aim of which was to collect information systematically to help prioritize NTD diagnos- tic needs in order to reach the 2030 targets. The WHO Department of Control of Neglected Tropical Diseases has developed a comprehensive meth- odology to ensure that the list of diseases prioritized for diagnostics best reflects targeted global health needs and focuses on the most pressing requirements of the 2030 road map targets. The approach relies on established best practice and is based on practical national and regional experiences in compiling similar lists. It also specifically attempts to address criticism of previous attempts by WHO and other parties to prioritize diseases by developing transparent tools and a stepped, wide-reaching consultative approach to addressing potential biases. Prioritization of diseases is difficult and requires a defined set of criteria on which to base prioritization. These criteria can be qualitative, intangible or subjective, and can be variable for different stakeholders. The criteria can also be interdependent, complicating separate assessment. Given the complexity and the challenges of disease prioritization, ensuring that the process is transparent and reproducible is import- ant. To narrow the list of potential priority diseases, a three-step semi-quantitative Delphi technique was adapted from established prioritization methods. Each NTD was to be scored from 0 to 1000 (through scoring 10 criteria), whereby 1000 represented a disease with the highest need for a new or improved diagnostic and 0 the lowest. A mean would then be taken to allow comparison with those in which some criteria were not applicable. The method entailed inviting a group of experts to reply anonymously to questionnaires. Subsequently, a smaller group would receive feedback, face to face, in the form of a statistical representation of the “group response”, after which the process would be repeated with only the members of the Working Group, the goal being to reduce the range of responses and arrive at expert consensus. The group was presented with the results they had sent before the meeting, and it was fed back that they considered the process too complex for the time available during the sessions. Dr Lammie presented a simplified algorithm to prioritize the needs (detailed in 4.1.1) and the group unanimously supported this approach. 4.1.1 Revised approach The revised approach distinguishes the indication addressed through preventive chemotherapy versus those requiring individual case management. The members and observers of the group were assigned to one or the other of these categories, with WHO focal points acting as resources for technical or specific questions. Three hours were allocated to each prioritization exercise, which only allowed a preliminary analysis. algorithm will be revisited at least once a year. 14 Report of the first meeting. Geneva, 30–31 October 2019 4.1.2 Preventive chemotherapy diseases The following diseases were included in the list for discussion: • lymphatic filariasis • onchocerciasis • scabies • schistosomiasis • soil-transmitted helminthiases • taeniasis and (neuro)cysticercosis • trachoma • yaws The algorithm starts by asking if epidemiological data are reported in the Weekly Epidemiological Re- cord (WER). If so, this indicates an active WHO programme. The next question is if the absence of a diagnostic is currently hampering effective decision-making for existing programmes. If so, the need is high. If not, the question is if the absence of a diagnostic test jeopardizes the 2030 goals. If so, the need is high again. Other use cases were deemed of lesser priority. Does WHO report progress against the disease in the WER? Is there reporting to the community, World Health Assembly Is the absence of a diagnostic test preventing the programme from making decisions? Is the absence of a diagnostic test preventing the 2030 targets from being reached? Pop-out group Focus on surveillance needs vs individual needs YES NO YES NOYES 15 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Does WHO report progress against the disease in the WER? Is there reporting to the community, World Health assembly? Is there an established intervention strategy? Is the absence of a diagnostic test preventing the 2030 targets from being reached? Is the absence of a diagnostic test preventing the programme from scaling up? Focus on surveillance needs vs individual needs YES NO YES NOYES Pop-out group YES Long-term horizon NO 4.1.3 Case management diseases The diseases discussed in this sub-group were: • Buruli ulcer • Chagas disease • cutaneous leishmaniasis • dengue and chikungunya • dracunculiasis • echinococcosis • human African trypanosomiasis • leprosy • mycetoma, chromoblastomycosis and other deep mycoses • rabies • snakebite envenoming • visceral leishmaniasis 16 Report of the first meeting. Geneva, 30–31 October 2019 4.2 Overview of discussion Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Onchocerciasis YES YES Preventing: (i) when-to-start decision in low-endemic areas, (ii) mapping in Loa loa co-endemic areas and (ii) when-to stop-decision based on serology YES PVS (long- term need) Entomological assay (O-150 PCR) is cumbersome so seeking a qPCR; serology for stopping is the main need; TPP developed with support from BMGF HIGH Lymphatic filariasis YES YES Mapping is affecting (i) Loa Loa endemic areas due to cross-reaction with FTS and (ii) there is no good tool for stopping decisions in IDA settings YES PTS surveil- lance is a major need Test for viable adult worms is need- ed; is what looks like recrudescence due to migration or to recent trans- mission? Long-term manufactur- ing partners are lacking, therefore posing a risk HIGH Trachoma YES NO But PVS would be enhanced with diagnostic tool that did not rely on clinical sign NO Fewer cases of trachoma, so more difficult to provide training for graders LOW Soil-transmit- ted helminthi- ases Ascaris Hookworm (including strongyloidi- asis) YES YES YES Kato–Katz works reasonably well for most infections except stron- gyloidiasis and is standardized; an improved test is desired, but it is not preventing some progress; faecal samples are suboptimal (easily ob- tained from children but not adults) HIGH Schistosomiasis YES YES YES Kato–Katz/urine filtration available for tracing progress towards mor- bidity targets; need to avoid future morbidity; as a public intervention; more sensitive test than Kato–Katz needed; M&E affected HIGH Yaws YES NO NO Detection of resistance would be helpful; certification of elimination; serological differentiation of syphi- lis; false positives are a problem M&E red in assessment of critical gaps; when should surveys be done; donation programme from EMS for eradication (153 million tablets) but no funding for implementation; ac- cess to the tests which are available is the issue LOW 17 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Scabies NO NO NO Diagnosis is clinical (skin exam- ination) so longer-term need; M&E strategy still under development LOW Taenia solium/ (neuro) cysticercosis NO YES No established strategy YES Neurocysticercosis (NCC) should be considered a case management disease, and taeniasis a preventive chemotherapy disease. Praziquantel is distributed for treatment of schis- tosomiasis, although the diseases are not co-endemic in many areas, and the target groups are different. No position of WHO on interven- tion strategy. There are limitations in establishing a programme due to lack of taeniasis diagnostics. Existing porcine cysticercosis test not adequately specific. Porcine tests complementary to taeniasis diag- nostics. TPPs are published already for taeniasis, NCC and porcine cysticercosis. LOW Foodborne trematodiases NO NO YES There is an established intervention strategy in Asia (e.g. specific Ab test would be easier than Ag test for mapping) Mapping test is most needed at this stage Are there Fasciola tests that could be repurposed for human use? LOW Human African trypanoso- miasis: T. b. rhodesiense T. b. gambiense YES YES Tests are available to guide treatment decisions for gHAT but not for rHAT, which is an acute disease YES rHAT gHAT is close to elimination DBS testing for surveillance rHAT: HIGH Cutaneous/ mucocutaneous leishmaniasis YES YES Better tests would facilitate diagnosis and treatment YES First priority: RDT for cutaneous leishmaniasis (now mainly macros- copy/clinical) HIGH Dengue/ chikungunya/ Zika virus disease YES YES Dengue diagnostic test for early infection would facili- tate clinical management YES First priority: Combo RDT test Highly sensitive RDT to facilitate initial diagnosis and reduce mortali- ty (including QC) = 2030 goal Action point: prequalification even more than EDL listing HIGH It was felt being addressed elsewhere Mycetoma YES YES Better tests would facilitate diagnosis and treatment YES RDT for early case detection HIGH 18 Report of the first meeting. Geneva, 30–31 October 2019 Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Dracunculiasis NO YES NO Non-issue for humans; in state of eradication; concentrate on detect- ing infection in dogs for contain- ment and surveillance LOW Buruli ulcer YES YES Better tests would facilitate diagnosis and treatment: Test for confirmation of diagnosis TLC and RDT YES RDT to confirm diagnosis Digital microscopy (cross-cutting)/ cell phone HIGH Snakebite envenoming NO YES Test to detect envenomation would facilitate clinical man- agement NO No objectives defined for 2030; clin- ical signs + epidemiology + clotting test: very useful RDT and clinical treatment deci- sions; minimum of two toxins vs usefulness to know the snake LOW Chagas disease NO YES RDT to detect infection and for treatment response Second priority • RDT congen- ital Chagas • RDT for discrete typing units • Automatic diagnosis (blood bank screening improvement) Digital microscopy: improving recognition of the parasite in slides, image library, reference material, tele diagnosis could be important; cross-cutting issue HIGH Echinococcosis NO YES Better tests would facilitate diagnosis and treatment NO Clear out- come/impact targets not yet established Based on imaging complemented by serology. Potential for expertise in China, Italy and other countries. Validation of serological tests for canine echinococcosis from China is required LOW Visceral leishmaniasis NO YES Better tests would facilitate diagnosis and treatment YES First priority: RDT in East Africa RDT for PKDL Leishmania skin test for mapping, disease transmission and to assess vaccine effectivenessSecond priority: RDT test cure (crucial for immuno- depressed) HIGH Sporotrichosis NO YES Better tests would facilitate diagnosis and treatment NO Clear targets not yet estab- lished First priority: telemicroscopy LOW 19 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Rabies NO No diagnostic need since immunization based on exposureSurveillance need in stray dogs (seroconversion rate) NO LOW Chromoblasto- mycosis NO YES Better tests would facilitate diagnosis and treatment NO Clear targets not yet estab- lished First priority: telemicroscopy LOW Leprosy YES YES YES Better POC tests would facilitate implementation of PEP and disease surveillance HIGH Ab, antibody; Ag, antigen; BMGF, Bill & Melinda Gates Foundation; DBS, dried blood spot; EDL, WHO Second Model List of Essential In Vitro Diagnostics; FTS, filariasis test strip; IDA, ivermectin, diethylcarbamazine (citrate), albendazole; M&E, monitoring and evaluation; NCC, neurocysticercosis; PCR, polymerase chain reaction; PEP, post-exposure prophylaxis; POC, point of care; PTS, post-transmission surveillance; PVS, post-validation surveillance; qPCR, quantitative PCR; RDT, rapid diagnostic test; TLC, thin-layer chromatography; TPP, target product profile. A detailed landscape analysis would facilitate future discussions, especially in identifying promising work on biomarkers and new test platforms. The discussion also touched on the need for back up supplies and other manufacturing concerns and capabilities; multiple tests will be needed to make certain that back- ups and confirmatory tests are available. The group called for an exercise to identify which companies are willing and able to manufacture on the scale needed for these diagnostics. The group also wanted to consider how best to engage with manufacturers (both big but especially small). The issue around quality assurance/quality control and regulatory pathways was discussed. This group needs to engage with the European Medicines Agency and the United States Food and Drug Administra- tion in order to adapt regulation on medical devices and serve as advisors to the committee. The need for technology to support the clinical diagnostic process was also discussed. 20 Report of the first meeting. Geneva, 30–31 October 2019 5. Recommendations After the discussion sessions, the members reviewed the outcomes in a closed session, with input from the WHO focal points around programmatic and diagnostic needs. The members discussed priorities for the year ahead as well as how to manage the complexity of supporting the diagnostics agenda across the entirety of WHO’s portfolio of NTDs. The following recommendations were made, based on the understanding that they would be reviewed at the next meeting, as it had been made clear that all NTDs had diagnostic needs which would have to be addressed in due course. 5.1 Tasks Among the important priorities to be addressed as early as possible in the work of the DTAG were the following: 5.1.1 Conduct a formal landscape analysis, including biomarker discovery Members recognized the limitations of their own knowledge of the “state of play” across the diagnostic landscape and the importance of this analysis to priority-setting. WHO will conduct or commission a detailed landscape analysis for review by the DTAG. 5.1.2 Expand the technical expertise that DTAG can all upon In recognition of the need for expanded technical expertise, WHO will draft terms of reference and guid- ance for the sub-groups or pop-out groups for review by the DTAG. 5.1.3 Formulate a process to bring existing TPPs under development into the DTAG structure The DTAG recognized the important investments of time and energy in the development of TPPs. WHO will establish a process to review existing TPPs for review by the DTAG. The DTAG pop-out groups will then review these TPPs against the WHO criteria to determine those that can be shared through WHO. 5.1.4 Develop a repository of TPPs WHO will establish a repository of approved TPPs and make them publicly available. The development of sub-groups or pop-out groups represents an important strategy to maximize the reach and impact of the DTAG. Extensive discussions in the closed session led to the prioritization of the sub-groups listed below. This list is not intended to be exclusive – new groups will be identified over time – or permanent. Sub-groups are intended to be time-limited in order to help channel or advocate for specific tasks and critical work. 5.2 Sub-groups The following sub-groups will be formed (within the next 12 months). Disease-specific topics (within 3 months) 21 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 5.2.1 Case management diseases The following skin-NTDs will require new diagnostic tests to facilitate treatment: • Buruli ulcer • mycetoma • leishmaniasis (cutaneous and post kala-azar dermal leishmaniasis) and • leprosy. For human African trypanosomiasis, diagnosis is needed to initiate treatment for the rhodesiense form of the disease. 5.2.2 Preventive chemotherapy diseases Diagnostic tests are required for the following diseases: • Onchocerciasis – tests for mapping and stopping mass treatment; • Lymphatic filariasis – tests for stopping IDA and starting MDA for lymphatic filariasis in areas endemic for Loa loa; • Soil-transmitted helminthiases – new tests for supporting changes in programme implementation; • Schistosomiasis – new tests for supporting changes in programme implementation. Cross-cutting topics (to be established within 6 months) 1) Surveillance and surveillance platforms, including: a. One Health b. Verification of elimination c. Post-elimination surveillance 2) Improving the quality of microscopy and clinical diagnosis a. Microscopy and image analysis b. Clinical examination 3) Manufacturing and regulatory pathways a. Access b. Quality assurance c. Regulatory pathways 22 Report of the first meeting. Geneva, 30–31 October 2019 WORKING GROUP MEMBERS Dr Pascal Millet Université de Bordeaux Laboratoire de Parasitologie Pôle Biologie, Hôpital Pellegrin 33000 Bordeaux, France Tel: +33 6 95070778 Email: pascal.millet@u-bordeaux.fr Dr Veerle Lejon Directeur de Recherche Institut de Recherche pour le Développement Unité Mixte de Recherche UMR177 Campus International de Baillarguet TA A17/G 34398 Montpellier, France Tel: +33 6 45 55 22 98 Email: veerle.lejon@ird.fr Professor Bruno Levecke Faculty of Veterinary Medicine Ghent University Salisburylaan 133, 9820 Merelbeke, Belgium Tel: +32 92647404 Email: bruno.levecke@ugent.be Professor Patrick Lammie NTD Support Center Task Force for Global Health 325 Swanton Way, Decatur, GA 30030, USA Tel: +1 404 687 5613 Email: plammie@taskforce.org Dr Fabricio K. Marchini Public Health Researcher Carlos Chagas Institute – Fiocruz Parana R. Prof. Algacyr Munhoz Madeer 3375-CIC Curitiba, Brazil Tel: +55 41996995444 Email: fabricio.marchini@fiocruz.br Dr René Paulussen Managing Director, Mondial Diagnostics 357 Woodcroft, Hudson, Quebec JOP 1HO Canada Tel: +1 4504580449 Email: rene.paulussen@mondialdx.com Professor Rahmah Noordin Director Institute for Research in Molecular Medicine Universiti Sains Malaysia 11800 Penang, Malaysia Tel: + 604 653 4800 Email: rahmah8485@gmail.com Dr Marco A. Biamonte Chief Executive Officer Drugs and Diagnostics for Tropical Diseases 4898 Ronson Ct. Suite C San Diego, CA 92111, USA Tel: +1 858 405 1277 Email: marco-biamonte@ddtd.org Dr Rhea N. Coler SVP, Preclinical and Translational Research Infectious Disease Research Institute 1616 Eastlake Ave. E., Ste 400 Seattle WA 98102, USA Tel: +1 206 612 2565 Email: Rhea.Coler@idri.org Professor Sammy M. Njenga Chief Research Scientist Kenya Medical Research Scientist (KMRI) P.O. Box 54840, 00200 Nairobi, Kenya Tel: +254 722945243 Email: sammynjenga@gmail.com Dr Esvawaran Sreekumar Chief Scientific Officer Rajiv Gandhi for Biotechnology Thycaud, P.O. Thiruvananthapuram 695 014 Kerala, India Tel: +919 447 698943 Email: esreekumar@rgcb.res.in Annex 1. List of participants 23 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Dr Isra Cruz* Head International Health Department National School of Public Health Instituto de Salud Carlos III 8 Sinesio Delgado, 28029 Madrid, Spain Tel: +34 918 222 312 Email: cruzi@isciii.es Dr Michael Marks* Associate Professor NIHR Clinical Lecturer in Infectious Diseases School of Hygiene and Tropical Medicine Keppel Street, London WC1E 7HT, United Kingdom Tel: +44 (0)7984 643424 Email: Michael.Marks@lshtm.ac.uk London OBSERVERS AND WHO COLLABORATING CENTRES Dr Francisco Javier Moreno Nuncio Instituto de Salud Carlos III Centro Nacional de Microbiologia Ctra. Majadahonda-Pozuelo KM. 2,2 28220 Majadahonda, Spain Tel: +34 918223771 Email: javier.moreno@isciii.es Dr Pascale Ondoa Director of Science and New Initiatives African Society for Laboratory Medicine Joseph Tito Street, Nega City Mall, Suite 800 P.O. Box 5487, Addis Ababa, Ethiopia Email: pondoa@aslm.org Dr Supaporn Wacharapluesadee Deputy Director WHO Collaborating Center for Research and Training on Viral Zoonoses Rama IV Road, 10330 Bangkok, Thailand Tel: +66 22564000 Email: spwa@hotmail.com Dr Men-Bao Qian Vice Chief of the Department of Soil and Food-Borne Parasitic Diseases National Institute of Parasitic Diseases Chinese Center for Disease Control and Prevention No. 207, Ruijin Er Road, Shanghai 200025, China Email: qianmb@nipd.chinacdc.cn Dr Emily Wainwright Senior NTD Advisor United States Agency for International Development Neglected Tropical Diseases Program 1300 Pennsylvania Ave, NW Washington, DC 20523, USA Tel: +1 571 551 7373 Email: ewainwright@usaid.gov Dr Michele Helinski Project Officer NTD diagnostic projects The European & Developing Countries Clinical Trials Partnership (EDCTP) P.O. Box 93015, 2509 AA The Hague, The Netherlands Email: helinski@edctp.org Dr William E. Secor Team Lead, Elimination and Control Laboratory Parasitic Diseases Branch Centers for Disease Control and Prevention 1600 Clifton Road, NE Atlanta, GA 30329–4018, USA Tel: +1 404 718 4141 Email: was4@cdc.gov Dr Stephanie R. Bialek Chief Parasitic Diseases Branch, Division of Parasitic Diseases and Malaria Centers for Disease Control and Prevention 1600 Clifton Road, NE Atlanta GA 30329–4027, USA Tel: 1 404 639 7785 Email: zqg7@cdc.gov 24 Report of the first meeting. Geneva, 30–31 October 2019 Dr Roger Peck Senior Program Officer PATH 2201 Westlake Avenue, Suite 200 Seattle, WA 981121, USA Tel: +1 206 218 2237 Email: rpeck@path.org Dr Allison Golden Scientific Program Officer Diagnostics Program PATH 2201 Westlake Avenue, Suite 200 Seattle, WA 981121, USA Tel: +1 206 302 4735 Email: algolden@path.org Dr Tom Cummins Senior Program Officer, Diagnostics Innovative Technology Solution Bill and Melinda Gates Foundation P.O. Box 23350 Seattle WA 98102, USA Tel: +1 585 704 3114 Email: tom.cummins@gatesfoundation.org Dr Jordan Tappero Senior Program Officer NTDs, Global Health Program P.O. Box 23350 Seattle WA98102, USA Tel: +1 206 770 1930 Email: jordan.tappero@gatesfoundation.org Dr Sarah Nogaro Scientific Officer – Schistosomiasis FIND, Campus Biotech Chemin des Mines 9 1202 Geneva, Switzerland Tel: +41 22 710 05 94 Email: sarah.nogaro@finddx.org Professor Joseph Ndung’u Head, Neglected Tropical Diseases Programme FIND Campus Biotech Chemin des Mines 9 1202 Geneva, Switzerland Tel: +41 79 540 4114 Email: joseph.ndungu@finddx.org Dr Olaf Valverde Mordt Clinical Team Leader Drugs for Neglected Diseases initiative Chemin Louis-Dunant 15 1202 Genève, Switzerland Tel: +41 79 543 1713 Email: ovalverde@dndi.org Dr Fabiana Alves Head of Visceral Leishmaniasis Clinical Program Drugs for Neglected Diseases initiative Chemin Louis-Dunant 15 1202 Genève, Switzerland Tel: +41 79 775 2344 Email: falves@dndi.org Dr Catherine K. Ohura CEO and Executive Director Global Health Innovative Technology Fund Ark Hills Sengokuyama Mori Tower 25F 1-9-10 Roppongi, Minato-ku Tokyo 106–0032, Japan Tel: +81 3 6441 2032 Email: catherine.ohura@ghitfund.org Dr Hayato Urabe Senior Director of Investment Strategy and Management Global Health Innovative Technology Fund Ark Hills Sengokuyama Mori Tower 25F 1-9-10 Roppongi, Minato-ku, Japan Tel: + 813 644 12032 Email: Hayato.urabe@ghitfund.org WHO SECRETARIAT Dr Mwelecele Ntuli Malecela, Director NTD Tel: +41 22 791 4611 Email: malecelam@who.int Dr Daniel Argaw Dagne, Coordinator IDM Tel: +41 22 791 4532 Email: daniel@who.int Dr Pedro Albajar Vinãs, NTD/IDM Tel: +41 22 791 1261 Email: albajarvinasp@who.int 25 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Dr Kingsley Asiedu, NTD/IDM Tel: +41 22 791 2803 Email: asieduk@who.int Dr Jose Ramon Franco Minguell, NTD/IDM Tel: + 41 22 791 3313 Email: francoj@who.int Dr Gerardo Priotto, NTD/IDM Tel: +41 22 791 1375 Email: priottog@who.int Dr Jose Ruiz Postigo, NTD/IDM Tel: +41 22 791 3870 Email: postigoj@who.int Dr Saurabh Jain, NTD/IDM Tel: +41 22 791 3849 Email: jains@who.int Dr Amadou Garba Djirmay, NTD/PCT* Tel: +41 22 791 3322 Email: garbadjirmaya@who.int Dr Jonathan King, NTD/PCT Tel: +41 22 791 1423 Email: kingj@who.int Dr Pamela Sabina Mbabazi, NTD/PCT Tel: +41 22 791 4855 Email: mbabazip@who.int Dr Antonio Montresor, NTD/PCT Tel: +41 22 7913367 Email: montresora@who.int Dr Dieudonné Sankara, NTD/PCT Tel: +41 22 791 2164 Email: sankarad@who.int Dr Anthony Solomon, NTD/PCT Tel: +41 22 791 2823 Email: solomona@who.int Dr Afework Tekle, NTD/PCT* Tel: +41 22 791 4640 Email: teklea@who.int Dr Raman Velayudhan, NTD/VEM Tel: +41 22 791 1868 Email: velayudhanr@who.int Dr Bernadette Abela-Ridder, NTD/NZD* Tel: +41 22 791 12072 Email: abelab@who.int Dr Camilla Ducker, NTD consultant diagnostics Email: camilla@troda.org Dr Lea Knopf, NTD consultant NZD* Email: knopfl@who.int Dr Lauren Carrington, NTD consultant VEM Email: carringtonl@who.int Dr Annette Kuesel, TDR Email: kuesela@who.int Ms Sophie Lambert, NTD/IDM support staff Email: lamberts@who.int * Unable to attend
Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Geneva, 30–31 October 2019
Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Geneva, 30–31 October 2019 Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases, Geneva, Switzerland, 30–31 October 2019 ISBN 978-92-4-000359-0 (electronic version) ISBN 978-92-4-000360-6 (print version) © World Health Organization 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareA- like 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, pro- vided 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. 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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. How- ever, 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 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Contents 1. Introduction 1 1.1 Declarations of interest 1 2. Background 1 3. Sessions 2 3.1 Terms of reference, structure and objectives of the Working Group 2 3.2 Introduction to WHO target product profiles 3 3.3 The road map for 2030 4 3.4 Diagnostic gaps for specific diseases 5 3.5 WHO Model List of Essential In Vitro Diagnostics and prequalification process 12 3.5.1 Prequalification 12 3.5.2 WHO Model List of Essential In Vitro Diagnostics 12 4. Discussion 13 4.1 Managing complexity 13 4.1.1 Revised approach 13 4.1.2 Preventive chemotherapy diseases 14 4.1.3 Case management diseases 15 4.2 Overview of discussion 16 5. Recommendations 20 5.1 Tasks 20 5.1.1 Conduct a formal landscape analysis, including biomarker discovery 20 5.1.2 Expand the technical expertise that DTAG can call upon 20 5.1.3 Formulate a process to bring existing TPPs under development into the DTAG structure 20 5.1.4 Develop a repository of TPPs 20 5.2 Sub-groups 21 5.2.1 Case management diseases 21 5.2.2 Preventive chemotherapy diseases 21 Annex 1. List of participants 23 1WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 1. Introduction The first meeting of the Diagnostic Technical Advisory Group (DTAG), an advisory group to the WHO Department of Control of Neglected Tropical Diseases, was held at the Inter-Parliamentary Union in Geneva, Switzerland, on 30–31 October 2019. The meeting was opened by Dr Mwele Malecela, Director, WHO Department of Control of Neglected Tropical Diseases, who welcomed participants. She noted the importance of this inaugural meeting given that, during the process of developing the road map on neglected tropical diseases 2021–2030, it became apparent that failing to give adequate consideration to critical diagnostic needs would lead not only to the NTD community missing new targets that were being set but also to losing or compromising the gains made during the past decade. Dr Malecela also noted that the Department currently manages a diverse portfolio of 20 diseases and disease groups, each with its own unique epidemiology and diagnostic challenges. The goals associated with individual disease programmes are disease-specific – whether for control, elimination as a public health problem, elimination of transmission or eradication – but each disease poses a unique diagnostic challenge that must be addressed in order to reach the 2030 road map targets. Dr Patrick Lammie, Director, Neglected Tropical Diseases Support Center, a programme of the Task Force for Global Health, was appointed Chair of the Working Group and Dr Veerle Lejon, Director of Research at Institut de Recherche pour le Développement, as vice chair. Dr Rhea Coler, Senior Vice Pres- ident of Preclinical and Translational Research, Infectious Disease Research Institute, was nominated rapporteur. The meeting was attended by 10 invited experts, 17 observers and 15 staff from the WHO Secretariat (Annex 1: List of participants). The Working Group met in both plenary and breakout sessions. 1.1 Declarations of interest All the members 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 experts 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 disease categories, each with its own unique epidemiological and diagnostic challenges. Programmes to address each of these diseases have different goals according to the targets set for a particular dis- ease: control, elimination as a public health problem, elimination of transmission, or eradication. These programmatic goals may also change over time as programmes achieve success and disease prevalence declines, as new tools are developed or as global attention attracts increased support and commitment. Accurate and reliable diagnostic tools are necessary for all of these programmes. While classical clinical and parasitological techniques are often adequate for mapping the distribution of disease and monitoring 2Report of the first meeting. Geneva, 30–31 October 2019 the progress of interventions against neglected tropical diseases (NTDs), the need for improved diagnos- tics becomes critical as infection prevalence declines and elimination becomes a possibility. For NTDs that require case management, diagnostics are essential to achieve the goals of control, elim- ination or eradication, as the intervention for this group of diseases relies on detecting individual cases and conducting surveillance. The addition of new diseases to the portfolio has highlighted the require- ment for improved diagnostic tools. For diseases targeted by preventive chemotherapy, diagnostic tests are required to support programmatic decisions on changing the frequency of treatment or stopping mass treatment, or on conducting surveillance and validating or verifying elimination. Reports from the field indicate that NTD programmes are facing a number of problems that require urgent solutions. Recognition of the achievements accomplished on the road to 2020, and the enthusiasm generated by the Sustainable Development Goals for 2030, have renewed momentum for consolidating programme gains and accelerating progress towards programme end-points, as reflected in the new road map, which identifies critical gaps in diagnostics in order to meet the ambitious targets for 2030. In view of the need to support programmes to deliver much-needed health interventions to vulnerable populations, and in order to demonstrate and maintain the health gains achieved so far, the Depart- ment has determined, in accordance with the recommendations of the Strategic and Technical Advisory Group for Neglected Tropical Diseases, that it is necessary to reassess needs and access-related issues around diagnostics for all the diseases in its portfolio. Despite the diversity of the programme goals, common areas exist across programmes that lend them- selves well to consideration by a single working group for diagnostics. Individual programmes, depend- ing on their goals, may need diagnostics for case detection, diagnosis, prognosis, mapping of endemicity, monitoring and evaluation, test of cure and whether to stop mass treatment, determination of infectivity and/or post-treatment surveillance. A single WHO working group will ensure a unified approach to identifying and prioritizing diagnostic needs and to informing WHO strategies and guidance on the subject. In accordance, the objectives of the first meeting of the DTAG were: • to review the terms of reference, structure and working modalities of the group; • to introduce the WHO process for developing target product profiles (TPPs) development and including TPPs in the WHO Model List of Essential In Vitro Diagnostics; and • to discuss critical gaps in and prioritization of NTD diagnostics and the use cases for these tools. 3. Sessions 3.1 Terms of reference, structure and objectives of the Working Group Dr Daniel Argaw Dagne, Coordinator, Innovative and Intensified Disease Management, WHO Depart- ment of Control of Neglected Tropical Diseases, summarized the terms of reference, structure and work- ing procedures of the DTAG. He reiterated that planning for the 2030 road map required a reassessment of diagnostic needs and links with partners to redefine priorities for new and in-development diagnostics and other platforms. Dr Dagne reviewed the responsibilities of the DTAG members. He noted that all of the NTDs in the road map require diagnostics and that limited resources will require the group to prioritize urgent needs, rec- ognizing that all such needs will have to be addressed over time in a phased manner. He noted also the need to define test characteristics – use case, target population, ideal performance and ease of use – in order to support WHO in ensuring a harmonized TPP and establishing standards that the wider com- munity can agree upon and endorse. 3WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Reflecting on the membership of the DTAG (12 members and one alternate member, to serve in a per- sonal capacity and represent a range of disciplines), Dr Dagne commented that maximum effort must be exerted to ensure representation by geographical WHO regions and various areas of NTDs and of the importance in securing a balanced perspective. He reminded the group that experts were present in the fields of epidemiology, public health, infectious diseases health systems and management, as well as reg- ulatory authorities. He reiterated that all members would serve for a 4-year term and may subsequently be invited for a further 3 years. Dr Dagne reminded the group that experts should not bring their institutional positions or interests to the discussions and that members should attend all meetings, if possible. Members who were not able to attend two consecutive meetings would be asked to step down. The DTAG would meet once a year, with additional meetings and teleconferences to be scheduled as agreed upon by the Chair and the Depart- ment. Furthermore, only DTAG members could participate in voting or decisions by consensus, and in the formulation of final recommendations. The report on the meeting will be written by the rapporteur and the WHO secretariat, approved by mem- bers of the DTAG and posted on the WHO website. The role of the DTAG is to define priority gaps, coordinate the creation of a TPP for each priority use case, including synopses of position/policy statements, and to advise on strategy and access to NTD diag- nostics. The DTAG will also advise the Department on the establishment of ad-hoc use-cases or disease specific sub-groups in order to deliver on specific tasks and target product characteristics. Discussion turned then to the scale of the task facing the DTAG and the need for its processes to be nimble. Dr Malecela reflected on the need for tests that could be used in the most remote areas, not just in primary care centres; she agreed with the group that feasibility and production are real issues that should be addressed via a rapid but rigorous TPP process. There was general agreement from the group that the practical end-use should be considered from the outset, especially as there are few resources for diagnostics. 3.2 Introduction to WHO target product profiles Dr Vaseeharan Sathiyamoorthy, Team Lead, Data Sharing and Target Product Profile workstreams of the R&D Blueprint, and Coordinator, Research, Ethics, Knowledge Uptake at the WHO Department of Information, Evidence and Research – summarized the new WHO process for TPPs. He explained that the existence of a WHO TPP in a given area should be taken as a strong indication that products meeting the criteria are highly desirable for public health, and that critical gaps exist in the current landscape of available products. WHO TPPs should be considered as guidance from an end-to- end perspective, linking product development, access and affordability, as well as regulatory, policy and financing considerations, in order to enable line-of-sight so that product development can proceed with public health goals in mind. Dr Sathiyamoorthy then explained the eight steps within the process. Step one consists of determining whether a WHO TPP is needed. The proposed TPP should focus on a public health issue or disease that is prioritized by WHO through the World Health Assembly or another documented WHO process for setting priorities that includes (i) a review of the available literature and (ii) external consultative processes. An analysis of the available products and of the development pipeline should be conducted before the TPP is developed, to indicate that existing products in development do not meet critical public health needs in settings where that need is greatest. This may be because products do not exist, or licensed prod- ucts are not suitable or accessible for relevant populations. 4Report of the first meeting. Geneva, 30–31 October 2019 Step two is the drafting of a one-page scope and purpose document with regard to the specific TPP, for planning clearance within the relevant WHO technical unit. An entry would also be added to the Intranet information sharing portal for WHO’s TPPs (once this is established). This portal will provide transparency across WHO about which TPPs are available or in development. Step three consists of engaging in external consultations with relevant audiences, including the product development audience for the technical area, to determine whether a need exists for such a TPP outside WHO. Step four involves constituting a scientific TPP development group including, where appropriate, lead- ing scientists and experts, public health officials, regulators (in liaison with the regulatory unit at WHO/ MVP cluster) and, as a minimum, some in-country end-user representatives. End-user representatives should include disease control programmes in health ministries and, where possible, patient represen- tatives and/or civil society. For the TPP development group, the standard WHO declaration of interest procedures should be followed and experts with declared interests that cannot be managed adequately should be excluded. The group should not include current members of staff at for-profit industry entities. Step five consists of developing a zero draft version of the TPP document and consulting on the draft with the TPP development group (via phone or face-to-face) to produce a 0.1 version. Step six is to post version 0.1 with a proforma comment form for public consultation for a period of 28 days, to disseminate news of the public consultation widely and, specifically, to seek comments from industry, funders, scientists and end-users. Step seven is to share the comments received with the TPP development group, along with a proposed next version of the TPP. Depending on agreement by the TPP development group, this version may then undergo further consultation with relevant audiences, or may be labelled as version 1.0, dated and posted on WHO’s website as the first non-draft TPP for use in the technical area. WHO TPPs should be widely disseminated and in particular be made available to groups involved in the development of WHO policy recommendations for use later on in the development process, when data on products are being reviewed for their public health value. Step eight is to consider all WHO TPPs as living documents that may require modification if the status of the associated science or the pipeline in the area changes. The status of active/archive should be changed in the Product Profile Directory. It is also part of the TPP process that 5 years from the initial publication date, TPPs should be considered expired unless they have undergone a formal review and been updated appropriately with versioning and dating to indicate changes made. Dr Sathiyamoorthy emphasized that throughout the process, each version of the TPP should be recorded and dated and kept current on the WHO intranet portal for transparency. 3.3 The road map for 2030 Dr Malecela presented the new road map for NTDs for 2021–2030, which had been prepared with her team at WHO over the previous 6 months through a global consultative process of the wider NTD community, national programme managers and various WHO departments. The road map will be a key guiding document for the global response to NTDs over the next decade and serve as a critical strategic document to assist in the delivery of programmes that span the 20 diseases and disease groups; it will also serve as a policy and advocacy document that draws attention to the key challenges in the NTD space and encourages continued commitment from the global community of partners. The WHO Department of Control of Neglected Tropical Diseases used a consultative approach to develop the road map, focused on cross-cutting themes and strategies that span multiple NTDs. Grateful thanks were expressed to those 5WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases who took part in developing the document, with the aim of ensuring that the road map itself reflects the views of all stakeholders who contribute to the fight against NTDs. The road map was submitted to the Executive Board for approval in September 2019 and will be officially launched in 2020. The road map has four chapters: • Chapter 1, on the context and purpose, including the landscape of NTDs and the progress made to date globally; • Chapter 2, on the overarching, cross-cutting and disease-specific targets and milestones; • Chapter 3, on the strategies and actions required to achieve the 2030 targets, structured accord- ing to a strategic framework; and • Chapter 4, on guidance for countries in developing their national NTD plans, including key components that should form part of this plan, and the process and steps required. Dr Malecela then presented the “heatmap” component of the road map, which reflects the program- matic progress made for each disease, and the following headings: scientific understanding; diagnostics; effective intervention; operational and normative guidance; planning, governance and programme man- agement; monitoring and evaluation; access and logistics; and health care infrastructure and workforce. The heatmap identifies areas of common need. Diagnostics was clearly shown as an area of critical need for many NTDs to reach their 2030 goals. Better diagnostics can accelerate progress towards elimination, reduce morbidity, minimize programme costs and support monitoring and evaluation. 3.4 Diagnostic gaps for specific diseases Each of the NTD focal points presented two slides describing the current status of diagnostics and the diagnostic needs identified by the technical focal point and team. The presentation is summarized in the table below. 6Report of the first meeting. Geneva, 30–31 October 2019 Disease Current diagnostics Diagnostic needs Dracunculiasis • Clinical with epidemiological link • Microscopy for individual clinical diag- nosis • PCR test – confirmatory for individual clinical diagnosis Serological tests to detect pre-patent Guin- ea worm: • to anticipate interventions to stop transmission in endemic areas; would also ultimately help in the certification process. • for humans, dogs and other animals to detect pre-patent Guinea worm; • field pond-side test for detecting D. medinensis DNA in copepods • to identify water sources that are con- taminated with D. medinensis to facilitate interventions Yaws • Clinical – unreliable, lesions similar to other causes • Dark field microscopy • POC test (SD Bioline) – individual diag- nosis and screening; very high sensitivity and specificity • Treponemal serological test (DPP) – diagnosis and screening • PCR – confirmation, identify subspecies, can be used for AZT resistance monitor- ing; cannot distinguish/determine latent from seropositive cases • Detection of azithromycin resistance at the health facility/district • Automated high-throughput non-trepo- nemal test for certification of elimi- nation; large-scale serosurveillance of asymptomatic persons • Serological differentiation of yaws and syphilis – for individual diagnosis espe- cially of adults Human African trypanosomiasis (gambiense) • CATT (Ab serology) – screening of T. b. gambiense, community; low prevalence during surveillance limits its use • RDT (SD Bioline HAT and Coris HAT Sero-K-SeT) – screening, community and peripheral health facility • Immune trypanolysis test (TL) – referral test for surveillance, feasible on dried- blood spots; cumbersome • ELISA serological test – test for surveil- lance (reference laboratories) • Microscopy of blood, lymph fluid or CSF – parasitological confirmation, low sensitivity • mAECT and HCT (Woo) • PCR; LAMP – to reinforce serological suspicion, lack of accuracy for confirma- tion (PCR-reference laboratories; LAMP – district hospitals • Confirmatory tests for gHAT to be used in peripheral health systems – for screen- ing of population at risk of gHAT and confirmation of cases • More sensitive and specific serological test, cheaper – for screening of popula- tion at risk of HAT • High throughput test on blood dried spots in filter paper – for surveillance in low prevalence or post-elimination settings; for validation/verification of elimination • Algorithm combining different tests – to improve specificity of current tests • Test of cure – to reduce long-term fol- low-up and replace the invasive lumbar puncture, depending on efficacy of treat- ment available • Availability of existing tests – to ensure that the production of currently available tests is continued and affordable … • Serological rHAT – no screening test currently available 7WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Disease Current diagnostics Diagnostic needs Leprosy • No test available for diagnosis of infec- tion • Microscopy (demonstration of acid-fast bacilli in slit-skin smear) • Individual clinical diagnosis (some forms only); disease classification (some forms of MB leprosy); follow up and diagnosis of relapse • ELISA, lateral flow assays – individual clinical diagnosis for PB leprosy; low accuracy • PCR – individual clinical diagnosis; higher sensitivity and specificity than ELISA and lateral flow assays; lack of standardization; not commercially avail- able; requires technical and laboratory expertise • Diagnosis of infection – to provide pro- phylaxis to those most at risk • Screening for potential disease – to bet- ter identify suspected leprosy patients • Diagnosis of disease – to confirm diag- nosis of all forms of leprosy (especially indeterminate and PB leprosy) • Prediction of future disease - to identify those at risk of disability • Diagnosis of nerve function loss – to rec- ognize early nerve function loss (before it becomes irreversible) Onchocerciasis • Ov16 IgG4 – mapping and stopping; commonly used version: in low preva- lence settings, low sensitivity and very high specificity; newer versions more sensitive but concerns about specificity • Ov16 IgG4 RDT – maybe mapping, M&E; not specific enough for stopping, issues with reading in field, much lower sensitivity in low prevalence areas; good quality assurance • O-150 PCR – entomology needed for stopping MDA and transitioning to post-treatment surveillance; being tweaked to enhance performance • Serological test – for mapping low prev- alence areas; have a bridge solution but may need new tools • Serological test – for stopping MDA; higher sensitivity • Serological test (ideally multiplex) – for post-transmission surveillance; need sensitive test of early recrudescence: possibly replace entomology long-term Chagas disease • Microscopy – screening and diagnosis • Blood concentration methods – screen- ing and diagnosis • Serology (including chemiluminescence and other related tests) – screening and diagnosis • Molecular biology – Screening, diagno- sis, discrete typing unit of T. cruzi • Diagnostics – to detect current infection and assess treatment response • RDT – for early detection of infection in neonates (congenital transmission) • RDT – to identify the discrete typing unit of T. cruzi Visceral leishmaniasis • Clinical plus epidemiological link – indi- vidual clinical diagnosis • Microscopy – individual clinical diagno- sis • RDT rK39; RDT rk28 – individual clini- cal diagnosis; epidemiological surveys • IFAT, ELISA – individual clinical diag- nosis • Loopamp™ Leishmania detection kit (LAMP) • PCR – individual clinical diagnosis, species typing • Rapid test – more sensitive and specific especially for eastern Africa and Latin America regions • Test (serological or other preferably rapid test) – to monitor treatment response or test of cure • Rapid test for PKDL – to distinguish PKDL from other skin conditions 8Report of the first meeting. Geneva, 30–31 October 2019 Disease Current diagnostics Diagnostic needs Lymphatic filariasis • Microscopy (microfilaria in blood) – mapping and monitoring; low sensitivity, particularly after MDA • Filariasis Test Strip – for mapping, mon- itoring, stopping and transitioning to surveillance in areas endemic for W. bancrofti; recently identified as cross-reactive in patients with high Loa loa mf; operational issues; recent reliabil- ity issues on “failure to flow” • Brugia Rapid Test (BmR1 IgG4 RDT) – for stopping MDA and transitioning to post-MDA surveillance in areas endemic for Brugia spp.; point-of-care complex- ity – takes several steps, requires buffer, results after 30 min; some previous issues of reliability • Serology – for areas co-endemic with Loa loa and for mapping and stopping MDA • Serology – for stopping triple-therapy (IVM-DEC-ALB) MDA; need specific marker of worm viability to better assess impact of IDA on transmission potential • Post-MDA and post-validation sur- veillance – need biomarker specific of early exposure to confirm elimination of transmission and/or detect early recru- descence Schistosomiasis • Urine filtration – for S. haematobium; morbidity control/elimination as a PHP • Haematuria – for S. haematobium; mor- bidity control/elimination as a PHP, lacks specificity • Kato–Katz – for intestinal schistosomi- asis; morbidity control/elimination as a PHP; lacks sensitivity in low prevalence settings • CCA – morbidity control/elimination as a PHP; recommended for S. mansoni only; used for mapping and surveillance • Serology tests – interruption of transmis- sion (high sensitivity); moderate to low specificity • Molecular (PCR, LAMP) – interruption of transmission with high sensitivity and specificity • Hatching tests – interruption of trans- mission with high specificity; mainly for cercaria; time-consuming • RDT – for monitoring and evaluation of S. haematobium, S. mekongi and S. japon- icum transmission; and of humans and animals in low transmission areas • RDT – for verification of interruption of transmission for verification surveys; human, animals, snails • RDT – to assess treatment/drug efficacy Soil-transmitted helminthiases in- cluding strongyloidiasis • Kato–Katz/microscopy – Ascariasis, trichuriasis, hookworm infection; poor sensitivity for infection of low intensi- ty; gold standard, widely used; samples should be examined in a few hours • Mini-FLOTAC/microscopy – Ascariasis, trichuriasis, hookworm infection; poor sensitivity for infection of low intensity • Baermann/microscopy – for strongyloi- diasis, good sensitivity; gold standard but long and complex procedure • ELISA – for strongyloidiasis, good sensitivity and good performance when prevalence > 20% • RDT or artificial intelligence slide reader • The method should be capable of differ- entiating among the causative species and quantifying the intensity of infec- tions 9WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Disease Current diagnostics Diagnostic needs Trachoma • Clinical examination for TT and active trachoma (WHO-recommended) • NAAT – detection of infection; for re- search use only • Antibody detection test – for post-vali- dation surveillance; potential application for excluding trachoma at baseline Buruli ulcer • PCR (IS2404) – individual diagnosis; sensitivity and specificity > 90%; used in reference laboratories only; some quality issues • F-TLC – individual diagnosis; sensitivity < 70%; under evaluation in four coun- tries. • Microscopy (standard Ziehl–Neelsen light microscopy) – sensitivity 60%; rarely done • Culture – only method to identify viable AFB; identifies clinically suspected relapses after antimicrobial treatment; unsuitable for quick laboratory confir- mation. • Rapid point-of-care tests targeting my- colactone – for individual diagnosis at PHC/community level • LAMP – design locked test could replace home-brewed PCR methods; RPA – for individual diagnosis; design locked test could replace home-brewed PCR meth- ods Dengue and chikungunya • RDT + ELISA–NS1 antigen – screening, individual clinical diagnosis; sensitivity range 49–90%; specificity range 91– 100%; low performance • RDT + ELISA–IgM antigen – screening, individual clinical diagnosis; sensitivity range 21–98%; specificity range 77–91%; low performance • NAT-PCR screening, individual clinical diagnosis; sensitivity range 83–93%; specificity range 99–100%; irregular and low performance • RDT + ELISA–IgG – for screening; high sensitivity, low specificity; cross-reactivi- ty with flaviviruses and certain vaccines • High performance dual IgM+NS1 – for screening and individual clinical diagno- sis Echinococcosis • Imaging: X-ray, ultrasound, computer- ized tomography, MRI – for individual diagnosis, classification and staging and for monitoring treatment response • Serology: indirect haemagglutination test, ELISA, latex agglutination, immu- noblotting – for individual diagnosis but must be used with imaging • Histopathology – definitive individual diagnosis • Molecular assays – conventional and real-time PCR; individual diagnosis and definitive after imaging • Screening – antigen assay needed for communities endemic for echinococco- sis; POC Ag detection • Staging – biomarker antigen needed for suspected individuals, POC Ag detection • Treatment follow up – Ab assay or NAT needed for suspected individuals; high throughput antibody assay or POC NAT 10 Report of the first meeting. Geneva, 30–31 October 2019 Disease Current diagnostics Diagnostic needs Foodborne trematodiases • Imaging: X-ray, ultrasound, computer- ized tomography, MRI – for individual diagnosis, classification and staging and for monitoring treatment response • Serology: indirect haemagglutination test, ELISA, latex agglutination, immu- noblotting – for individual diagnosis but must be used with imaging • Histopathology – definitive individual diagnosis • Molecular assays (conventional and re- al-time PCR) – individual diagnosis and definitive after imaging • Screening – antigen assay needed for communities endemic for echinococco- sis; POC Ag detection • Staging – biomarker antigen needed for suspected individuals, POC Ag detection • Treatment follow up – Ab assay or NAT needed for suspected individuals; high throughput antibody assay or POC NAT Taeniasis/(neuro) cysticercosis • Microscopy (Kato–Katz) – taeniasis indi- vidual diagnosis, low sensitivity • Copro-Ag ELISA (taeniasis) – screening, clinical diagnosis, validation; sensitivity in field lower than published; not com- mercially available. • Copro-PCR (taeniasis) – confirmatory, test of cure; no test independently vali- dated • EITB assay – for screening but verify positives with other methods • Serology: Ag-ELISA, Ab-ELISA (neu- rocysticercosis) – to support clinical diagnosis • Serology: Ag ELISA, Ab ELISA (porcine cysticercosis) – for selecting pigs for necropsy • Screening, track and treat (taeniasis) – biomarker not available; Copro Ag under evaluation; POC antigen detection or POC NAT (e.g. PCR or LAMP) • Test for selection of patients in need of brain scan (neurocysticercosis); treat- ment follow up – POC antigen detection or POC NAT (e.g. PCR or LAMP) • Porcine cysticercosis – screening, valida- tion • Determination of cure and surveillance – biomarker not available; POC NAT (e.g. PCR or LAMP) Cutaneous leishmaniasis • Clinical and epidemiological link • Microscopy – smear, biopsy, gold stan- dard but variable sensitivity • Immunological (ELISA, LST) and molec- ular (PCR, qPCR, LAMP) tests – occa- sionally used in reference laboratories, field surveys (LST) • Detect rapid test – not validated inde- pendently • Rapid test – for confirmation of sus- pected cases that at peripheral health facilities Mycetoma • Clinical diagnosis – triad of a subcutane- ous mass, sinuses and granular discharge • Microscopy – smear, biopsy, gold stan- dard but variable sensitivity • Culture • Histopathology, aspiration cytology • Serological tests • Molecular – PCR, LAMP • (1→3)-β-D glucan assay • Early (subclinical) case detection – to identify early (subclinical) cases in the general population • Treatment response – test to determine when to stop treatment • Culture – to determine optimum treat- ment; may require species identification • Susceptibility testing – to determine optimal therapy 11 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Disease Current diagnostics Diagnostic needs Chromoblastomy- cosis and sporotrichiosis Chromoblastomycosis: • Clinical – itching nodulo-verrucous chronic skin lesion depicting a “black dot” surface usually after cutaneous trau- ma • Microscopy – direct exam skin scrapings, crusts, secretions, biopsied tissues • Histopathology • Culture • Immunodiagnosis – immunodiffusion and ELISA • Molecular Sporotrichiosis: • Commercially available lateral flow test in distinguishing cases from leishman- iasis, cutaneous NTM infection and chromoblastomycosis • Extracutaneous clinical form • Sensitive, specific molecular and POC tests Snakebite envenoming • Diagnostic algorithms and checklists • Clinical signs aided by aided by a 20-min whole-blood clotting test (20WBCT) • Currently only one diagnostic test is commercially available to confirm the type of snake venom present in the body of an envenomed patient. • Diagnostic for envenoming • POC diagnostic – to confirm envenom- ing through detection of two or more of a group of ubiquitous venom compo- nents • Test to confirm envenoming by detection of two or more toxins present in almost all venoms • Bioclimatic analysis of venomous snake distributions • Risk mapping to improve prevention and control of snakebite envenoming Ab, antibody; Ag, antigen; AZT, azithromycin; CATT, card agglutination test for trypanosomiasis; CCA, circulating cathodic antigen; DPP, dual path platform; ELISA, enzyme-linked immunosorbent assay; EITB, enzyme-linked immunoelectrotransfer blot; HCT, micro-haematocrit centrifugation test; IFAT, immunofluorescence antibody test; IVM-DEC-ALB, albendazole–diethylcarbamazine (citrate)–albendazole; LAMP, loop-mediated isothermal amplification; LST, Leishmania skin test MB, multibacillary; M&E, monitoring and evaluation; MDA, mass drug ad- ministration; mAECT, mini-anion exchange centrifugation technique; mf, microfilaraemia; MRI, magnetic resonance imaging; NAAT, nucleic acid amplification test; NAT, nucleic acid test; NTM, nontuberculous mycobacteria; PB, paucibacillary; PCR, polymerase chain reaction; PHC, primary health care; PHP, public health problem; qPCR, quantitative PCR; PKDL, post kala-azar dermal leishmaniasis; POC, point of care; RDT, rapid diagnostic test; RPA, recombinase polymerase amplification; TT, trachomatous trichiasis 12 Report of the first meeting. Geneva, 30–31 October 2019 3.5 WHO Model List of Essential In Vitro Diagnostics and prequalification process 3.5.1 Prequalification The Prequalification Programme, set up in 2001, is a service provided by WHO to facilitate access to med- icines that meet unified standards of quality, safety and efficacy for treatment of HIV/AIDS, malaria and tuberculosis. From the outset, the Programme was supported by the Joint United Nations Programme on HIV/AIDS (UNAIDS), the United Nations Children’s Fund (UNICEF), the United Nations Population Fund (UNFPA) and the World Bank as a measurable contribution to the United Nations’ priority goal of addressing widespread diseases in countries with limited access to quality-assured medicines. Its mis- sion is to work in close cooperation with national regulatory agencies and partner organizations to make quality-assured priority medicines available for those who urgently need them by conducting assessment and inspection activities, building national capacity for manufacture, regulation and monitoring of med- icines and working with regulators to register those medicines quickly. WHO has been assessing the performance and operational characteristics of in-vitro diagnostics (IVDs) since 1988; however, the Prequalification Programme for IVDs was introduced in 2008. Although diag- nostics for NTDs are currently not included in the process, discussions are under way with the WHO Department of Control of Neglected Tropical Diseases to include selected diseases based on needs. The aim of prequalification of diagnostics (PQDx) is to promote and facilitate access to safe, appropriate and affordable IVDs of good quality. Focus is placed on IVDs for priority diseases and their suitability for use in resource-limited settings. The findings of PQDx generate independent technical information on safety, quality and performance of IVDs, principally used by other United Nations agencies, WHO Member States and other interested organizations to guide their procurement of IVDs. The prequalification assessment process includes three components: • review of a product dossier; • inspection of manufacturing site(s); and • performance evaluation (that is, independent verification of the performance of IVDs submitted for prequalification assessment). 3.5.2 WHO Model List of Essential In Vitro Diagnostics (EDL) The EDL provides evidence-based guidance and sets a reference for developing or updating national lists of essential in vitro diagnostic tests. National lists of essential medicines have been successful in raising awareness and political will, guiding procurement and regulation policies and facilitating ac- cess to affordable medicines, particularly in low-resourced countries, by prioritizing the most important medicines all countries need to make available to their populations. It is expected that such national lists will provide similar benefits and improve access to essential in vitro diagnostic tests, as well as contribute towards health system strengthening and realizing universal health coverage, which is central to Goal 3 of the Sustainable Development Goals (“Ensure healthy lives and promote well-being for all at all ages”). The second EDL, published in 2019, includes a section on disease-specific IVDs (dengue, schistosomiasis and visceral leishmaniasis) for use in clinical laboratories. The third meeting of the Strategic Advisory Group of Experts on In Vitro Diagnostics will take place at WHO headquarters in Geneva on 23–27 March 2020 and is currently accepting submissions for discus- sion. 13 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 4. Discussion 4.1 Managing complexity The Chair, Dr Lammie, opened the discussion. Prior to the meeting the group had been sent a prioritiza- tion exercise the aim of which was to collect information systematically to help prioritize NTD diagnos- tic needs in order to reach the 2030 targets. The WHO Department of Control of Neglected Tropical Diseases has developed a comprehensive meth- odology to ensure that the list of diseases prioritized for diagnostics best reflects targeted global health needs and focuses on the most pressing requirements of the 2030 road map targets. The approach relies on established best practice and is based on practical national and regional experiences in compiling similar lists. It also specifically attempts to address criticism of previous attempts by WHO and other parties to prioritize diseases by developing transparent tools and a stepped, wide-reaching consultative approach to addressing potential biases. Prioritization of diseases is difficult and requires a defined set of criteria on which to base prioritization. These criteria can be qualitative, intangible or subjective, and can be variable for different stakeholders. The criteria can also be interdependent, complicating separate assessment. Given the complexity and the challenges of disease prioritization, ensuring that the process is transparent and reproducible is import- ant. To narrow the list of potential priority diseases, a three-step semi-quantitative Delphi technique was adapted from established prioritization methods. Each NTD was to be scored from 0 to 1000 (through scoring 10 criteria), whereby 1000 represented a disease with the highest need for a new or improved diagnostic and 0 the lowest. A mean would then be taken to allow comparison with those in which some criteria were not applicable. The method entailed inviting a group of experts to reply anonymously to questionnaires. Subsequently, a smaller group would receive feedback, face to face, in the form of a statistical representation of the “group response”, after which the process would be repeated with only the members of the Working Group, the goal being to reduce the range of responses and arrive at expert consensus. The group was presented with the results they had sent before the meeting, and it was fed back that they considered the process too complex for the time available during the sessions. Dr Lammie presented a simplified algorithm to prioritize the needs (detailed in 4.1.1) and the group unanimously supported this approach. 4.1.1 Revised approach The revised approach distinguishes the indication addressed through preventive chemotherapy versus those requiring individual case management. The members and observers of the group were assigned to one or the other of these categories, with WHO focal points acting as resources for technical or specific questions. Three hours were allocated to each prioritization exercise, which only allowed a preliminary analysis. algorithm will be revisited at least once a year. 14 Report of the first meeting. Geneva, 30–31 October 2019 4.1.2 Preventive chemotherapy diseases The following diseases were included in the list for discussion: • lymphatic filariasis • onchocerciasis • scabies • schistosomiasis • soil-transmitted helminthiases • taeniasis and (neuro)cysticercosis • trachoma • yaws The algorithm starts by asking if epidemiological data are reported in the Weekly Epidemiological Re- cord (WER). If so, this indicates an active WHO programme. The next question is if the absence of a diagnostic is currently hampering effective decision-making for existing programmes. If so, the need is high. If not, the question is if the absence of a diagnostic test jeopardizes the 2030 goals. If so, the need is high again. Other use cases were deemed of lesser priority. Does WHO report progress against the disease in the WER? Is there reporting to the community, World Health Assembly Is the absence of a diagnostic test preventing the programme from making decisions? Is the absence of a diagnostic test preventing the 2030 targets from being reached? Pop-out group Focus on surveillance needs vs individual needs YES NO YES NOYES 15 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Does WHO report progress against the disease in the WER? Is there reporting to the community, World Health assembly? Is there an established intervention strategy? Is the absence of a diagnostic test preventing the 2030 targets from being reached? Is the absence of a diagnostic test preventing the programme from scaling up? Focus on surveillance needs vs individual needs YES NO YES NOYES Pop-out group YES Long-term horizon NO 4.1.3 Case management diseases The diseases discussed in this sub-group were: • Buruli ulcer • Chagas disease • cutaneous leishmaniasis • dengue and chikungunya • dracunculiasis • echinococcosis • human African trypanosomiasis • leprosy • mycetoma, chromoblastomycosis and other deep mycoses • rabies • snakebite envenoming • visceral leishmaniasis 16 Report of the first meeting. Geneva, 30–31 October 2019 4.2 Overview of discussion Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Onchocerciasis YES YES Preventing: (i) when-to-start decision in low-endemic areas, (ii) mapping in Loa loa co-endemic areas and (ii) when-to stop-decision based on serology YES PVS (long- term need) Entomological assay (O-150 PCR) is cumbersome so seeking a qPCR; serology for stopping is the main need; TPP developed with support from BMGF HIGH Lymphatic filariasis YES YES Mapping is affecting (i) Loa Loa endemic areas due to cross-reaction with FTS and (ii) there is no good tool for stopping decisions in IDA settings YES PTS surveil- lance is a major need Test for viable adult worms is need- ed; is what looks like recrudescence due to migration or to recent trans- mission? Long-term manufactur- ing partners are lacking, therefore posing a risk HIGH Trachoma YES NO But PVS would be enhanced with diagnostic tool that did not rely on clinical sign NO Fewer cases of trachoma, so more difficult to provide training for graders LOW Soil-transmit- ted helminthi- ases Ascaris Hookworm (including strongyloidi- asis) YES YES YES Kato–Katz works reasonably well for most infections except stron- gyloidiasis and is standardized; an improved test is desired, but it is not preventing some progress; faecal samples are suboptimal (easily ob- tained from children but not adults) HIGH Schistosomiasis YES YES YES Kato–Katz/urine filtration available for tracing progress towards mor- bidity targets; need to avoid future morbidity; as a public intervention; more sensitive test than Kato–Katz needed; M&E affected HIGH Yaws YES NO NO Detection of resistance would be helpful; certification of elimination; serological differentiation of syphi- lis; false positives are a problem M&E red in assessment of critical gaps; when should surveys be done; donation programme from EMS for eradication (153 million tablets) but no funding for implementation; ac- cess to the tests which are available is the issue LOW 17 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Scabies NO NO NO Diagnosis is clinical (skin exam- ination) so longer-term need; M&E strategy still under development LOW Taenia solium/ (neuro) cysticercosis NO YES No established strategy YES Neurocysticercosis (NCC) should be considered a case management disease, and taeniasis a preventive chemotherapy disease. Praziquantel is distributed for treatment of schis- tosomiasis, although the diseases are not co-endemic in many areas, and the target groups are different. No position of WHO on interven- tion strategy. There are limitations in establishing a programme due to lack of taeniasis diagnostics. Existing porcine cysticercosis test not adequately specific. Porcine tests complementary to taeniasis diag- nostics. TPPs are published already for taeniasis, NCC and porcine cysticercosis. LOW Foodborne trematodiases NO NO YES There is an established intervention strategy in Asia (e.g. specific Ab test would be easier than Ag test for mapping) Mapping test is most needed at this stage Are there Fasciola tests that could be repurposed for human use? LOW Human African trypanoso- miasis: T. b. rhodesiense T. b. gambiense YES YES Tests are available to guide treatment decisions for gHAT but not for rHAT, which is an acute disease YES rHAT gHAT is close to elimination DBS testing for surveillance rHAT: HIGH Cutaneous/ mucocutaneous leishmaniasis YES YES Better tests would facilitate diagnosis and treatment YES First priority: RDT for cutaneous leishmaniasis (now mainly macros- copy/clinical) HIGH Dengue/ chikungunya/ Zika virus disease YES YES Dengue diagnostic test for early infection would facili- tate clinical management YES First priority: Combo RDT test Highly sensitive RDT to facilitate initial diagnosis and reduce mortali- ty (including QC) = 2030 goal Action point: prequalification even more than EDL listing HIGH It was felt being addressed elsewhere Mycetoma YES YES Better tests would facilitate diagnosis and treatment YES RDT for early case detection HIGH 18 Report of the first meeting. Geneva, 30–31 October 2019 Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Dracunculiasis NO YES NO Non-issue for humans; in state of eradication; concentrate on detect- ing infection in dogs for contain- ment and surveillance LOW Buruli ulcer YES YES Better tests would facilitate diagnosis and treatment: Test for confirmation of diagnosis TLC and RDT YES RDT to confirm diagnosis Digital microscopy (cross-cutting)/ cell phone HIGH Snakebite envenoming NO YES Test to detect envenomation would facilitate clinical man- agement NO No objectives defined for 2030; clin- ical signs + epidemiology + clotting test: very useful RDT and clinical treatment deci- sions; minimum of two toxins vs usefulness to know the snake LOW Chagas disease NO YES RDT to detect infection and for treatment response Second priority • RDT congen- ital Chagas • RDT for discrete typing units • Automatic diagnosis (blood bank screening improvement) Digital microscopy: improving recognition of the parasite in slides, image library, reference material, tele diagnosis could be important; cross-cutting issue HIGH Echinococcosis NO YES Better tests would facilitate diagnosis and treatment NO Clear out- come/impact targets not yet established Based on imaging complemented by serology. Potential for expertise in China, Italy and other countries. Validation of serological tests for canine echinococcosis from China is required LOW Visceral leishmaniasis NO YES Better tests would facilitate diagnosis and treatment YES First priority: RDT in East Africa RDT for PKDL Leishmania skin test for mapping, disease transmission and to assess vaccine effectivenessSecond priority: RDT test cure (crucial for immuno- depressed) HIGH Sporotrichosis NO YES Better tests would facilitate diagnosis and treatment NO Clear targets not yet estab- lished First priority: telemicroscopy LOW 19 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Preventive chemotherapy diseases Reported in WER? Is absence of test hamper- ing decision-making? Is absence of test threat- ening 2030 targets Additional comments Overall priority at this time Rabies NO No diagnostic need since immunization based on exposureSurveillance need in stray dogs (seroconversion rate) NO LOW Chromoblasto- mycosis NO YES Better tests would facilitate diagnosis and treatment NO Clear targets not yet estab- lished First priority: telemicroscopy LOW Leprosy YES YES YES Better POC tests would facilitate implementation of PEP and disease surveillance HIGH Ab, antibody; Ag, antigen; BMGF, Bill & Melinda Gates Foundation; DBS, dried blood spot; EDL, WHO Second Model List of Essential In Vitro Diagnostics; FTS, filariasis test strip; IDA, ivermectin, diethylcarbamazine (citrate), albendazole; M&E, monitoring and evaluation; NCC, neurocysticercosis; PCR, polymerase chain reaction; PEP, post-exposure prophylaxis; POC, point of care; PTS, post-transmission surveillance; PVS, post-validation surveillance; qPCR, quantitative PCR; RDT, rapid diagnostic test; TLC, thin-layer chromatography; TPP, target product profile. A detailed landscape analysis would facilitate future discussions, especially in identifying promising work on biomarkers and new test platforms. The discussion also touched on the need for back up supplies and other manufacturing concerns and capabilities; multiple tests will be needed to make certain that back- ups and confirmatory tests are available. The group called for an exercise to identify which companies are willing and able to manufacture on the scale needed for these diagnostics. The group also wanted to consider how best to engage with manufacturers (both big but especially small). The issue around quality assurance/quality control and regulatory pathways was discussed. This group needs to engage with the European Medicines Agency and the United States Food and Drug Administra- tion in order to adapt regulation on medical devices and serve as advisors to the committee. The need for technology to support the clinical diagnostic process was also discussed. 20 Report of the first meeting. Geneva, 30–31 October 2019 5. Recommendations After the discussion sessions, the members reviewed the outcomes in a closed session, with input from the WHO focal points around programmatic and diagnostic needs. The members discussed priorities for the year ahead as well as how to manage the complexity of supporting the diagnostics agenda across the entirety of WHO’s portfolio of NTDs. The following recommendations were made, based on the understanding that they would be reviewed at the next meeting, as it had been made clear that all NTDs had diagnostic needs which would have to be addressed in due course. 5.1 Tasks Among the important priorities to be addressed as early as possible in the work of the DTAG were the following: 5.1.1 Conduct a formal landscape analysis, including biomarker discovery Members recognized the limitations of their own knowledge of the “state of play” across the diagnostic landscape and the importance of this analysis to priority-setting. WHO will conduct or commission a detailed landscape analysis for review by the DTAG. 5.1.2 Expand the technical expertise that DTAG can all upon In recognition of the need for expanded technical expertise, WHO will draft terms of reference and guid- ance for the sub-groups or pop-out groups for review by the DTAG. 5.1.3 Formulate a process to bring existing TPPs under development into the DTAG structure The DTAG recognized the important investments of time and energy in the development of TPPs. WHO will establish a process to review existing TPPs for review by the DTAG. The DTAG pop-out groups will then review these TPPs against the WHO criteria to determine those that can be shared through WHO. 5.1.4 Develop a repository of TPPs WHO will establish a repository of approved TPPs and make them publicly available. The development of sub-groups or pop-out groups represents an important strategy to maximize the reach and impact of the DTAG. Extensive discussions in the closed session led to the prioritization of the sub-groups listed below. This list is not intended to be exclusive – new groups will be identified over time – or permanent. Sub-groups are intended to be time-limited in order to help channel or advocate for specific tasks and critical work. 5.2 Sub-groups The following sub-groups will be formed (within the next 12 months). Disease-specific topics (within 3 months) 21 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 5.2.1 Case management diseases The following skin-NTDs will require new diagnostic tests to facilitate treatment: • Buruli ulcer • mycetoma • leishmaniasis (cutaneous and post kala-azar dermal leishmaniasis) and • leprosy. For human African trypanosomiasis, diagnosis is needed to initiate treatment for the rhodesiense form of the disease. 5.2.2 Preventive chemotherapy diseases Diagnostic tests are required for the following diseases: • Onchocerciasis – tests for mapping and stopping mass treatment; • Lymphatic filariasis – tests for stopping IDA and starting MDA for lymphatic filariasis in areas endemic for Loa loa; • Soil-transmitted helminthiases – new tests for supporting changes in programme implementation; • Schistosomiasis – new tests for supporting changes in programme implementation. Cross-cutting topics (to be established within 6 months) 1) Surveillance and surveillance platforms, including: a. One Health b. Verification of elimination c. Post-elimination surveillance 2) Improving the quality of microscopy and clinical diagnosis a. Microscopy and image analysis b. Clinical examination 3) Manufacturing and regulatory pathways a. Access b. Quality assurance c. Regulatory pathways 22 Report of the first meeting. Geneva, 30–31 October 2019 WORKING GROUP MEMBERS Dr Pascal Millet Université de Bordeaux Laboratoire de Parasitologie Pôle Biologie, Hôpital Pellegrin 33000 Bordeaux, France Tel: +33 6 95070778 Email: pascal.millet@u-bordeaux.fr Dr Veerle Lejon Directeur de Recherche Institut de Recherche pour le Développement Unité Mixte de Recherche UMR177 Campus International de Baillarguet TA A17/G 34398 Montpellier, France Tel: +33 6 45 55 22 98 Email: veerle.lejon@ird.fr Professor Bruno Levecke Faculty of Veterinary Medicine Ghent University Salisburylaan 133, 9820 Merelbeke, Belgium Tel: +32 92647404 Email: bruno.levecke@ugent.be Professor Patrick Lammie NTD Support Center Task Force for Global Health 325 Swanton Way, Decatur, GA 30030, USA Tel: +1 404 687 5613 Email: plammie@taskforce.org Dr Fabricio K. Marchini Public Health Researcher Carlos Chagas Institute – Fiocruz Parana R. Prof. Algacyr Munhoz Madeer 3375-CIC Curitiba, Brazil Tel: +55 41996995444 Email: fabricio.marchini@fiocruz.br Dr René Paulussen Managing Director, Mondial Diagnostics 357 Woodcroft, Hudson, Quebec JOP 1HO Canada Tel: +1 4504580449 Email: rene.paulussen@mondialdx.com Professor Rahmah Noordin Director Institute for Research in Molecular Medicine Universiti Sains Malaysia 11800 Penang, Malaysia Tel: + 604 653 4800 Email: rahmah8485@gmail.com Dr Marco A. Biamonte Chief Executive Officer Drugs and Diagnostics for Tropical Diseases 4898 Ronson Ct. Suite C San Diego, CA 92111, USA Tel: +1 858 405 1277 Email: marco-biamonte@ddtd.org Dr Rhea N. Coler SVP, Preclinical and Translational Research Infectious Disease Research Institute 1616 Eastlake Ave. E., Ste 400 Seattle WA 98102, USA Tel: +1 206 612 2565 Email: Rhea.Coler@idri.org Professor Sammy M. Njenga Chief Research Scientist Kenya Medical Research Scientist (KMRI) P.O. Box 54840, 00200 Nairobi, Kenya Tel: +254 722945243 Email: sammynjenga@gmail.com Dr Esvawaran Sreekumar Chief Scientific Officer Rajiv Gandhi for Biotechnology Thycaud, P.O. Thiruvananthapuram 695 014 Kerala, India Tel: +919 447 698943 Email: esreekumar@rgcb.res.in Annex 1. List of participants 23 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Dr Isra Cruz* Head International Health Department National School of Public Health Instituto de Salud Carlos III 8 Sinesio Delgado, 28029 Madrid, Spain Tel: +34 918 222 312 Email: cruzi@isciii.es Dr Michael Marks* Associate Professor NIHR Clinical Lecturer in Infectious Diseases School of Hygiene and Tropical Medicine Keppel Street, London WC1E 7HT, United Kingdom Tel: +44 (0)7984 643424 Email: Michael.Marks@lshtm.ac.uk London OBSERVERS AND WHO COLLABORATING CENTRES Dr Francisco Javier Moreno Nuncio Instituto de Salud Carlos III Centro Nacional de Microbiologia Ctra. Majadahonda-Pozuelo KM. 2,2 28220 Majadahonda, Spain Tel: +34 918223771 Email: javier.moreno@isciii.es Dr Pascale Ondoa Director of Science and New Initiatives African Society for Laboratory Medicine Joseph Tito Street, Nega City Mall, Suite 800 P.O. Box 5487, Addis Ababa, Ethiopia Email: pondoa@aslm.org Dr Supaporn Wacharapluesadee Deputy Director WHO Collaborating Center for Research and Training on Viral Zoonoses Rama IV Road, 10330 Bangkok, Thailand Tel: +66 22564000 Email: spwa@hotmail.com Dr Men-Bao Qian Vice Chief of the Department of Soil and Food-Borne Parasitic Diseases National Institute of Parasitic Diseases Chinese Center for Disease Control and Prevention No. 207, Ruijin Er Road, Shanghai 200025, China Email: qianmb@nipd.chinacdc.cn Dr Emily Wainwright Senior NTD Advisor United States Agency for International Development Neglected Tropical Diseases Program 1300 Pennsylvania Ave, NW Washington, DC 20523, USA Tel: +1 571 551 7373 Email: ewainwright@usaid.gov Dr Michele Helinski Project Officer NTD diagnostic projects The European & Developing Countries Clinical Trials Partnership (EDCTP) P.O. Box 93015, 2509 AA The Hague, The Netherlands Email: helinski@edctp.org Dr William E. Secor Team Lead, Elimination and Control Laboratory Parasitic Diseases Branch Centers for Disease Control and Prevention 1600 Clifton Road, NE Atlanta, GA 30329–4018, USA Tel: +1 404 718 4141 Email: was4@cdc.gov Dr Stephanie R. Bialek Chief Parasitic Diseases Branch, Division of Parasitic Diseases and Malaria Centers for Disease Control and Prevention 1600 Clifton Road, NE Atlanta GA 30329–4027, USA Tel: 1 404 639 7785 Email: zqg7@cdc.gov 24 Report of the first meeting. Geneva, 30–31 October 2019 Dr Roger Peck Senior Program Officer PATH 2201 Westlake Avenue, Suite 200 Seattle, WA 981121, USA Tel: +1 206 218 2237 Email: rpeck@path.org Dr Allison Golden Scientific Program Officer Diagnostics Program PATH 2201 Westlake Avenue, Suite 200 Seattle, WA 981121, USA Tel: +1 206 302 4735 Email: algolden@path.org Dr Tom Cummins Senior Program Officer, Diagnostics Innovative Technology Solution Bill and Melinda Gates Foundation P.O. Box 23350 Seattle WA 98102, USA Tel: +1 585 704 3114 Email: tom.cummins@gatesfoundation.org Dr Jordan Tappero Senior Program Officer NTDs, Global Health Program P.O. Box 23350 Seattle WA98102, USA Tel: +1 206 770 1930 Email: jordan.tappero@gatesfoundation.org Dr Sarah Nogaro Scientific Officer – Schistosomiasis FIND, Campus Biotech Chemin des Mines 9 1202 Geneva, Switzerland Tel: +41 22 710 05 94 Email: sarah.nogaro@finddx.org Professor Joseph Ndung’u Head, Neglected Tropical Diseases Programme FIND Campus Biotech Chemin des Mines 9 1202 Geneva, Switzerland Tel: +41 79 540 4114 Email: joseph.ndungu@finddx.org Dr Olaf Valverde Mordt Clinical Team Leader Drugs for Neglected Diseases initiative Chemin Louis-Dunant 15 1202 Genève, Switzerland Tel: +41 79 543 1713 Email: ovalverde@dndi.org Dr Fabiana Alves Head of Visceral Leishmaniasis Clinical Program Drugs for Neglected Diseases initiative Chemin Louis-Dunant 15 1202 Genève, Switzerland Tel: +41 79 775 2344 Email: falves@dndi.org Dr Catherine K. Ohura CEO and Executive Director Global Health Innovative Technology Fund Ark Hills Sengokuyama Mori Tower 25F 1-9-10 Roppongi, Minato-ku Tokyo 106–0032, Japan Tel: +81 3 6441 2032 Email: catherine.ohura@ghitfund.org Dr Hayato Urabe Senior Director of Investment Strategy and Management Global Health Innovative Technology Fund Ark Hills Sengokuyama Mori Tower 25F 1-9-10 Roppongi, Minato-ku, Japan Tel: + 813 644 12032 Email: Hayato.urabe@ghitfund.org WHO SECRETARIAT Dr Mwelecele Ntuli Malecela, Director NTD Tel: +41 22 791 4611 Email: malecelam@who.int Dr Daniel Argaw Dagne, Coordinator IDM Tel: +41 22 791 4532 Email: daniel@who.int Dr Pedro Albajar Vinãs, NTD/IDM Tel: +41 22 791 1261 Email: albajarvinasp@who.int 25 WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases Dr Kingsley Asiedu, NTD/IDM Tel: +41 22 791 2803 Email: asieduk@who.int Dr Jose Ramon Franco Minguell, NTD/IDM Tel: + 41 22 791 3313 Email: francoj@who.int Dr Gerardo Priotto, NTD/IDM Tel: +41 22 791 1375 Email: priottog@who.int Dr Jose Ruiz Postigo, NTD/IDM Tel: +41 22 791 3870 Email: postigoj@who.int Dr Saurabh Jain, NTD/IDM Tel: +41 22 791 3849 Email: jains@who.int Dr Amadou Garba Djirmay, NTD/PCT* Tel: +41 22 791 3322 Email: garbadjirmaya@who.int Dr Jonathan King, NTD/PCT Tel: +41 22 791 1423 Email: kingj@who.int Dr Pamela Sabina Mbabazi, NTD/PCT Tel: +41 22 791 4855 Email: mbabazip@who.int Dr Antonio Montresor, NTD/PCT Tel: +41 22 7913367 Email: montresora@who.int Dr Dieudonné Sankara, NTD/PCT Tel: +41 22 791 2164 Email: sankarad@who.int Dr Anthony Solomon, NTD/PCT Tel: +41 22 791 2823 Email: solomona@who.int Dr Afework Tekle, NTD/PCT* Tel: +41 22 791 4640 Email: teklea@who.int Dr Raman Velayudhan, NTD/VEM Tel: +41 22 791 1868 Email: velayudhanr@who.int Dr Bernadette Abela-Ridder, NTD/NZD* Tel: +41 22 791 12072 Email: abelab@who.int Dr Camilla Ducker, NTD consultant diagnostics Email: camilla@troda.org Dr Lea Knopf, NTD consultant NZD* Email: knopfl@who.int Dr Lauren Carrington, NTD consultant VEM Email: carringtonl@who.int Dr Annette Kuesel, TDR Email: kuesela@who.int Ms Sophie Lambert, NTD/IDM support staff Email: lamberts@who.int * Unable to attend