WHO | NEGLECTED TROPICAL DISEASES TARGET PRODUCT PROFILE for a point-of-care diagnostic test for dermal leishmaniases
TARGET PRODUCT PROFILE for a point-of-care diagnostic test for dermal leishmaniases Target product profile for a point-of-care diagnostic test for dermal leishmaniases ISBN 978-92-4-004522-4 (electronic version) ISBN 978-92-4-004523-1 (print version) © World Health Organization 2022 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. iii Contents Acknowledgements iv 1. Epidemiology 1 2. Public health response 1 3. Available diagnostic tools 1 4. The WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 2 5. NTD road map 2021–2030 2 6. Background and scope for the Target product profile (TPP) 2 7. Audiences engaged and external consultations to develop the TPP 3 References 3 TPP for a point-of-care diagnostic test for dermal leishmaniases 5 iv Acknowledgements The World Health Organization (WHO) is grateful to the following individuals who contributed to the preparation of this document. Writer: Isra Cruz, National School of Public Health, Instituto de Salud Carlos III, Spain Contributors: Byron Arana, Audrey Albertini and Albert Picado, Foundation for Innovative New Diagnostics (FIND), Switzerland; Mady Barbeitas, Drugs for Neglected Diseases initiative (DNDi), Latin America, Brazil; and Joseph Ndung’u, FIND, Kenya. WHO staff: Kingsley Asiedu, Daniel Argaw Dagne, Jose Antonio Ruiz Postigo and Anthony Solomon, Department of Control of Neglected Tropical Diseases 11. Epidemiology Localized cutaneous leishmaniasis and its evolving forms (diffuse cutaneous leishmaniasis, mucosal leishmaniasis and cutaneous leishmaniasis recidivans), together with the sequela of visceral leishmaniasis (post-kala-azar dermal leishmaniasis), account for about one million cases of dermal leishmaniases per year worldwide. Although not lethal, the dermal leishmaniases cause chronic, disfiguring skin lesions which are an important cause of morbidity and stigma. Microscopy remains the reference test for diagnosis of dermal leishmaniases; however, it has low and variable sensitivity and requires well-trained personnel. The technical complexity and cost of the more sensitive molecular techniques (e.g. polymerase chain reaction) limit their application for routine diagnosis in endemic areas (1). As a result, a high number of patients are put on treatment without laboratory confirmation, exposing a variable number of them to unnecessary toxic treatment (2, 3). A great need thus exists for point-of-care tests for early diagnosis of dermal leishmaniases in order to benefit both patients and communities by early identification of those who need treatment, thereby reducing the risk of both sequelae and ongoing Leishmania transmission. 2. Public health response In 2007, the Sixtieth World Health Assembly adopted resolution WHA60.13 on control of leishmaniasis, urging Member States, among other actions: • to strengthen prevention, active detection and treatment of cases of both cutaneous and visceral leishmaniasis in order to decrease the disease burden; and • to strengthen the capacity of peripheral health centres to deliver primary and secondary care, so that they provide appropriate affordable diagnosis and treatment and act as sentinel surveillance sites. Furthermore, the WHO Director-General was requested to “promote research pertaining to leishmaniasis control, including in the areas of safe, effective and affordable vaccines, diagnostic tools and medicines with less toxicity, and dissemination of the findings of that research …”. 3. Available diagnostic tools Microscopy of Giemsa-stained samples from lesions, including skin scrapings, fine-needle aspirates or slit-skin smears, remains the reference test for diagnosis of the different forms of dermal leishmaniasis. However, microscopy has significant shortcomings, and more sensitive molecular tests have not yet been widely adopted. Other simpler tests for detection of leishmanial DNA, such as loop-mediated isothermal amplification, have yet to be implemented. Other potential approaches include serology, which may be useful for screening of post-kala-azar dermal leishmaniasis and mucosal leishmaniasis, but cannot be used for confirmation, as presence of antibodies may be due to previous episodes or exposure to the parasite by living in endemic areas. The leishmanin (Montenegro) skin test can also aid in the diagnosis of cutaneous leishmaniasis, but again the test is not a marker of active infection, and therefore has limited value (1). In 2016, FIND involved a panel of 47 international experts on leishmaniasis in a survey to rank diagnostic priorities. A rapid test for cutaneous leishmaniasis was identified among the top priorities (4). Currently there is an FDA-cleared and CE-marked rapid test targeting Leishmania antigen that is designed for diagnosis of cutaneous leishmaniasis: the CL DetectTM Rapid Test for Cutaneous Leishmaniasis (InBios International Inc., Seattle (WA), USA; https://inbios.com/cl-detecttm-rapid-test-for-cutaneous- leishmaniasis-intl/). Studies have shown high specificity, but unfortunately the sensitivity is quite variable across Leishmania species and endemic regions (5–8). 24. The WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases The WHO Department of Control of Neglected Tropical Diseases manages a diverse portfolio of 20 diseases and disease groups, each with its own unique epidemiological and diagnostic challenges. At its 12th meeting (Geneva, 29–30 April 2019), the Strategic and Technical Advisory Group for Neglected Tropical Diseases, the principal advisory group to WHO on the control, elimination and eradication of neglected tropical diseases (NTDs), decided to establish a single WHO working group to ensure use of a unified approach to identify and prioritize diagnostic needs and to inform WHO strategies and guidance on the subject (9). The Diagnostic Technical Advisory Group (DTAG) was thus established as the principal advisory group to WHO on NTD diagnostics. At its inaugural meeting (Geneva, 30–31 October 2019), the DTAG identified the following diagnostic needs for dermal leishmaniases (10): • a rapid test for post-kala-azar dermal leishmaniasis – to distinguish this form of the disease from other skin conditions; and • a rapid test for confirmation of suspected cases of cutaneous leishmaniasis at peripheral health facilities. This target product profile (TPP) for a point-of-care diagnostic test for dermal leishmaniases was developed in response to those needs. 5. NTD road map 2021–2030 Cutaneous leishmaniasis is targeted for control in the new road NTD map for 2021–2030. The main target for 2030 is to detect, report and treat at least 87% of cases. At least 64 countries are expected to be validated for elimination of visceral leishmaniasis as a public health problem by 2030; which means that post-kala-azar dermal leishmaniasis (which plays an important role in transmission) must be specifically addressed in the Indian subcontinent and in some countries in eastern Africa (11). To achieve these goals, more effective and user-friendly diagnostics for cutaneous and post-kala-azar dermal leishmaniasis are needed. Enabling decentralized testing is essential for both individual cases and mass screening in the context of near-elimination of visceral leishmaniasis; i.e. testing in public health centres and/or among communities. A rapid test targeting Leishmania antigens common across Leishmania species will address major diagnostic needs for dermal leishmaniasis, and, by addressing post-kala-azar dermal leishmaniasis, may also contribute to the control and elimination of visceral leishmaniasis. 6. Background and scope for the TPP There is thus a great need for point-of-care tests for early diagnosis of dermal leishmaniases in order to benefit both patients and communities by early identification of those who need treatment, thereby reducing the risk of both sequelae and ongoing Leishmania transmission. It is therefore important that new point-of-care tests be developed to meet the needs of the target population and the requirements for implementation in resource-limited settings, where most cases of dermal leishmaniasis occur. This TPP for a point-of-care test for dermal leishmaniases was defined through several rounds of discussions and by consensus with stakeholders and experts in dermal leishmaniases from different types of organizations and endemic regions. 37. Audiences engaged and external consultations to develop the TPP A draft TPP was developed by leishmaniasis experts at FIND and DNDi and presented at the second redeLEISH Meeting (Medellín, Colombia, July 2015) for discussion with a panel of 70 experts on leishmaniasis (12). The draft was then refined based on the inputs from the experts and a new document was shared with a second panel of experts comprising 31 experts from different organizations and endemic regions. Consensus was reached to define a TPP with 29 priority features (1). The TPP was presented at different stakeholder meetings, including the 6th World Congress on Leishmaniasis in 2017 (13, 14) and the biennial meeting of the Global Buruli Ulcer Initiative in 2017 (15). In the same period, more specifically in March 2016, and as part of a consultation to develop FIND’s leishmaniasis strategy, 40 experts on leishmaniasis helped to identify and rank diagnostic priorities. The experts had experience in the different forms of leishmaniasis from different endemic regions and represented academia, international organizations and product development partnerships, among others. The experts identified a rapid point-of-care test for dermal leishmaniasis as one of the highest priorities. This was further discussed at the 6th World Congress on Leishmaniasis (13, 14). After further refinement, the TPP was published in Parasite Epidemiology and Control with authors from FIND, DNDi and WHO in 2019 (1). When the WHO Department of Control of Neglected Tropical Diseases began work on TPPs, the leishmaniasis TPP published in 2019 (1) was subsequently reviewed by its lead author Dr Isra Cruz in line with the WHO guide for TPP development. The draft was then submitted to DTAG for comments before finalization and publication for online consultation (23 November–24 December 2021). No feedback was received. The TPP was therefore considered final. References 1. HCruz I, Albertini A, Barbeitas M, Arana B, Picado A, Ruiz-Postigo JA, et al. Target Product Profile for a point-of-care diagnostic test for dermal leishmaniases. Parasite Epidemiol Control. 2019;5:e00103. doi: https://10.1016/j.parepi.2019.e00103. 2. Zijlstra EE, Alves F, Rijal S, Arana B, Alvar J. Post-kala-azar dermal leishmaniasis in the Indian subcontinent: a threat to the South-East Asia region kala-azar elimination programme PLoS Negl Trop Dis. 2017; 11(11):e0005877. doi: https://10.1371/journal.pntd.0005877. 3. Leishmaniasis in high-burden countries: an epidemiological update based on data reported in 2014. Wkly Epidemiol. Rec. 2016; 91 (22):286–96 (http://www.who.int/iris/handle/10665/254453, accessed 9 February 2022). 4. 6th World Congress on Leishmaniasis, Toledo, Spain, 16–20 May 2017: abstracts book. Drugs for Neglected Diseases initiative and Instituto de Salud Carlos III in collaboration with PLoS Collections; 2017 (https://www.dndi.org/wp-content/uploads/2017/10/WL6_Abstracts_Book. zip, accessed 17 February 2022). 5. Bennis I, Verdonck K, El Khalfaoui N, Riyad M, Fellah H, Dujardin JC, et al. Accuracy of a rapid diagnostic test based on antigen detection for the diagnosis of cutaneous leishmaniasis in patients with suggestive skin lesions in Morocco. Am J Trop Med Hyg. 2018; 99(3):716–22. doi: https://10.4269/ajtmh.18-0066. 6. Vink MMT, Nahzat SM, Rahimi H, Buhler C, Ahmadi BA, Nader M, et al. Evaluation of point- of-care tests for cutaneous leishmaniasis diagnosis in Kabul, Afghanistan. EBioMedicine. 2018; 37:453–60. doi: https://10.1016/j.ebiom.2018.10.063. 47. Schallig HDFH, Hu RVP, Kent AD, van Loenen M, Menting S, Picado A, et al. Evaluation of point of care tests for the diagnosis of cutaneous leishmaniasis in Suriname. BMC Infect Dis. 2019; 19(1):25. doi: https://10.1186/s12879-018-3634-3. 8. De Silva G, Somaratne V, Senaratne S, Vipuladasa M, Wickremasinghe R, Wickremasinghe R, et al. Efficacy of a new rapid diagnostic test kit to diagnose Sri Lankan cutaneous leishmaniasis caused by Leishmania donovani. PLoS One. 2017; 12(11):e0187024. doi: https://10.1371/journal. pone.0187024. 9. Souza AA, Ducker C, Argaw D, King JD, Solomon AW, Biamonte MA, et al. Diagnostics and the neglected tropical diseases roadmap: setting the agenda for 2030. Trans R Soc Trop Med Hyg. 115(2):129–35. doi:10.1093/trstmh/traa118. 10. Report of the first meeting of the WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/ handle/10665/331954, accessed 9 February 2022). 11. Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021–2030. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/ handle/10665/338565, accessed 9 February 2022). 12. From neglected diseases to neglected patients and populations: 2015 annual report. Geneva: Drugs for Neglected Diseases initiative; 2015 (https://dndi.org/wp-content/uploads/2016/08/ DNDi_AR_2015.pdf, accessed 17 February 2022) 13. Cruz I, Alvar J, Alves F, Boelaert M, Chappuis F, Ruiz-Postigo JA, et al. An update of the leishmaniasis diagnostics priorities [C1710]. In: 6th World Congress on Leishmaniasis, Toledo, Spain, 16–20 May 2017: abstracts book. Drugs for Neglected Diseases initiative and Instituto de Salud Carlos III in collaboration with PLoS Collections; 2017: 176 (https://www.dndi.org/wp- content/uploads/2017/10/WL6_Abstracts_Book.zip, accessed 17 February 2022). 14. Cruz I, Albertini A, Arana B, Barbeitas M, Picado A, Ruiz-Postigo JA, et al. Target product profile for a point-of-care test for diagnosis of dermal leishmaniasis [C1724]. In: 6th World Congress on Leishmaniasis, Toledo, Spain, 16–20 May 2017: abstracts book. Drugs for Neglected Diseases initiative and Instituto de Salud Carlos III in collaboration with PLoS Collections; 2017: 1257 (https://www.dndi.org/wp-content/uploads/2017/10/WL6_Abstracts_Book.zip, accessed 17 February 2022). 15. Report from the meeting of the Buruli ulcer Technical Advisory Group. Geneva, 21 March 2017. Geneva : World Health Organization; 2017 (https://www.who.int/neglected_diseases/events/ WHO_BU_TAG_2017_report.pdf?ua=1 , accessed 9 February 2022). 5TPP for a point-of-care diagnostic test for dermal leishmaniases 1. Scope of the test Minimum Ideal Annotations 1.1 Goal of test. Intended use Detection of active localized cutaneous leishmaniasis (LCL) Detection of active cutaneous leishmaniasis (CL, any form) or post-kala-azar dermal leishmaniasis (PKDL) with the purpose of initiating treatment during the same clinical encounter (or same day) LCL is the most prevalent of dermal leishmaniases (> 80% of cases). This clinical form is present in all CL- endemic regions. All Leishmania species cause LCL. Other forms of CL usually evolve from LCL 1.2 Target popu- lation Individuals with clinical signs suggestive of LCL Individuals with clinical signs suggestive of any form of CL, or PKDL 1.3 Target operator of test Trained laboratory staff Health worker at primary health care level without laboratory training Most patients go to health facilities with limited human resources 1.4 Lowest setting for implementation Decentralized health care facilities with minimum laboratory infrastructure Decentralized health care facilities with no laboratory infrastructure, or mobile team This test could replace microscopy, as has happened with other diseases (e.g. malaria) 1.5 Target analyte to be detected Leishmania antigen 2. Performance characteristics Minimum Ideal Annotations 2.1 Clinical sensitivity 95% in parasitologically-confirmed cases 100% in parasitologically-confirmed cases Measured in frozen or fresh samples from parasitologically-confirmed patients (microscopy and/or culture and/or PCR from skin scrapings, swabs, biopsies, aspirates, etc.). A combined reference standard according to each region should be considered 2.2 Clinical specificity > 90% > 95% Tested against reference standard (according to each endemic setting), including subjects with other diseases affecting the skin 2.3 Leishmania species-specificity Leishmania genus-specific Leishmania species-specific Different treatment options might be needed for different species 2.4 Type of analysis. Quantitation Qualitative There is no need for quantification as parasite burden will not guide therapy 63. Test procedure Minimum Ideal Annotation 3.1 Training needs. Time dedicated to training session for end-users One day for any level of health care worker. Job aid provided Less than half a day for any level of health care worker. Job aid provided 3.2 Sample type Lesion fine-needle aspirate, skin scrapping, biopsy, etc. Lesion swab Minimally invasive sampling procedures will be pre- ferred 3.3 Sample prepara- tion. Total steps 3–5 simple steps Direct testing from lesion swab 3.4 Number of steps to be per- formed by operator < 10; 1 timed step < 3; 1 timed step 3.5 Need for operator to transfer a precise volume of sample Acceptable with a disposable transfer device provided No Sample may need to be eluted in specific buffer (included in the kit) 3.6 Time to result < 1 h < 20 min 3.7 Internal control Included Positive control to confirm validity of the test 3.8 Reading system. Interpretation of results Visual (naked eye) or simple reading device Visual (naked eye) See 3.9 3.9 Auxiliary equipment Test reader (for lateral flow assay, dual path platform or similar) None, instrument free (required materials are included in the kit) There are rapid diagnostic tests that generate a fluorescent signal that increases sensitivity; a reader is needed to detect this signal. In these cases a connectivity option could be desirable, enabling sending results to a reference laboratory, coordinator, reporting system, etc. thresholds 3.10 Power require- ments Battery operated None required If a reading device is needed it should be a small, portable or hand-held instrument (< 1 kg) that can operate on rechargeable battery or solar power lasting at least 4 h (8 h preferred) 3.11 Need for maintenance/spare parts None 74. Operational characteristics Minimum Ideal Annotations 4.1 Operating conditions –40 °C, up to 80% relative humidity (RH), 0–2000 m above sea level 5–50 °C, up to 90% RH, 0–4000 m above sea level High environmental temperatures and high humidity are often a problem in countries where CL is endemic. Some laboratories for CL diagnosis are located at high altitude (e.g. La Paz, Bolivia [Plurinational State of]) 4.2 Reagent kit transport No cold chain required; tolerance of transport stress for a minimum of 48 h at −15 °C to 50 °C No cold chain required; tolerance of transport stress for a minimum of 72 h at −15 °C to 50 °C Refrigerated transport is costly and often cannot be guaranteed during the entire transportation process. Frequent delays in transport are common 4.3 Reagent kit storage/stability No cold chain required. Up to 12 months at 40 °C, up to 70% RH No cold chain required. Up to 24 months at 50 °C, up to 90% RH Should be able to tolerate transport stress (48 h at 50 ºC). To include test quality detector (for surpassed temperature or humidity) 4.4 Reagents reconstitution. Need to prepare the reagents before use A few simple steps All reagents ready-to-use Simple steps like resuspension of lyophilized reagent 4.5 In-use stability > 1 h for single use test after opening the pouch High environmental temperatures and high humidity are often a problem in countries where CL is endemic 4.6 Biosafety requirement. Level of protection to be made available for the staff and the samples No need for biosafety cabinet. Standard biosafety precautions when handling potentially infectious materials. No contraindications to routine use 5. Pricing Minimum Ideal Annotations 5.1 Maximum price for individual test < 5 US$ per test < 1 US$ per test Assumption that the test is produced at a large scale, transport costs from manufacturing company not included 5.2 Maximum price for instrumentation, if needed < 2000 US$ < 2000 US$ In case a test reading device is needed 5.3 Expected scale of manufacture 1.0 million tests/year 2.5 million tests/year Based on 0.7–1.2 million estimated CL cases; and provided the test has better performance than microscopy Neglected tropical diseases 20 Avenue Appia 1211 Geneva 27 Switzerland neglected.diseases@who.int https://www.who.int/teams/control-of-neglected-tropical-diseases