WHO | NEGLECTED TROPICAL DISEASES TARGET PRODUCT PROFILE for a diagnostic test to confirm leprosy in individuals with clinical signs and symptoms
TARGET PRODUCT PROFILE for a diagnostic test to confirm leprosy in individuals with clinical signs and symptoms Target product profile for a diagnostic test to confirm leprosy in individuals with clinical signs and symptoms ISBN 978-92-4-007373-9 (electronic version) ISBN 978-92-4-007374-6 (print version) © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/rules/). Suggested citation. Target product profile for a diagnostic test to confirm leprosy in individuals with clinical signs and symptoms. Geneva: World Health Organization; 2023. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see https://www.who.int/publications/book-orders. To submit requests for commercial use and queries on rights and licensing, see https://www.who.int/copyright. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. iii Contents Acknowledgements iv Declarations of interest iv 1. Epidemiology 1 2. Public health response 1 3. Available diagnostic tools 2 4. WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases 2 5. WHO Technical Advisory Group on Leprosy 3 6. Purpose of the Target product profile (TPP) 3 7. Audiences engaged and external consultations to develop the diagnostic TPP 4 iv Acknowledgements The World Health Organization (WHO) is grateful to the following individuals who contributed to the preparation of this document. Writer: Christopher Hanna, Global Project Partners, LLC, United States of America Contributors: Sundeep Chaitanya Vedithi, American Leprosy Mission, United Kingdom of Great Britain and Northern Ireland; Isra Cruz, National School of Public Health, Spain; Camilla Ducker, Tro Da Global Health Consulting, United Kingdom of Great Britain and Northern Ireland; Petra Kukkaro, Novartis, Switzerland; Andie Tucker, Global Partnership of Zero Leprosy, United States of America. WHO staff: Kingsley Asiedu, Daniel Argaw Dagne, Jose Antonio Ruiz Postigo, Anthony Solomon, WHO Department of Neglected Control of Neglected Tropical Diseases; Erwin Cooreman, Venkata Ranganadha Rao Pemmaraju, WHO Regional Office for South-East Asia. Declarations of interest The writer and contributors signed the WHO Declaration of Interest which were reviewed by the Skin NTDs Team. Dr Petra Kukkaro works for Norvatis which provides the multi-drug therapy for leprosy elimination. The interests declared were assessed and deemed to be non-specific and did not constitute a conflict of interest. 11. Epidemiology Leprosy, also known as Hansen’s disease, is a chronic infectious disease caused by Mycobacterium leprae or, in some cases, by Mycobacterium lepromatosis. The bacteria is likely transmitted via tiny droplets (aerosols) from the nose and mouth during close and frequent contact with untreated cases. In some circumstances, skin-to-skin contact has also been implicated. Close and frequent contact increase the risk of contacts developing leprosy. Stigmatization and discrimination impede the life of an individual suffering from leprosy; overcoming them is an essential part of leprosy control. As with other neglected tropical diseases (NTDs), the occurrence of leprosy is often related to socioeconomic determinants of health. M. leprae multiplies slowly and the incubation period of the disease averages 5 years. Symptoms may occur within 1 year but can also take up to 20 years or longer to appear. The disease mainly affects the skin, the peripheral nerves, the mucosal surfaces of the upper respiratory tract and the eyes. Leprosy is known to occur at all ages, from early infancy to advanced old age. It is curable with multidrug therapy (MDT) and treatment administered in the early stages can prevent disability. Untreated, leprosy can cause progressive and permanent damage to the skin, nerves, limbs and eyes. Despite the available treatment, more than 200 000 new leprosy patients were diagnosed globally in 2019, with more than 120 countries reporting cases (including non-autochthonous cases); 80% of the burden is in India, Brazil and Indonesia. Early case detection is important to help contain the spread of infection and prevent disabilities. 2. Public health response Leprosy is an age-old disease, described in the literature of ancient civilizations. Throughout history, people afflicted by leprosy have often been ostracized by their communities and families. The first treatment for leprosy became available in the 1940s with the development of dapsone. In the 1960s, however, M. leprae started to develop resistance to this medicine. In the early 1960s, rifampicin and clofazimine were discovered and were added to the treatment regimen, which was labelled MDT. In 1981, WHO recommended that all patients be treated with MDT. The currently recommended MDT regimen consists of dapsone, rifampicin and clofazimine for multibacillary (MB) cases, whereas treatment for paucibacillary (PB) comprises only dapsone and rifampicin. The treatment lasts for 12 months for MB and 6 months for PB. MDT kills the pathogen, thereby curing the patient. In the new WHO road map for neglected tropical diseases for 2021−2030 (“the road map”), leprosy is targeted for elimination (interruption of M. leprae transmission). The following critical actions, among others, are required to reach the 2030 targets for leprosy: • Update country guidelines to include use of single-dose rifampicin for post-exposure prophylaxis (PEP) for contacts; advance research on new preventive approaches. • Continue investment into research for diagnostics for disease and infection; develop surveillance strategies, systems and guidelines for case-finding and treatment; ensure resources for validation. • Ensure medicines supply, including access to MDT, prophylactic drugs, single-dose rifampicin, second-line treatments and medicines to treat reactions; monitor adverse events (pharmacovigilance) and resistance to antibiotics. 23. Available diagnostic tools Leprosy is classified as Paucibacillary (PB) or Multibacillary (MB), based on the number of skin lesions, the presence of nerve involvement and the identification of bacilli in slit-skin smear. The WHO guidelines for the diagnosis, treatment and prevention of leprosy1 recommend no further tests in addition to standard methods for diagnosis of leprosy. The diagnosis is based on the presence of at least one of three cardinal signs: these are: (i) definite loss of sensation in a pale (hypopigmented) or reddish skin patch; (ii) thickened or enlarged peripheral nerve with loss of sensation and/or weakness of the muscles supplied by that nerve; (iii) presence of acid-fast bacilli in a slit-skin smear. With the dwindling clinical expertise in leprosy, clinical diagnosis of indeterminate, pure neuritic and certain cases of PB and MB leprosy with confusing clinical signs can be challenging. Therefore, a number of point-of-care and laboratory assays have been developed and tested in various patient and control groups to supplement clinical diagnostic methods. These assays encompass both direct (pathogen) and indirect (host response) detection of the disease, utilizing various technologies such as enzyme-linked immunosorbent assays (ELISA), lateral flow assays (LFA) and polymerase chain reaction (PCR)-based assays. However, most of the currently developed tools are only of research grade and are not available commercially for broad use in clinical settings. Additionally, some of these tools face various challenges such as: low diagnostic accuracy for PB leprosy, lack of standardization and high level of complexity/ needed instrumentation for most primary health-care settings. To date, only a few leprosy diagnostic assays detecting M. leprae, or immune responses to it, are authorized for in-vitro diagnostic use and are commercially available. Hain Lifescience GmbH (Nehren, Germany) has a test system for the identification of M. leprae and its resistance to rifampicin, ofloxacin and dapsone. GenoType LepraeDR, a PCR-based DNA strip technology, requires three separate instruments; as such, it is not suitable for use in low-resource settings. OrangeLife (Rio de Janeiro, Brazil), in collaboration with the Infectious Disease Research Institute (Seattle, USA) has developed a qualitative LFA to detect M. leprae specific IgM antibodies against PGL-1 and IgG antibodies to LID-1. CTK Biotech (San Diego, USA) has developed qualitative GOLD-LFA, utilizing the same antigens as OrangeLife. However, both of these assays are for research use only and may no longer be available at this time. Once appropriate diagnostic tools are developed, it would be imperative to ensure that products stay on the market, as efforts to eliminate leprosy would be hampered if tests are not maintained. Mechanisms to secure commitment from vendors should be explored. 4. WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases The WHO Department of Control of Neglected Tropical Diseases (WHO/NTD) 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 for the control, elimination and eradication of 1 Guidelines for the diagnosis, treatment and prevention of leprosy. New Delhi: World Health Organization Regional Office for South-East Asia; 2018 (https://apps.who.int/iris/handle/10665/274127, accessed 9 May 2022). 3NTDs, 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. The Diagnostic Technical Advisory Group (DTAG) was thus formed as an advisory group to WHO/ NTD. At its inaugural meeting (30−31 October 2019, Geneva, Switzerland), DTAG members discussed priorities for the year ahead as well as how to manage the complexity of supporting the diagnostics agenda across the entirety of the WHO/NTD portfolio. Recommendations were made 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. The diagnostic needs for leprosy, as determined by the DTAG, are: • detection of M. leprae infection – to provide prophylaxis to those most at risk; • screening for potential leprosy cases – to better identify individuals with suggestive signs of leprosy; • diagnosis of leprosy – to confirm diagnosis of all forms of leprosy (especially indeterminate and PB leprosy); • prediction of future disease - to identify those at risk of disability; and • diagnosis of nerve function loss – to recognize early nerve function changes that can lead to sensorimotor neuropathy associated with leprosy. 5. WHO Technical Advisory Group on Leprosy At its 17th meeting, the WHO Technical Advisory Group on Leprosy (TAG-Leprosy) discussed topics related to M. lepromatosis, zoonotic leprosy, environmental sources of M. leprae and target product profiles (TPPs) related to diagnostics. Further research was recommended in the following areas: • researchers to find a reliable diagnostic test/tests for confirming leprosy in symptomatic as well as asymptomatic individuals (e.g., household contacts); • more epidemiological and bacteriological research studies to understand the role of M. lepromatosis in transmission of infection; • more studies to understand the extent of zoonotic transmission to humans caused by infected animals and its spread among animals; and • further research studies on environmental sources of M. leprae and their role in transmission of infection. The TAG-Leprosy also recommended the development of two TPPs for tests to assess bacteriological cure and to assess infection levels in the community to assist in ascertaining interruption of transmission. 6. Purpose of the Target product profile (TPP) As the number of leprosy cases is reducing, so too is the clinical expertise even in endemic countries. This often leads to delay or misdiagnosis and delayed initiation of MDT. Early detection and treatment of leprosy are important to prevent disability but may also aid in breaking the transmission chain. 4As identified in both the road map and the DTAG meeting report, a test confirming (or ruling out) leprosy of all types, including indeterminate and PB leprosy, is of high priority. The purpose of this TPP is to guide the development of a tool that can be used at all health-care levels where MDT is prescribed, to aid health-care providers in deciding when to initiate treatment. The clinical validation of such a test should take into account performance requirements for the entire spectrum of leprosy, including manifestations with low levels of bacilli. Although ideally such a test would be available as a point-of-care test, it is recognized that to reach the required sensitivity and specificity, laboratory-based testing might be required. The TPP target performance characteristics were modelled to reduce health-care provider delays in diagnosis as a function of diagnostic performance. In the modelling, prevalence of leprosy in tested populations assumed endemicity levels similar to household contacts, as this would be the most likely group to seek medical consultation. It was observed through modelling that, to have a meaningful impact on reduction on time to diagnosis, very high stringency around specificity is required. It is of note that in cases where performance requirements are high and cannot be met with a single test, a combined, two- step test approach may be used to achieve the required testing specificity. 7. Audiences engaged and external consultations to develop the diagnostic TPP To initiate the development of a diagnostic TPP for leprosy, Dr Sundeep Chaitanya Vedithi and Dr Petra Kukkaro identified priority areas and consulted a group of experts under the Leprosy Diagnostic Working Group of the Global Partnership for Zero Leprosy. The Working Group brought together experts in laboratory science, clinical aspects of leprosy and representatives from stakeholder groups in the leprosy community. After discussions with the Group, a TPP was drafted by Mr Christopher Hanna, Dr Sundeep Chaitanya Vedithi and Dr Petra Kukkaro. The draft was reviewed by members of the Working Group and submitted to the DTAG chair, Dr Patrick Lammie, for comments before finalization and posting on the WHO website for public consultation (30 November to 20 December 2021). In addition to the public online consultation, the TAG-Leprosy also reviewed the TPP, provided comments and made suggestions on use case narratives for incorporation by the Working Group chairs Dr Sundeep Chaitanya Vedithi and Dr Petra Kukkaro. The final document was reviewed by the DTAG subgroup chair on skin NTDs, Dr Isra Cruz, and a WHO staff representative, Dr Pemmaraju Ranganatha Rao. 5TP P fo r a d ia gn os tic te st to co nfi rm le pr os y i n in di vi du al s w ith cl in ic al si gn s a nd sy m pt om s 1. P ro du ct u se su m m ar y M in im um Id ea l Ba ck gr ou nd , a nn ot at io n re re qu ire m en t r isk , e tc . 1. 1 In te nd ed u se A la bo ra to ry -b as ed te st fo r t he d et ec tio n of a na ly te sp ec ifi c to M . l ep ra e ( an d M . l ep ro m at os is in id ea l ca se s) fo r t he p ur po se s o f p ro vi di ng c on fir m at io n (o r el im in at io n) o f c lin ic al le pr os y. A p oi nt -o f- ca re te st fo r t he d et ec tio n of a na ly te sp ec ifi c to M . l ep ra e ( an d M . l ep ro m at os is in id ea l ca se s) fo r t he p ur po se s o f p ro vi di ng c on fir m at io n (o r el im in at io n) o f c lin ic al le pr os y. “C lin ic al le pr os y” is c ha ra ct er iz ed b y in di vi du al s in fe ct ed w ith M . l ep ra e o r M . l ep ro m at os is w ho h av e an y st ag e of th e di se as e w ith in th e cl in ic al le pr os y sp ec tr um , n am el y: pa uc ib ac ill ar y ( PB ), w hi ch in cl ud es : · tu be rc ul oi d (T T) , · bo rd er lin e tu be rc ul oi d (B T) , · in de te rm in at e (I ) a nd · pu re n eu rit ic (P N ) l ep ro sy an d m ul tib ac ill ar y ( M B) , w hi ch in cl ud es : · m id -b or de rli ne (B B) , · bo rd er lin e le pr om at ou s ( BL ) a nd · le pr om at ou s ( LL ) l ep ro sy . 1. 2 Ta rg et ed po pu la tio n A ll ag e gr ou ps . A ll ag e gr ou ps . 1. 3 Lo w es t in fr as tr uc tu re le ve l Fo r a la bo ra to ry -b as ed te st , t es ts c an b e pe rf or m ed in a p er ip he ra l h ea lth fa ci lit y/ re fe rr al c en tr e, p ri m ar y ca re c en tr es , t er tia ry c ar e le pr os y ce nt re s, re gi on al o r na tio na l d ia gn os tic te st in g la bo ra to ry . Fo r a p oi nt -o f- ca re te st , t he te st w ill b e pe rf or m ed un de r “ ze ro -in fr as tr uc tu re ” c on di tio ns in cl ud in g bu t no t l im ite d to sc ho ol s, co m m un ity h ea lth c en tr es , a d ho c “s ki n ca m ps ”, pl us th e lo ca tio ns fo r “ m in im um ” co nd iti on s. 1. 4 Lo w es t l ev el us er Fo r a la bo ra to ry -b as ed te st , t he te st w ill b e pe rf or m ed by tr ai ne d la bo ra to ry te ch ni ci an s. Fo r a p oi nt -o f- ca re te st , t he te st w ill b e pe rf or m ed by h ea lth p er so nn el , c om m un ity h ea lth w or ke rs a nd co m m un ity v ol un te er s. 1. 5 Tr ai ni ng re qu ire m en ts Fo r a la bo ra to ry -b as ed te st , l es s t ha n on e w ee k fo r t ra in ed la bo ra to ry te ch ni ci an s; te st in g jo b ai d/ in st ru ct io ns fo r u se sh ou ld b e m ad e av ai la bl e vi a th e In te rn et fo r d ow nl oa d (i. e. a re p ub lic ly a va ila bl e) . Fo r a p oi nt -o f- ca re te st , o ne d ay o r l es s f or h ea lth pe rs on ne l, co m m un ity v ol un te er s a nd la y pe rs on s; te st in g jo b ai d/ in st ru ct io ns fo r u se sh ou ld b e m ad e av ai la bl e vi a th e In te rn et fo r d ow nl oa d (i. e. a re pu bl ic ly a va ila bl e) . N O TE : I t i s n ot a re qu ire m en t t o ha ve In te rn et a cc es s to o bt ai n jo b ai ds /in st ru ct io ns fo r u se si nc e th es e m us t be in cl ud ed w ith th e te st it se lf (p er R eq ui re m en t 4 .5 ); ra th er , j ob a id s/ in st ru ct io ns fo r u se sh ou ld a lw ay s b e av ai la bl e vi a th e In te rn et . 62. D es ig n M in im um Id ea l A nn ot at io n 2. 1 Po rt ab ili ty Fo r a la bo ra to ry -b as ed te st , s pe ci fic p or ta bi lit y an d tr an sp or t r eq ui re m en ts sh ou ld n ot b e be yo nd th os e as so ci at ed w ith st an da rd la bo ra to ry e qu ip m en t. Fo r a p oi nt -o f- ca re te st , h ig hl y po rt ab le w ith n o sp ec ia liz ed tr an sp or t n ee ds . "F or “m in im um ”, th e la bo ra to ry -b as ed te st w ill n ee d to fu nc tio n w ith sa m pl es th at h av e be en c ol le ct ed u p to 1 da y pr io r. Fo r “ id ea l”, “p or ta bi lit y” im pl ie s t ho se c ha ra ct er ist ic s de sc ri be d in 2 .2 –2 .4 a s w el l a s n o lo ca tio na l l im ita tio ns to w he re th e te st c an b e pe rf or m ed . 2. 2 In st ru m en t/ po w er re qu ire m en t Fo r a la bo ra to ry -b as ed te st , a cc es s t o m ai ns p ow er is ac ce pt ab le . Fo r a p oi nt -o f- ca re te st , s el f- co nt ai ne d ki t o pe ra te s in de pe nd en t o f a ny m ai ns p ow er . 2. 3 W at er re qu ire m en t Fo r a la bo ra to ry -b as ed te st , a cc es s t o la bo ra to ry -g ra de w at er is a cc ep ta bl e. Fo r a p oi nt -o f- ca re te st , s el f- co nt ai ne d ki t o pe ra te s in de pe nd en t o f a ny w at er su pp ly. 2. 4 M ai nt en an ce an d ca lib ra tio n Fo r a la bo ra to ry -b as ed te st , p er io di c m ai nt en an ce a nd ca lib ra tio n of a ny in st ru m en ta tio n m us t b e av ai la bl e in th e co un tr ie s, an d sh ou ld n ot b e ne ed ed m or e fr eq ue nt ly th an o nc e a ye ar . Fo r a p oi nt -o f- ca re te st , n o m ai nt en an ce re qu ire d (i. e. di sp os ab le ) a nd n o ca lib ra tio n re qu ire d. 2. 5 Sa m pl e ty pe / co lle ct io n C ap ill ar y bl oo d fr om fi ng er st ic k, v en ou s b lo od d ra w, co lle ct ed u ri ne , n as al sw ab , s lit sk in sm ea rs (S SS ) a nd pu nc h bi op sie s i f t he p un ch b io ps y fo rm at a llo w s f or su b- m ill im et re b io ps ie s. C ap ill ar y bl oo d fr om fi ng er st ic k, c ol le ct ed u ri ne o r na sa l s w ab . “I de al ” d iff er s f ro m “M in im um ” b y el im in at io n of S SS an d pu nc h bi op sy sa m pl in g an d ve no us b lo od d ra w. N O TE : N as al sw ab s ( or a ny o th er sa m pl e ty pe ) m us t b e sh ow n to g en er at e re su lts fo r c ur re nt in fe ct io n an d no t co lo ni za tio n. 2. 6 Sa m pl e pr ep ar at io n/ tr an sf er d ev ic e · Sa m pl e pr ep ar at io n sh ou ld n ot e xc ee d tr an sf er o f bl oo d (c ap ill ar y fin ge r s tic k or v en ou s d ra w ), se ru m (f ro m c en tr ifu ge d ve no us b lo od fo r l ab -b as ed te sts ), co lle ct ed u ri ne , n as al sw ab , S SS o r p un ch b io ps y to a sa m pl e pr oc es sin g tu be h ol di ng n o m or e th an 50 0 µL o f e xt ra ct io n/ p ro ce ss in g bu ffe r, w hi ch is th en tr an sf er re d to th e te st in g de vi ce a fte r a d efi ne d pe ri od o f t im e. · Tr an sf er o f t he sa m pl e vo lu m e to th e te st in g de vi ce sh al l o cc ur b y us e of a p re de fin ed a nd p ro vi de d sin gl e- us e tr an sf er d ev ic e (e .g . i nv er te d cu p, di sp os ab le fi xe d- vo lu m e tr an sf er p ip et ). · Sa m pl e pr ep ar at io n fo r c ap ill ar y fin ge r s tic k bl oo d or u ri ne sh ou ld n ot e xc ee d tr an sf er o f s am pl e to th e te st in g de vi ce . · Sa m pl e pr ep ar at io n fo r n as al sw ab sh ou ld n ot e xc ee d tr an sf er o f n as al sw ab to a sa m pl e pr oc es sin g tu be ho ld in g no m or e th an 5 00 µ L of e xt ra ct io n bu ffe r, w hi ch is th en tr an sf er re d to th e te st in g de vi ce a fte r a de fin ed d ur at io n. · Tr an sf er o f t he sa m pl e vo lu m e to th e te st in g de vi ce sh al l o cc ur b y us e of a p re de fin ed a nd p ro vi de d sin gl e- us e tr an sf er d ev ic e (e .g . i nv er te d cu p, di sp os ab le fi xe d- vo lu m e tr an sf er p ip et . “I de al ” d iff er s f ro m “M in im um ” b y el im in at io n of S SS an d pu nc h bi op sy sa m pl in g an d ve no us b lo od d ra w. 72. 7 Sa m pl e vo lu m e <1 00 u L <1 0 µL “S am pl e vo lu m e” re pr es en ts th e vo lu m e i nt ro du ce d to th e te st d ev ic e its el f; th e co lle ct ed sa m pl e vo lu m e m ay be la rg er th an th is. 2. 8 Ta rg et a na ly te Bi om ar ke r( s) sp ec ifi c fo r i nf ec tio n w ith M . l ep ra e. Bi om ar ke r( s) sp ec ifi c fo r i nf ec tio n w ith M . l ep ra e a nd M . l ep ro m at os is. Bi om ar ke rs b as ed o n an tig en s o r o th er ty pe s ( e. g. so m e nu cl ei c ac id -b as ed m ar ke rs ) w ill p re su m ab ly p ro vi de m or e fa vo ur ab le h al f- lif e ki ne tic s a nd th us e na bl e m or e ac cu ra te d et er m in at io n of c ur re nt in fe ct io n w ith M . l ep ra e o r M . l ep ro m at os is in a ll ag e gr ou ps . A b- ba se d se ro lo gy b io m ar ke rs m ay p os se ss h al f- lif e ki ne tic s t ha t e na bl e de te rm in at io n of p ri or in fe ct io n fr om M . l ep ra e o r M . l ep ro m at os is, b ut th ei r h al f- lif e m ay p re cl ud e th ei r u se a s m ar ke rs o f c ur re nt in fe ct io n or im m un e st at us . I n ad di tio n, in a ll ca se s t he bi om ar ke r a pp lie d m us t a lso c on sid er th e de pe nd en cy on th e sa m pl e ty pe u se d. E ve n if ot he r m ar ke rs a re di sc ov er ed a nd p ro po se d, th ei r q ua lifi ca tio n an d va lid at io n w ill re qu ire si gn ifi ca nt ti m e an d eff or t go in g fo rw ar d. F or th is re as on , t hi s i s a h ig h- ris k re qu ire m en t. 2. 9 Ty pe o f a na ly sis Se m i-q ua nt ita tiv e fo r d et er m in in g ba ci lli lo ad o r im m un e st at us . Q ua nt ita tiv e fo r d et er m in in g ba ci lli lo ad o r i m m un e st at us . · Th e ab ili ty to d et ec t c ur re nt M . l ep ra e i nf ec tio ns (a nd M . l ep ro m at os is in “I de al ” s itu at io ns ) s ha ll be in de pe nd en t o f b ac te ri al lo ad /in de x. · U lti m at e de ci sio n on tr ea tm en t r eg im en w ill b e ba se d up on c on fir m in g le pr os y in fe ct io n an d ba ci lli lo ad w ith th e te st (a ss um in g th e in fe ct io n is no t y et cl ea re d) o r i m m un e st at us c om bi ne d w ith c lin ic al ev al ua tio n; re gi m en s a re d et er m in ed th ro ug h co ns ul ta tio n of th e re le va nt le pr os y tr ea tm en t gu id el in es . 2. 10 D et ec tio n Fo r l ab or at or y- ba se d te st s, m ay in cl ud e in st ru m en t- ba se d de te ct io n of a si gn al th at p ro vi de s u na m bi gu ou s de te rm in at io n of a se m i-q ua nt ita tiv e or q ua nt ita tiv e m ea su re . Fo r p oi nt -o f- ca re te st s, re su lts sh al l b e a hi gh c on tr as t, cl ea r r es ul t f or th e na ke d ey e; in do or a nd o ut do or re ad in g of a si gn al th at p ro vi de s a n un am bi gu ou s se m i-q ua nt ita tiv e or q ua nt ita tiv e re su lt w ith ou t t he ne ed fo r c ol ou r d is cr im in at io n. 82. 11 Q ua lit y co nt ro l · Ex og en ou s p ro ce ss c on tr ol in di ca to r ( e. g. c on tr ol lin e on a ra pi d di ag no st ic te st (R D T) , c on tr ol w el l i n an e nz ym e- lin ke d im m un os or be nt a ss ay (E LI SA ). · Ex og en ou s p ro ce ss c on tr ol in di ca to r ( e. g. c on tr ol lin e on a n RD T, c on tr ol w el l i n an E LI SA ) · C ol or im et ri c or o th er in di ca to r t o id en tif y ex ce ss iv e he at /h um id ity e xp os ur e of th e te st k its Fo r f ur th er c on sid er at io n (i. e. b ey on d TP P sc op e) : de fin iti on o f h ow e nd og en ou s p os iti ve c on tr ol s s ho ul d/ w ou ld b e us ed if th ey a re to b e in cl ud ed w ith a te st , e. g. w ill th er e be a c om m un ity -w id e qu al ity p an el , ce nt ra liz ed re po rt in g of re su lts ? 2. 12 S up pl ie s ne ed ed A ll re ag en ts a nd su pp lie s i nc lu de d in te st k it, w ith m in im al im po rt re st ri ct io ns (e .g ., an im al -f re e, re ag en ts fr ee fr om to xi ci ty le ve ls th at tr ig ge r i m po rt re st ri ct io ns ). A ll re ag en ts a nd su pp lie s i nc lu de d in te st k it, w ith m in im al im po rt re st ri ct io ns (e .g ., an im al -f re e, re ag en ts fr ee fr om to xi ci ty le ve ls th at tr ig ge r i m po rt re st ri ct io ns ). A ss um ed th at a ll m at er ia ls ar e in cl ud ed , b ut d oe s n ot in cl ud e sa m pl e co lle ct io n de vi ce s. 2. 13 S af et y N or m al u se d oe s n ot c re at e an y ad di tio na l h az ar ds to th e op er at or w he n ob se rv in g U ni ve rs al B lo od S af et y/ Bo dy F lu id p re ca ut io ns . N or m al u se d oe s n ot c re at e an y ad di tio na l h az ar ds to th e op er at or w he n ob se rv in g U ni ve rs al B lo od S af et y/ Bo dy F lu id p re ca ut io ns . 93. P er fo rm an ce M in im um Id ea l A nn ot at io n 3. 1 Sp ec ie s di ffe re nt ia tio n/ de te ct io n M . l ep ra e M . l ep ra e a nd M . l ep ro m at os is Th er e sh ou ld b e no in te rf er en ce /n on sp ec ifi c sig na ls as a re su lt of o th er c om m on h um an e ct op ar as ite s, in pa rt ic ul ar ly o th er m ite sp ec ie s t ha t m ay in cl ud e (b ut ar e no t l im ite d to ): · Th er e sh ou ld b e pa rt ic ul ar fo cu s t o en su re n o in te rf er en ce fr om o th er m yc ob ac te ri a. · D ue to c o- en de m ic ity o f o th er m yc ob ac te ri a (e .g . M . t ub er cu lo sis ) a s w el l a s s tr on g sim ila rit ie s i n cl in i- ca l p re se nt at io n w ith o th er c o- en de m ic sk in d is ea se s (e .g . p os t- ka la -a za r d er m al le ish m an ia sis , w hi ch co nt ri bu te s t o ov er al l s pe ci fic ity ), th is is co ns id er ed a hi gh -r isk re qu ire m en t, i.e . t he in he re nt c ha lle ng es in m ee tin g th is re qu ire m en t r el at iv e to c ur re nt p ra ct ic es m us t b e ta rg et ed a nd a dd re ss ed to e ns ur e th e te st ’s su cc es s. 3. 2 D ia gn os tic / cl in ic al se ns iti vi ty .≥ 9 0% .≥ 9 0% A ss um pt io ns m ad e f or d ia gn os tic p er fo rm an ce m od ell in g · M od el le d th e eff ec t o f r ed uc in g he al th -c ar e pr ov id er de la ys in d ia gn os is as a fu nc tio n of d ia gn os tic p er fo r- m an ce . · Ex am in ed th e eff ec t o f c ha ng in g bo th se ns iti vi ty a nd sp ec ifi ci ty o n th e od ds ra tio su rr ou nd in g th e im pa ct of d ia gn os tic d el ay o n th e de ve lo pm en t o f d isa bi lit y. In a dd iti on , t he e ffe ct o f c ha ng in g bo th se ns iti vi ty a nd sp ec ifi ci ty o n ne ga tiv e pr ed ic tiv e va lu e an d po sit iv e pr ed ic tiv e va lu e fo r a ra ng e of n ew c as e pr ev al en c- es a m on g in de x ca se h ou se ho ld c on ta ct s w as a lso ev al ua te d. · “M in im um ” a ss um es a h ig h- en de m ic ity se tti ng w he re th e ne w c as e de te ct io n ra te s w ith in h ou se ho ld co nt ac ts o f i nd ex c as es a re e st im at ed to b e 5% , w hi le “i de al ” a ss um es a lo w -e nd em ic ity se tti ng w he re th is sa m e ne w c as e de te ct io n ra te is 0 .5 % . N O TE : V al id at io n of th es e pe rf or m an ce re qu ire m en ts m us t t ak e in to c on sid er at io n th e pr es en ce o f b ot h M B an d PB c as es . 3. 3 D ia gn os tic / cl in ic al sp ec ifi ci ty .≥ 9 9% .≥ 9 9. 9% A ss um pt io ns m ad e f or d ia gn os tic p er fo rm an ce m od ell in g · Sa m e as a bo ve . · Th is is co ns id er ed a h ig h- ris k re qu ire m en t, i.e . t he in - he re nt c ha lle ng es in m ee tin g th is re qu ire m en t r el at iv e to c ur re nt p ra ct ic es m us t b e ta rg et ed a nd a dd re ss ed to e ns ur e th e te st ’s su cc es s. 10 3. 4 Ti m e to re su lts < 4 h to d ev el op ed te st re su lt < 0. 5 ho ur to d ev el op ed te st re su lt Th is re qu ire m en t r el at es to th e an al ys is of a sa m pl e w ith th e te st it se lf an d do es n ot in clu de a ny a dd iti on al tim e as so ci at ed w ith sa m pl e co lle ct io n, sa m pl e tr an sp or t a nd st or ag e, e tc ., w hi ch w ill v ar y co ns id er ab ly be tw ee n te st u se c on di tio ns . 3. 5 Re su lt st ab ili ty D ev el op ed te st re su lt re m ai ns st ab le fo r 0 .5 h . D ev el op ed te st re su lt re m ai ns st ab le fo r a t l ea st 2 4 h. A bi lit y to in te rp re t fi na l t es t r es ul ts in a m an ne r n ot co ns tr ai ne d by ti m ed st ep s h el ps g re at ly in re so ur ce - co ns tr ai ne d se tti ng s. 3. 6 Th ro ug hp ut Fo r l ab or at or y- ba se d te st s, ≥ 10 0 te st s/ da y pe r t es te r. Fo r fi el d- ba se d te st s, ≥ 10 te st s/ h pe r t es te r. “Th ro ug hp ut ” r ep re se nt s h ow m an y te st s c an b e ru n w ith in a n ho ur /d ay b y on e pe rs on a nd is se pa ra te fr om th e tim e to re su lts . N O TE : Th es e th ro ug hp ut re qu ire m en ts d o no t i nf er th at te st in g m us t b e ba tc he d in a ll ci rc um st an ce s. A s ju st o ne e xa m pl e, a n EL IS A -b as ed te st sh ou ld n ot re qu ire th e ru nn in g of a ll 96 w el ls w ith in a p la te , s o de sig ns sh ou ld c on sid er fl ex ib ili ty w he n ru nn in g te st s, e. g. h av in g 8- w el l s tr ip s a s p ar t o f a 9 6- w el l p la te de sig n. 3. 7 Ta rg et sh el f- lif e/ st ab ili ty ≥ 18 m on th s, 4– 40 °C , 7 5% re la tiv e hu m id ity (R H ); te m pe ra tu re e xc ur sio n/ pr ol on ge d de vi at io n of 5 0 °C fo r 2 w ee ks a cc ep ta bl e. ≥ 24 m on th s, 4– 40 °C , 7 5% R H ; t em pe ra tu re ex cu rs io n/ pr ol on ge d de vi at io n of 5 0 °C fo r 2 w ee ks ac ce pt ab le . Re qu ire m en ts re la te to te st k its (i .e . c on su m ab le s, w he th er p oi nt -o f- ca re te st s o r s pe ci m en c ol le ct io n ki ts fo r l ab or at or y- ba se d te st in g) th at a re u se d in th e fi eld . N O TE : c on su m ab le s u se d in a la bo ra to ry fo r la bo ra to ry -b as ed te st in g pr oc ed ur es m ay re qu ire a c ol d ch ai n. 3. 8 Ea se o f u se Fo r l ab or at or y- ba se d te st s, ≤ 5 tim ed st ep s; ≤ 15 u se r st ep s, in st ru ct io ns fo r u se sh ou ld in cl ud e di ag ra m o f m et ho d an d re su lts in te rp re ta tio n. ≤ 1 tim ed st ep ; ≤ 5 u se r s te ps , i ns tr uc tio ns fo r u se sh ou ld in cl ud e di ag ra m o f m et ho d an d re su lts in te rp re ta tio n. F or fi el d- ba se d te st , m us t b e ab le to u se in a n un pr ot ec te d ex te rn al e nv iro nm en t. Th is is in re la tio n to th e te st o pe ra tio n on ly a nd d oe s no t r ef er to sa m pl in g st ep s, sa m pl e st or ag e st ep s, et c. 3. 9 Ea se o f r es ul ts in te rp re ta tio n Fo r l ab or at or y- ba se d te st s, re su lts c an b e de fin iti ve ly in te rp re te d by a su ita bl e in st ru m en t t ha t m ee ts re qu ire m en ts d efi ne d in 2 .1 0 “M in im um ”. Fo r p oi nt -o f- ca re te st s, a de fin iti ve ly in te rp re te d re su lt is ac hi ev ed b y m ee tin g re qu ire m en ts d efi ne d in 2 .1 0 “I de al ”. 3. 10 O pe ra tin g te m pe ra tu re 20 –4 0 °C , 7 5% R H 15 –4 0 °C , 7 5% R H 11 4. P ro du ct co nfi gu ra tio n M in im um Id ea l A nn ot at io n 4. 1 Sh ip pi ng co nd iti on s Fo r l ab or at or y- ba se d te st s, co nf or m an ce to a pp lic ab le re qu ire m en ts o f A ST M D 41 69 -0 5 an d IS O 1 16 07 - 1: 20 06 (o r e qu iv al en t) ; c ol d- ch ai n sh ip pi ng (e .g . 0 –4 °C ) i s a cc ep ta bl e fo r a ny te st c om po ne nt s/ co ns um ab le s us ed in th e la bo ra to ry Fo r p oi nt -o f- ca re te st s, co nf or m an ce to a pp lic ab le re qu ire m en ts o f A ST M D 41 69 -0 5 an d IS O 1 16 07 - 1: 20 06 (o r e qu iv al en t) ; n o co ld -c ha in sh ip pi ng re qu ire d. 4. 2 St or ag e co nd iti on s Fo r l ab or at or y- ba se d te st s, co ld st or ag e is ac ce pt ab le fo r a ny la bo ra to ry -b as ed te st in g co m po ne nt s/ co ns um ab le s. A m bi en t s to ra ge c on di tio ns , 2 –4 0 °C ; n o co ld st or ag e re qu ire d. 4. 3 Se rv ic e an d su pp or t Fo r l ab or at or y- ba se d te st s, su pp or t m us t b e av ai la bl e fr om m an uf ac tu re r f or a ny la bo ra to ry -b as ed eq ui pm en t a nd /o r p ro ce du re s. Fo r p oi nt -o f- ca re te st s, no ne re qu ire d. 4. 4 W as te d isp os al D oe s n ot in cl ud e m at er ia l t ha t c an no t b e di sp os ed o f in n or m al la bo ra to ry b io ha za rd w as te st re am s. · D oe s n ot in cl ud e m at er ia l t ha t c an no t b e di sp os ed o f in n or m al la bo ra to ry b io ha za rd w as te st re am s. · D ai ly th ro ug hp ut n ee ds a re c on sid er ed in th e pa ck ag in g so a s t o m in im iz e th e ne ed to d isp os e of ex tr an eo us p ro du ct w as te . 4. 5 La be lli ng a nd in st ru ct io ns fo r u se (I FU s) C om pl ia nc e re qu ire d pe r r el ev an t C E M ar k/ In V itr o D ia gn os tic R eg ul at io n (I V D R) re qu ire m en ts (o r o th er SR A , e .g . 2 1 C FR 8 20 ) a nd W H O p re qu al ifi ca tio n gu id an ce (s ee W H O T G S- 5: D es ig ni ng in str uc tio ns fo r u se fo r i n vi tr o di ag no sti c m ed ic al d ev ic es ); pr od uc t in se rt sh al l b e av ai la bl e in re le va nt lo ca l l an gu ag e( s) an d sh al l i nc lu de IF U s f or th e te st . M us t p ro vi de ac cu ra te m at er ia l s af et y da ta sh ee t i nf or m at io n on co m po ne nt s t ha t a re p ot en tia lly to xi c. C om pl ia nc e re qu ire d pe r r el ev an t C E M ar k/ IV D R re qu ire m en ts (o r o th er S RA , e .g . 2 1 C FR 8 20 ) a nd W H O p re qu al ifi ca tio n gu id an ce (s ee W H O T G S- 5: D es ig ni ng in str uc tio ns fo r u se fo r i n vi tr o di ag no sti c m ed ic al d ev ic es ); pr od uc t i ns er t s ha ll be a va ila bl e in re le va nt lo ca l l an gu ag e( s) a nd sh al l i nc lu de IF U s f or th e te st . M us t p ro vi de a cc ur at e m at er ia l s af et y da ta sh ee t i nf or m at io n on c om po ne nt s t ha t a re p ot en tia lly to xi c. W H O p re qu al ifi ca tio n la be l/I FU g ui da nc e sh ou ld b e ap pl ie d, re ga rd le ss o f w he th er te st is p re qu al ifi ed b y W H O o r n ot . 12 5. P ro du ct c os t a nd ch an ne ls M in im um Id ea l A nn ot at io n 5. 1 Ta rg et p ri ci ng pe r t es t < U S$ 3 < U S$ 1 A ct ua l p ri ce d et ai ls w ill d ep en d on o th er fa ct or s se pa ra te fr om th e te st it se lf, w hi ch in cl ud e sh ip pi ng , st or ag e, q ua nt iti es p ur ch as ed a nd o th er fa ct or s co m m on ly e nc ou nt er ed in n at io na l p ro cu re m en t f or N TD p ro gr am m es . 5. 2 C ap ita l c os t Fo r l ab or at or y- ba se d te st s, ca pi ta l c os ts m ay v ar y bu t sh ou ld n ot e xc ee d U S$ 5 00 0. Fo r p oi nt -o f- ca re te st s, no ne re qu ire d. 5. 3 Pr od uc t l ea d tim es < 8 w ee ks < 6 w ee ks “L ea d tim e” in cl ud es fu lfi llm en t a nd d el iv er y of or de re d te st s t o pr oc ur er . N O TE : M ay b e ad ju st ed to lo ng er le ad ti m es p ro vi de d sh el f- lif e is of su ffi ci en t d ur at io n, e .g . 2 y ea rs . Pu rp os e fo r i nf or m at io n is to a dd re ss d es ig n de ci sio ns th at c an im pa ct li ne /p ro ce ss d es ig n fo r p ro du ct io n, a nd h en ce im pa ct le ad ti m es . 5. 4 Ta rg et la un ch co un tr ie s C ou nt ri es w ith a re as e nd em ic fo r l ep ro sy C ou nt ri es w ith a re as e nd em ic fo r l ep ro sy 5. 5 Pr od uc t re gi st ra tio n (i. e. su bs ta nt ia tio n to re gu la to ry b od y of pr od uc t c la im s) · C E M ar k/ IV D R (o r o th er S RA ) a s r ele va nt · A ny re gi st ra tio n re qu ire d fo r e xp or t f ro m c ou nt ry o f or ig in (e .g . f ro m K or ea n M in ist ry o f F oo d an d D ru g Sa fe ty ) · W H O p re qu al ifi ca tio n, if re qu ire d/ ap pl ic ab le · C ou nt ry -le ve l r eg ist ra tio n (if re qu ire d/ ap pl ic ab le fo r ta rg et c ou nt ri es ) · C E M ar k/ IV D R (o r o th er S RA ) a s r ele va nt · A ny re gi st ra tio n re qu ire d fo r e xp or t f ro m c ou nt ry o f or ig in (e .g . f ro m K or ea n M in ist ry o f F oo d an d D ru g Sa fe ty ) · W H O p re qu al ifi ca tio n, if re qu ire d/ ap pl ic ab le · C ou nt ry -le ve l r eg ist ra tio n (if re qu ire d/ ap pl ic ab le fo r ta rg et c ou nt ri es ) N ee d to c on fir m th e re le va nt p ro du ct re gi st ra tio n pa th w ay s w ith D TA G .
Neglected tropical diseases World Health Organization 20 Avenue Appia 1211 Geneva 27 Switzerland neglected.diseases@who.int https://www.who.int/teams/control-of-neglected-tropical-diseases