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TARGET PRODUCT PROFILE FOR NEXT-GENERATION DRUG-SUSCEPTIBILITY TESTING AT PERIPHERAL CENTRES
TARGET PRODUCT PROFILE FOR NEXT-GENERATION DRUG-SUSCEPTIBILITY TESTING AT PERIPHERAL CENTRES
Target product profile for next-generation drug-susceptibility testing at peripheral centres
ISBN 978-92-4-003236-1 (electronic version) ISBN 978-92-4-003237-8 (print version)
© World Health Organization 2021
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Contents iii
Contents
Abbreviations and acronyms iv
Definitions v
Acknowledgements vi
Executive summary vii
1 Introduction 1
1.1 Background 1
1.2 Objective and target audience 4
1.3 Development of TPPs 4
2 Methodology 6
2.1 Delphi process 6
2.2 Public comment 6
2.3 Stakeholder consultation 7
3 TPP: next-generation DST at peripheral centres 8
4 Conclusion 24
References 25
Annexes 29
Annex 1: List of participants to the stakeholder consultation 29
Annex 2: Overview of results of the WHO public comment process 34
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
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Abbreviations and acronyms
AMK amikacin
BDQ bedaquiline
BPaL bedaquiline-, pretomanid- and linezolid-based regimen
CFZ clofazimine
DLM delamanid
DCS D-cycloserine
DR-TB drug-resistant tuberculosis
DST drug-susceptibility testing
EMB ethambutol
FQ fluoroquinolones
GDF Global Drug Facility
HIV human immunodeficiency virus
Hr-TB isoniazid-resistant TB
INH isoniazid
KAN kanamycin
LFX levofloxacin
LMIC low- and middle-income countries
LPA line probe assay
LZD linezolid
MDR/RR-TB multidrug-resistant or rifampicin-resistant tuberculosis
MDR-TB multidrug-resistant tuberculosis
MXF moxifloxacin
NDWG New Diagnostics Working Group
NGS next-generation sequencing
Pa pretomanid
PPV positive predictive value
pre-XDR TB pre-extensively drug-resistant tuberculosis
PZA pyrazinamide
RIF rifampicin
RR-TB rifampicin-resistant tuberculosis
R&D research and development
TB tuberculosis
TPP target product profile
WHO World Health Organization
XDR-TB extensively drug-resistant tuberculosis
Definitions v
Definitions
Drug-susceptibility testing (DST)1 refers to in vitro testing using either phenotypic methods to determine susceptibility, or molecular techniques to detect resistance-conferring mutations to a particular medicine.
Rifampicin-susceptible, isoniazid-resistant tuberculosis (Hr-TB)2 refers to Mycobacterium tuberculosis strains with resistance to isoniazid (INH) and susceptibility to rifampicin (RIF) confirmed in vitro.
Rifampicin-resistant tuberculosis (RR-TB)2 is caused by M. tuberculosis strains that are resistant to RIF. These strains may be susceptible or resistant to INH (i.e. multidrug-resistant TB [MDR-TB]), or resistant to other first-line or second-line TB medicines. In these guidelines and elsewhere, MDR-TB and RR-TB cases are often grouped together as MDR/RR-TB and are eligible for treatment with MDR-TB regimens.
Multidrug-resistant tuberculosis (MDR-TB)2 is caused by M. tuberculosis strains that are resistant to at least RIF and INH.
Pre-extensively drug-resistant tuberculosis (pre-XDR-TB)3 is caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and that are also resistant to any fluoroquinolone (FQ).
Extensively drug-resistant tuberculosis (XDR-TB)3 is caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any FQ and at least one additional Group A drug.
1 Implementing tuberculosis diagnostics: policy framework. (WHO/HTM/TB/2015.11). Geneva: World Health Organization. 2015 (https://apps.who.int/iris/bitstream/handle/10665/162712/9789241508612_eng.pdf?sequence=1&isAllowed=y).
2 WHO consolidated guidelines on drug-resistant tuberculosis: Module 4: treatment: drug-resistant tuberculosis treatment. Geneva: World Health Organization. 2020 (https://www.who.int/publications/i/item/9789240007048).
3 Meeting report of the WHO expert consultation on the definition of extensively drug-resistant tuberculosis, 27–29 October 2020. Geneva: World Health Organization. 2021 (https://www.who.int/publications/i/item/meeting-report-of-the-who-expert-consultation-on-the-definition-of-extensively-drug-resistant-tuberculosis).
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
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Acknowledgements
The updating of the Target product profile on next-generation drug-susceptibility testing (DST) was led by Nazir Ismail and Lice Y González-Angulo under the guidance of Matteo Zignol, and under the overall direction of Tereza Kasaeva, Director of the Global TB Programme of the World Health Organization (WHO), with the support of the New Diagnostics Working Group (NDWG) of the Stop TB Partnership. WHO is grateful to Daniella Cirillo, Morten Ruhwald and Karishma Saran for their contributions in the planning of this update, and to Paolo Miotto for writing the first draft of this document, with the support of Mikashmi Kohli and Emily MacLean.
WHO would like to thank Emmanuel André, Martina Casenghi, Paolo Miotto, Camilla Rodrigues, Timothy Rodwell, Philip Supply and Timothy Walker, members of the NDWG Task Force on next-generation DST, who conducted the first revision of this target product profile (TPP). This initial revision was guided by the results of a Delphi-like process, to reach agreement on required updates to each section of the TPP; that process was conducted with support from Matteo Chiacchiaretta.
This document was further revised and finalized following a stakeholder consultation convened by the WHO Global TB Programme on March 2021, where experts shared information and exchanged views on updated product characteristics. This document was finalized after consideration of all comments and suggestions made by the following experts (in alphabetical order): Kindi Adam, Fabiola Arias-Muñoz, Ramon P Basilio, Lynette Berkeley, Dina Bisara, David Branigan, Grania Brigden, Roger Calderón-Espinosa, Martina Casenghi, Fatim Cham-Jallow, Emma Cherneykina, Petra de Haas, Eduardo de Souza Alves, Claudia Denkinger, Ravindra Kumar Dewan, Keertan Dheda, Anzaan Dippenaar, Fernanda Dockhorn Costa Johansen, Marjan Farzami, Patricia Hall, Rumina Hasan, Cathy Hewison, Farzana Ismail, Moses Joloba, Brian Kaiser, Nishant Kumar Kumar, Endang Lukitosari, Troy Murrel, Sreenivas Nair, Norbert Ndjeka, Van Hung Nguyen, Pang Yu, Amy Piatek, Zully Puyén-Guerra, Paolo Redner, Camilla Rodrigues, Timothy C Rodwell, Andriansyah Rukmana, Samuel G. Schumacher, Sella Senthil, Tom Shinnick, S Shivakumar, Alena Skrahina, Tatyana Smirnova, Titiek Sulistowati, Philip Supply, Sabira Tahseen, Ezio Távora dos Santos Filho, Diana Vakrusheva, Irina Vasilyeva, Timothy Walker and Aihua Zhao.
The contributions of individuals who provided inputs through the 2021 public consultation and earlier Delphi-like processes are gratefully acknowledged.
The following WHO staff contributed to the planning of this update and revision process: Draurio Barreira Cravo Neto (Unitaid), Kenza Bennani, Vineet Bhatia, Lou Maureen Comia, Medea Gegia, Jean de Dieu Iragena, Alexei Korobitsyn, Corinne Merle, Fuad Mirzayev, Ernesto Montoro, Carl-Michael Nathanson, Jasmine Solangon and María de los Ángeles Vargas.
This document was edited by Hilary Cadman of Cadman Editing Services.
Executive summary vii
Executive summary
Drug-resistant tuberculosis (DR-TB) is a significant driver of antimicrobial resistance worldwide. The lack of comprehensive, fast and accessible diagnostic tools threatens the progress made in the global TB response over the past two decades. Although the TB diagnostic pipeline has significantly improved in recent years, challenges remain for TB testing and diagnosis; for example, some current tools have limited diagnostic utility for some patient populations, and others present logistic and operational hurdles that hamper their uptake.
In an effort to inform research and development (R&D) priorities for TB diagnostics, the World Health Organization (WHO) released its first high-priority target product profiles (TPPs) for new TB diagnostics in April 2014.4 TPPs provide detailed technical specifications that are important to end-users (e.g. a test’s required performance) and operational characteristics to inform product developers. Four TPPs were developed in 2014, including targets on next-generation drug-susceptibility testing (DST) at the peripheral level. These TPPs were primarily identified through a priority-setting exercise and Delphi consultations,5 and were finalized through consensus after consultation with key stakeholders.
As the term initially set for the 2014 TPPs reached the 5-year mark, the pressing need to guide the development of new technologies further led the World Health Organization (WHO) Global TB Programme to embark on an update process. That process started with the revision of the TPP on DST at the peripheral level, with support from the New Diagnostics Working Group’s (NDWG) Task Force on next-generation DST. This update responds to the global community’s need to accelerate progress towards universal health coverage and focus on tools that could be accessible at lower levels of care, especially DST. Improved access to DST is an essential component to tackle inequities in TB services coverage, particularly in settings where DST is mainly available at the tertiary or referral level. Treatment of rifampicin-resistant TB (RR-TB) has changed dramatically over recent years, with shorter regimens using fluoroquinolones with new and repurposed anti-TB agents (e.g. bedaquiline, linezolid and clofazamine). These are now the core drugs in the new regimens to treat DR-TB, and they have led to improved patient outcomes and reduced treatment duration. However, the emergence of drug resistance threatens these successes, necessitating accurate and early detection of resistance beyond rifampicin resistance. Additionally, the landscape has changed owing to advances in the treatment of drug-susceptible TB with shorter regimens, and increasing recognition of the need to identify isoniazid-resistant TB (which remains largely under-detected). Both regimens use fluoroquinolones, which are currently second-line drugs; thus, there is an urgent need to prioritize R&D for the TPP for DST, to address new and existing gaps.
4 High-priority target product profiles for new TB diagnostics: report of a consensus meeting, 28–29 April 2014, Geneva, Switzerland (WHO/HTM/TB/2014.18). Geneva: World Health Organization. 2014 (https://apps.who.int/iris/handle/10665/135617).
5 The Delphi process involves surveying a panel of experts, to reach a group opinion or decision. After each of several rounds of surveys, responses are aggregated and shared with the panel.
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
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New technologies such as next-generation sequencing (NGS) have moved from the research domain to clinical evaluations. NGS can provide rapid and comprehensive DST with nucleotide-level specificity, and therefore needs to be considered in future planning. Thus, the update of this TPP sought to:
• provide revised TPPs, adjusted to the current context and patient and population needs, and aligned with WHO’s overall strategic priorities in its thirteenth General Programme of Work (2019–2023), including the triple billion targets, and the End TB Strategy (2016–2035); and
• inform TB diagnostic developers and product development partnerships of which target products have been revised and prioritized, the required performance of new diagnostic tools to help reach the milestones of the End TB Strategy, and the operational characteristics of such tools.
Although technical or performance improvements to DST platforms are important, a crucial element of this TPP is the expectation that next-generation DST technologies will be closer to the patient and suitable for implementation at the peripheral level, and will thus improve and expedite access to care.
Efforts in updating the TPP on next-generation DST brought together multidisciplinary experts and stakeholders who contributed to this work through participation in Delphi processes, surveys, public engagement and, in March 2021, a stakeholder consultation with almost 70 experts from 25 countries.
Multiple levels of engagement with stakeholders to revise and finalize this TPP resulted in the following changes:
• the priority for testing of anti-TB agents now includes resistance testing of fluoroquinolones and other group A agents such as bedaquiline;
• the target population is more inclusive, covering individuals of all ages who require drug resistance assessment;
• sample types have been revised to include other clinically relevant specimens for TB; and• there are new considerations for time-to-result linked to treatment decisions.
In relation to the price of individual tests, there were multiple views and perceptions about to how much these tests could cost. The common ground was to support a pricing scheme that is evidence-based and allows wide access in low- and middle-income settings; the balance of potential trade-offs (with no compromise of test performance) was also considered.
There were revisions to and clarifications in the description and targets of the level of the health care system, performance characteristics (e.g. limit of detection, analytical specificity for TB detection, indeterminate results during DST and interfering substances) and specific operational characteristics.
WHO expects that these revisions will help to inform and guide stakeholders involved in developing and implementing DST, including TB diagnostics developers, product development partnerships, academics and other stakeholders.
1 Introduction 1
1 Introduction
About 10 million individuals develop tuberculosis (TB) each year. Although the number of bacteriologically confirmed TB cases has increased, the diagnostic gap remains, with many cases being missed. For example, in 2019 alone, only 57% of pulmonary TB cases had bacteriological confirmation, and 61% of these underwent further testing to determine rifampicin (RIF) resistance (1). Although progress is being made, there is still a long way to go to ensure that access to rapid molecular testing methods and drug susceptibility testing (DST) is a reality for all presumed TB cases.
Almost half a million people developed rifampicin-resistant TB (RR-TB) in 2019, and 78% of those cases were estimated to have developed multidrug-resistant TB (MDR-TB). To compound the problem, there are considerable gaps between the number of individuals tested for DR-TB, and those who are enrolled in treatment. In 2019, for example, only 38% of those estimated to have MDR-TB or RR-TB (MDR/RR-TB) were enrolled for treatment. Closing these gaps in the cascade of care requires a multifaceted approach that includes improving TB care and testing for drug resistance with increased accuracy and a faster turnaround time. Meeting the 2030 targets set in the United Nations Sustainable Development Goals and End TB strategy requires intensified research and innovation in the field of diagnostics and care, to rapidly identify those affected, detect drug resistance and provide appropriate treatment. DST is, therefore, crucial to ensure that TB patients receive appropriate anti-TB therapy. Doing so will help to decrease TB-related morbidity and mortality, and help to slow the spread and development of further drug resistance. There is an urgent need for new technologies and strategies to close diagnostic gaps, including for DR-TB.
1.1 Background
The incidence of TB globally is steadily declining year on year, but is still below the targets set in the End TB Strategy (1). DR-TB continues to be an additional threat owing to delays in diagnosis and treatment that fuel onward transmission. The latest global TB report from the World Health Organization (WHO) indicates that samples from 61% of the 3.6 million bacteriologically confirmed pulmonary TB cases notified globally were tested for RIF resistance, up from 7% in 2012 (1). This improvement illustrates remarkable progress, but also highlights substantial challenges and gaps in resistance detection, particularly for isoniazid (INH) resistance, which is largely undetected. An estimated 13% of all new TB cases are INH resistant whereas only 3% have RIF resistance. Innovations to produce novel diagnostic tools are needed to address current and emerging gaps.
WHO’s TPPs are strategic reference documents that are intended to facilitate and expedite the development of products addressing the greatest and most urgent public health need. In the context of public health, a TPP emphasizes access, equity and affordability as integral parts of the innovation process. In an effort to inform research and development (R&D) priorities for TB diagnostics, WHO released its first high-priority TPPs for new TB diagnostics in April 2014 (2).
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
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The time frame of development for tests envisioned in the initial TPP was 5 years (2). Hence, this updated TPP supersedes the earlier key assumptions and targets for DST for Mycobacterium tuberculosis (2) and is aimed at guiding the next 5 years and moving the field forward. As described below, the present update takes into account:
• the most recent developments on new drugs and regimens (3);• recommendations on the use of novel regimens;• new technologies entering the TB diagnostic landscape (4); and• updated definitions for pre-extensively drug-resistant TB (pre-XDR) and XDR-TB (5).
For drug-susceptible TB treatment, WHO has evaluated an alternative to the 6-month regimen using RIF, INH, pyrazinamide (PZA) and ethambutol (EMB); the alternative is a 4-month combination regimen that includes a fluoroquinolone (FQ) (6).
RIF-susceptible, INH-resistant TB (Hr-TB), which is more common than MDR/RR-TB, is associated with poorer treatment outcomes (7); however, Hr-TB goes largely undetected because of the lack of upfront detection of INH resistance. In addition, Hr-TB requires treatment with a FQ and there is thus an increasing need for upfront testing of resistance to RIF, INH and FQ (8).
Treatment regimens for DR-TB have undergone substantial changes over the past 5 years, with the emergence of new medicines such as bedaquiline (BDQ) and pretonamid (Pa) and repurposed medicines such as linezolid (LZD) and clofazimine (CFZ) (8). New regimens for DR-TB regimens use a standardized shorter approach or an individualized longer one. The common factor is a need for a test that detects both TB and resistance to relevant anti-TB agents, and that is used at the peripheral level of the health care system so that it can guide treatment decisions at that level based on DST profiles.
Two shorter standardized regimens for DR-TB are recommended by WHO:
• a regimen for MDR/RR-TB where the injectable agent has been replaced by BDQ (used for 6 months), in combination with levofloxacin (LFX)/moxifloxacin (MXF), ethionamide (ETO), EMB, high-dose INH, PZA and CFZ for 4 months in the intensive phase; and
• a 6-month regimen for pre-XDR-TB that includes the new anti-TB agent, Pa, which was also recommended by WHO in 2020 for use under operational research conditions, in combination with BDQ and LZD (BPaL regimen) (8, 9).
Next-generation DST at the peripheral level will need to aid regimen selection; hence, this TPP was updated to guide R&D and address relevant emerging needs. Novel diagnostic tests to be used at peripheral sites should ideally test for resistance to RIF, INH, FQ (MFX & LFX) and BDQ, to enable selection of the most appropriate treatment regimen. The prioritization of testing for these drugs is based on an assessment of the importance of each anti-TB agent in currently recommended regimens.
Changes in the treatment domain have been paralleled by rapid new developments on the diagnostics technology front. The first molecular tests that WHO has recommended for the rapid detection of drug resistance were based on reverse hybridization technologies; they provided accurate DST but required specialized infrastructure and skills. Since then, real-time molecular tests have been developed that can detect resistance to RIF and now to other drugs (e.g. INH and FQs). These tests can produce results in a matter of hours, and
1 Introduction 3
because they are largely automated they can provide testing capacity outside of centralized laboratory structures.
Molecular drug resistance determination ultimately depends on a knowledge base of the mutations associated with drug resistance and their relative frequency in populations. To address this, WHO has developed a catalogue of mutations and their association with resistance, by collating a large collection of isolate data with phenotypic DST and whole-genome sequencing results. The catalogue is aimed at developers and researchers, to allow new tests to be developed and ensure consistent and robust interpretation of mutations for sequencing technologies (10).
Next-generation sequencing (NGS) methods are emerging that could provide comprehensive DST profiles covering multiple gene targets with nucleotide-level resistance information and be rapid enough to affect clinical decision-making. Several targeted NGS products are coming to market that can detect resistance to the new and repurposed drugs, filling a major gap. NGS technologies are of varying complexity and size, with some small enough to be handheld.
As these treatment and diagnostic changes have evolved, WHO has revised the definition for XDR-TB and introduced a new definition for pre-XDR-TB (5). The revision was also driven by a change in the positioning of the second-line injectable agents, which are no longer considered core drugs for the treatment of DR-TB. Amikacin was relegated to a Group C drug, whereas kanamycin and capreomycin are no longer recommended for use following an evidence review. The new definition was also updated to prioritize the Group A drugs that are now recommended as core drugs. The revised definitions are:
• Pre-extensively drug-resistant TB (pre-XDR-TB) is caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any FQ.
• Extensively drug-resistant (XDR-TB) is caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any FQ and at least one additional Group A drug.
These changes further support the need for an update of the TPP, because of the strong requirement for rapid and accurate testing for Group A medicines and the relegation in priority of the injectable agents.
The prevalence of drug resistance in a population can vary owing to factors such as prior exposure, treatment practices in different regions and the frequency of primary or acquired drug resistance. A study in five countries showed that the population-based point prevalence of FQ resistance was 4.4% or lower in four countries but 11.1% in the fifth country (11). In contrast, among people with RR-TB, the point prevalence of FQ resistance was even higher, at 12.3–30.7%. Prior treatment history is also an important factor; it is well recognized that the prevalence of resistance to RIF and INH is higher among previously treated individuals than among those without a prior treatment history. In addition, heteroresistance, which is uncommon for most drugs, is well described for FQs, and is therefore an important consideration for drug and diagnostic developers. Cross-resistance has also been observed; such resistance allows a single gene target to inform treatment modifying decisions to more than one drug. Thus, for instance, mutations in the inhA promoter region are associated with resistance to ETO and INH, whereas mutations in the Rv0678 gene can lead to resistance to both BDQ and CFZ (12, 13).
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
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Another important consideration is the pre-existence of drug resistance to one or more drugs, because this can alter the likelihood of resistance to other drugs and affect test performance, depending on the population selected for testing. RIF, for example, is an indicator drug – if resistance to RIF is present, resistance against other anti-TB agents is more likely to be present. In a multicountry surveillance study, the point prevalence among cases with RR-TB was above 40% for PZA and above 65% for INH, but below 30% for FQs (14).
Several factors make it essential to adopt appropriate and specific implementation strategies for any given new assay developed. These factors are the diversity of resources and needs in different countries; the geographical variation in the epidemiology of TB and related comorbidities, and in DR-TB; and the specialized nature of the different technical procedures. Providing guidance for implementation strategies is beyond the scope of this document; however, the characteristics defined in the TPP should be regarded from the perspective of an implementation framework (15).
This document outlines current needs and provides direction for the development of a rapid DST that can be used at the peripheral level of the health care system (the rapid DST test). As with other TPPs, the updated targets for next-generation DST consider characteristics pertinent to the performance of a diagnostic tool and to the sustainability of envisioned technologies (e.g. feasibility, cost and cost–effectiveness).
1.2 Objective and target audience
The overall objective of this TPP is to align developers’ performance and operational targets for a next-generation DST assay for use at peripheral level with the needs of users. The target audience comprises test developers and manufacturers interested in entering the TB diagnostic market, regulatory agencies, academia, research institutions, product development partnerships, nongovernmental organizations (NGOs), civil society organizations and donors.
1.3 Development of TPPs
Diagnostic manufacturers require TPPs at an early stage of the development process so that they can be informed of the targets, technical specifications and diagnostic performance of the products. These parameters are set by a series of processes among and consensus of stakeholders, keeping in mind the objective of the TPP and its feasibility and utility for the end-user. Each TPP has specific characteristics that refer to the measurable requirement or specification (e.g. diagnostic specificity, biosafety aspects, data interpretability and storage).
This document also provides both the “minimal” and the “optimal” outputs for each characteristic in the TPP (Table 1). The minimal requirements are the lowest acceptable output for that characteristic, and the optimal are the ideal, realistically achievable output for that characteristic. Products should meet all of the minimal characteristics and as many of the optimal characteristics as possible.
1 Introduction 5
Table 1. TPP terminology
Termsa Definitions
Characteristic A specific requirement or specification that is measurable.
Minimal For a specific characteristic, “minimal” refers to the lowest acceptable output for that characteristic. To be acceptable, solutions must meet the minimal characteristic. However, a test may still be acceptable if shortcomings pertain to soft targets and if specific hard targets (marked with an asterisk) are missed only marginally.
Optimal For a specific characteristic, “optimal” provides the ideal output that is believed to be realistically achievable. Meeting the optimal characteristics will provide the greatest impact for the end-users, clinicians and patients. Developers would ideally design and develop their solutions to meet the optimal requirements for all characteristics.
TPP: target product profile.a The optimal and minimal requirements and characteristics define a range.
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
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2 Methodology
This update process has built on earlier activities conducted during the development of the first high-priority TPPs for new TB diagnostics (2) and further engagement with key stakeholders. In addition, the methodology used in this update allowed engagement with relevant audiences, including the product development audience, at different stages of the process, in line with WHO requirements for TPP development.
2.1 Delphi process
A draft TPP document was prepared to promote discussion between the different groups of stakeholders. The draft document and a Delphi-like survey (in April–May 2019) were shared with a wide range of stakeholders: technical agencies and researchers, funding organizations, reference TB laboratories, national TB programmes, implementers and clinicians, representatives from industry, and advocates for patients. They were also shared with a broader audience through general dissemination channels such as the website of the New Diagnostics Working Group (NDWG) and the Global Tuberculosis Network. Additional working groups invited to participate in the Delphi consultation included the Global Laboratory Initiative and the European Laboratory Initiative. Participants were ask to reply to 47 specific questions, expressing their level of agreement on the proposed characteristics according to a predefined Likert scale ranging from 1 to 5 (1 – disagree, 2 – mostly disagree, 3 – don’t agree or disagree, 4 – mostly agree and 5 – fully agree). Individuals were asked to provide comments when they did not agree with a statement about a characteristic (i.e. scored it at 1, 2 or 3). The Delphi process used is detailed in a report from the NDWG (16).
Overall, the outcomes of the stakeholder process showed a high level of agreement for 89% of the TPP components explored (16). No agreement on either the minimal or optimal requirements was reached for the following characteristics: priority of anti-TB agents for testing, price of the individual test, capital costs for the instrument, limit of detection of minor variants and indeterminate results during detection.
2.2 Public comment
A proposed revised version of the 2014 TPP on next-generation DST (2), which followed changes made after the Delphi consultation, was shared online for public comment on any of the characteristics in the TPP document. The intended audience included TB programme managers, laboratory specialists, clinical practitioners, implementers, researchers, civil society organizations, industry and patient advocates. Comments were analysed quantitatively and grouped into themes when possible. Results of this public comment process are provided in Annex 2.
2 Methodology 7
2.3 Stakeholder consultation
Feedback from the public comment process was presented at a stakeholder consultation, which was conducted remotely over four sessions during March 2021. Almost 70 stakeholders from 25 countries attended the sessions, and they included participants from technical agencies and funding agencies, as well as researchers, implementers and policy-makers (see Annex 1). During the consultation, the stakeholders discussed each characteristic included in the TPP, and incorporated the feedback from the public comment to promote information sharing, exchange of views or clarification.
Changes and suggestions made during the stakeholder consultation were incorporated into the final TPP presented in Section 3, below.
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
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t lea
st in
itial
ly
Rat
ion
ale
To p
rovi
de s
uppo
rt fo
r tim
ely
and
effec
tive
an
ti-T
B t
her
apy
in th
e co
ntex
t of t
he ro
ll-ou
t of n
ew T
B m
edic
ines
and
regi
men
s;
and
to p
rovi
de th
e ch
arac
teris
tics
and
qual
ities
of a
test
that
wou
ld h
ave
a su
ffici
ently
rapi
d tu
rnar
ound
tim
e fo
r TB
dete
ctio
n an
d w
ould
pro
vide
dat
a ab
out D
ST th
at c
an b
e us
ed to
info
rm tr
eatm
ent d
ecis
ions
Go
alD
iagn
osis
of T
B di
seas
e an
d de
tect
ion
of d
rug
resi
stan
ce to
pro
vide
ra
pid
tria
ge o
f pat
ient
s an
d id
entifi
catio
n of
ad
equa
te tr
eatm
ent
regi
men
(firs
t-lin
e tr
eatm
ent v
ersu
s se
cond
-lin
e tr
eatm
ent)
Dia
gnos
is o
f TB
dise
ase
and
de
tect
ion
of d
rug
resi
stan
ce to
in
form
dec
isio
n-m
akin
g ab
out
the
optim
al (i
ndiv
idua
lized
) re
gim
en
The
mar
ket f
or a
test
that
incl
udes
TB
dete
ctio
n an
d D
ST is
all
peop
le w
ith p
resu
mpt
ive
TB, w
hich
is a
ppro
xim
atel
y 10
tim
es th
e nu
mbe
r of d
etec
ted
case
s, o
r abo
ut 6
0–70
mill
ion
patie
nts.
If D
ST
wer
e pe
rfor
med
in a
sec
ond
step
, the
mar
ket w
ould
be
all p
atie
nts
in w
hom
bac
terio
logi
cally
con
firm
ed T
B ha
d be
en d
etec
ted
(abo
ut
7 m
illio
n).
The
mar
ket f
or a
test
to d
etec
t BD
Q re
sist
ance
is d
iffer
ent b
ecau
se
the
curr
ent a
chie
vabl
e pe
rfor
man
ce c
hara
cter
istic
s of
a m
olec
ular
te
st fo
r BD
Q re
sist
ance
are
stil
l unc
erta
in. F
urth
erm
ore,
BD
Q is
cu
rren
tly re
com
men
ded
for u
se in
MD
R/RR
-TB
patie
nts
only
; th
eref
ore,
a te
st fo
r BD
Q re
sist
ance
cou
ld b
e us
ed a
s a
follo
w-o
n te
st o
nly
if RI
F re
sist
ance
has
bee
n co
nfirm
ed (b
ecau
se a
hig
her
prev
alen
ce o
f res
ista
nce
lead
s to
a h
ighe
r PPV
for t
he d
etec
tion
of
resi
stan
ce to
a p
artic
ular
ant
i-TB
agen
t). T
his
mea
ns th
at th
e m
arke
t fo
r tes
ting
for B
DQ
resi
stan
ce is
as
larg
e as
the
num
ber o
f pat
ient
s co
nfirm
ed to
hav
e M
DR/
RR-T
B, w
hich
was
abo
ut 2
06 0
00, a
lthou
gh
the
estim
ated
num
ber i
s m
uch
larg
er, c
orre
spon
ding
to a
n es
timat
ed
465
000
MD
R/RR
-TB
inci
dent
cas
es in
201
9.
3 TPP: next-generation DST at peripheral centres 9
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Prio
rity
of
anti
-TB
ag
ents
fo
r te
stin
ga
RIF
+ IN
H+
FQ +
BD
Q (s
ee
info
rmat
ion
on B
DQ
in
the
expl
anat
ory
note
s)
(FQ
alw
ays
incl
udes
LFX
an
d M
FX)
In o
rder
of
decr
easi
ng im
port
ance
:
Min
imal
+
1. P
ZA +
LZD
+ P
a/D
LM +
CFZ
2. A
MK
+ D
CS
3. A
ny a
dditi
onal
dru
g lis
ted
in
the
WH
O tr
eatm
ent
guid
elin
es
Dru
g pr
iorit
izat
ion
cons
ider
s un
iver
sal a
cces
s to
DST
(EN
D T
B St
rate
gy) a
nd th
at e
ffec
tive
adm
inis
trat
ion
of a
nti-T
B dr
ugs
can
be a
chie
ved
only
by
know
ing
susc
eptib
ility
test
ing
resu
lts. T
his
is a
gen
eral
prin
cipl
e th
at is
bec
omin
g cr
ucia
l, es
peci
ally
for t
he
trea
tmen
t of D
R-TB
.
The
prop
osed
prio
ritiz
atio
n fo
r min
imal
requ
irem
ents
con
side
red:
(i)
Impa
cts
of u
ndet
ecte
d RI
F an
d IN
H re
sist
ance
on
patie
nt o
utco
mes
.
(ii) F
Qs
are
rele
vant
for b
oth
first
-line
and
sec
ond-
line
trea
tmen
t re
gim
ens
and
resi
stan
ce to
thes
e dr
ugs
is c
entr
al to
the
upda
ted
pre-
XD
R an
d X
DR
defin
ition
s.
(iii)
BDQ
is n
ow o
ne o
f the
med
icin
es th
at d
efine
XD
R-TB
, a G
roup
A
med
icin
e th
at is
incl
uded
in a
ll D
R-TB
regi
men
s in
clud
ing
the
curr
ent
shor
ter M
DR/
RR-T
B re
gim
en. N
ew te
sts
shou
ld in
form
dec
isio
n-m
akin
g fo
r sho
rter
and
nov
el M
DR
regi
men
s.
The
diff
eren
tiatio
n of
resi
stan
ce a
mon
g FQ
s is
mor
e a
func
tion
of
inte
rpre
ting
mut
atio
ns (i
.e. e
valu
atin
g th
e hi
erar
chic
al s
truc
ture
of
mut
atio
ns) t
han
of d
etec
ting
diff
eren
t mut
atio
ns.
BD
Q is
a h
igh
prio
rity
drug
, but
it is
reco
gniz
ed th
at re
leva
nt
mut
atio
ns a
ssoc
iate
d w
ith re
sist
ance
are
cur
rent
ly n
ot fu
lly
eluc
idat
ed. T
his
is e
xpec
ted
to c
hang
e in
the
com
ing
year
s.
Furt
herm
ore,
the
feas
ibili
ty o
f con
duct
ing
DST
for t
his
med
icin
e at
the
perip
hera
l lev
el m
ay re
quire
alte
rnat
ive
tech
nolo
gica
l ap
proa
ches
com
pare
d w
ith th
ose
used
for o
ther
dru
gs (e
.g. R
IF).
The
optim
al re
quire
men
ts a
re a
imed
to b
e al
igne
d w
ith th
e ne
w W
HO
gu
idel
ines
and
to c
onsi
der c
ross
-res
ista
nce
of c
erta
in d
rugs
(e.g
. BD
Q
and
CFZ
).
Seq
uen
ce o
f TB
det
ecti
on
an
d d
rug
res
ista
nce
tes
tin
g: T
he
prop
ortio
n of
pat
ient
s di
agno
sed
with
TB
who
exp
erie
nced
pr
etre
atm
ent l
oss
to fo
llow
-up
is in
the
rang
e of
4%
to 3
8%. T
his
scen
ario
mig
ht v
ary
subs
tant
ially
am
ong
coun
trie
s. In
itial
ly, t
estin
g fo
r TB
and
DST
mig
ht c
ome
at th
e ex
pens
e of
the
sens
itivi
ty fo
r TB
dete
ctio
n, d
epen
ding
on
the
plat
form
use
d an
d co
st o
f the
test
. H
owev
er, a
del
ay in
DST
mig
ht re
sult
in p
atie
nts
rece
ivin
g
(5,6
,8)
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
10
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
inap
prop
riate
trea
tmen
t unt
il th
ey re
turn
. In
the
inte
rim, d
isea
se
tran
smis
sion
may
hav
e oc
curr
ed. T
he a
ccep
tabi
lity
of a
long
er w
ait
time
mig
ht v
ary
amon
g co
untr
ies,
and
info
rmin
g th
e pa
tient
of
resu
lts o
n th
e sa
me
day
if th
e re
sult
is n
ot a
vaila
ble
durin
g th
e fir
st
visi
t mig
ht b
e as
soci
ated
with
sub
stan
tial c
osts
.
Ass
ay d
esig
nTh
e as
say
shou
ld b
e de
sign
ed in
suc
h a
man
ner t
hat t
he
addi
tion
or re
mov
al o
f ana
lyte
s do
es n
ot re
quire
ext
ensi
ve
anal
ytic
al a
nd c
linic
al re
verifi
catio
n an
d re
valid
atio
n of
the
assa
y
The
assa
y sh
ould
be
desi
gned
to b
e ca
pabl
e of
bei
ng m
odifi
ed o
r up
grad
ed a
s ne
eded
, with
min
imal
rede
velo
pmen
t req
uire
d. F
or
sequ
enci
ng-b
ased
ass
ays,
this
sho
uld
incl
ude
the
poss
ibili
ty to
adj
ust
sequ
ence
inte
rpre
tatio
n fo
r new
dru
gs.
This
is n
ot a
regu
lato
ry re
quire
men
t; ra
ther
, it r
efer
s to
the
adap
tabi
lity
of th
e as
say
for u
pdat
ing
and
addi
ng n
ewer
ana
lyte
s.
Targ
et p
op
ula
tio
nPe
ople
of a
ll ag
es in
nee
d of
eva
luat
ion
for T
B an
d th
ose
requ
iring
dru
g re
sist
ance
ass
essm
ent
Chi
ldre
n ag
ed <
11 y
ears
hav
e lim
ited
abili
ty to
pro
duce
spu
tum
for
test
ing;
ther
efor
e, in
itial
val
idat
ion
stud
ies
shou
ld fo
cus
on a
dults
an
d ad
oles
cent
s.
Targ
et u
ser
of
test
a
Hea
lth c
are
wor
kers
with
m
inim
al o
r mod
erat
e tr
aini
ng
Hea
lth c
are
wor
kers
with
m
inim
al tr
aini
ng n
eces
sary
Min
imal
trai
ning
: use
rs a
re h
ealth
car
e w
orke
rs w
ith li
mite
d or
no
com
pete
ncy
in g
ener
al la
bora
tory
pra
ctic
e (b
egin
ner u
sers
).
Mod
erat
e tr
aini
ng: u
sers
are
hea
lth c
are
wor
kers
with
min
imal
or
mod
erat
e co
mpe
tenc
y in
gen
eral
labo
rato
ry p
ract
ice
(com
pete
nt o
r pr
ofici
ent u
sers
).
Com
pet
ency
gui
del
ines
for p
ublic
hea
lth la
bor
ator
y p
rofe
ssio
nals
was
us
ed to
pro
vide
a te
rm o
f ref
eren
ce (1
7)
(1,1
8)
Sett
ing
(le
vel
of
the
hea
lth
ca
re s
yste
m)
Perip
hera
l lev
el o
f the
he
alth
car
e sy
stem
Poin
t-of
-car
eIm
plem
enta
tion
at th
e pe
riphe
ral l
evel
sho
uld
be fe
asib
le u
sing
th
e sp
ecifi
catio
ns o
utlin
ed. T
his
wou
ld e
mbe
d th
e te
st in
an
infr
astr
uctu
re th
at is
bas
ed a
roun
d sm
ear m
icro
scop
y. H
owev
er, t
he
test
cou
ld b
e im
plem
ente
d at
hig
her l
evel
s of
car
e as
wel
l. Te
stin
g fo
r res
ista
nce
to th
e an
ti-TB
age
nts
incl
uded
in s
econ
d-lin
e th
erap
y co
uld
be in
corp
orat
ed in
to s
epar
ate
reac
tions
, but
idea
lly it
wou
ld b
e fe
asib
le to
test
the
sam
e sp
ecim
en.
For o
ptim
al re
quire
men
ts, i
t is
sugg
este
d th
at th
e te
st b
e at
poi
nt-
of-c
are,
with
imm
edia
te a
cces
sibi
lity
for p
atie
nts
(e.g
. bed
side
av
aila
bilit
y fo
r any
pat
ient
).
(18–
21)
3 TPP: next-generation DST at peripheral centres 11
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Pric
ing
Pric
e o
f in
div
idu
al
test
, ap
plic
able
to
all
pu
blic
p
rog
ram
mes
, N
GO
s,
inte
rnat
ion
al
org
aniz
atio
ns
in
LMIC
(In
clu
des
th
e co
st
of
reag
ents
an
d
con
sum
able
s o
nly
, aft
er
scal
e-u
p,
ex-w
ork
s;
excl
ud
es s
hip
pin
g
and
pri
ce
sub
sid
ies.
Cei
ling
p
rice
)a
RIF
+ IN
H +
FQ
:
US$
10–
15
Add
ing
BDQ
(pric
e no
t defi
ned,
see
Ex
plan
ator
y no
tes)
a) R
IF +
INH
+ F
Q:
max
imum
US$
5
b) P
ZA +
LZD
+ P
a/D
LM +
C
FZ (p
rice
not d
efine
d, s
ee
Expl
anat
ory
note
)
c) A
MK
+ D
CS:
(pric
e no
t defi
ned,
see
Ex
plan
ator
y no
te)
The
right
to h
ealth
con
tain
s en
title
men
ts th
at e
mbr
ace
acce
ss
to b
asic
hea
lth s
ervi
ces;
in tu
rn, t
his
incl
udes
ear
ly a
cces
s to
TB
diag
nost
ic to
ols
and
dete
ctio
n of
dru
g re
sist
ance
. The
pric
e of
a te
st
affec
ts a
cces
s an
d re
quire
s du
e co
nsid
erat
ion.
Cos
t–eff
ectiv
enes
s an
alys
es s
houl
d id
eally
be
perf
orm
ed b
ecau
se th
ese
resu
lts p
rovi
de
a fr
amew
ork
to c
ompa
re th
e co
sts
and
bene
fits
of a
pro
duct
aga
inst
re
leva
nt c
ompa
rato
rs, i
nclu
ding
cur
rent
pra
ctic
e. U
ltim
atel
y, c
ost–
effec
tiven
ess
anal
ysis
con
side
rs w
heth
er a
pro
duct
dem
onst
rate
s va
lue
for m
oney
; thu
s, it
is m
ore
mea
ning
ful t
han
a pr
ice
poin
t alo
ne.
How
ever
, a c
ost-
effec
tive
prod
uct m
ay b
e un
affor
dabl
e, e
spec
ially
in
hig
h-bu
rden
, low
- and
mid
dle-
inco
me
sett
ings
, so
prov
idin
g an
in
dica
tive
pric
e is
hel
pful
. A p
rice
rang
e is
pro
vide
d fo
r the
min
imal
re
quire
men
t with
DST
for R
IF, I
NH
and
FQ
, but
thes
e ra
nges
are
in
dica
tive
not a
bsol
ute.
Idea
lly, t
he p
rice
of te
sts
shou
ld b
e ba
sed
on
evi
denc
e of
the
actu
al c
ost o
f goo
ds a
nd e
stim
ated
vol
umes
, and
a
reas
onab
le p
rofit
mar
gin.
Cur
rent
ly, t
he p
rice
of a
sin
gle
Xpe
rt
XD
R-TB
ass
ay (f
or IN
H, F
Q, s
econ
d-lin
e in
ject
able
s an
d et
hion
amid
e)
is a
bout
US$
20.
Thi
s te
st w
as o
rigin
ally
aim
ed a
t MD
R/RR
-TB
patie
nts,
but
exp
andi
ng th
is to
all
TB p
atie
nts
or a
ll pr
esum
ptiv
e TB
cas
es w
ould
sub
stan
tially
incr
ease
the
mar
ket.
A p
rice
that
is
high
er th
an a
vaila
ble
tech
nolo
gies
wou
ld b
e ju
stifi
ed o
nly
if it
is
evid
ence
-bas
ed a
nd th
e ne
w te
st b
rings
sub
stan
tial a
dded
val
ue
in te
rms
of g
reat
ly im
prov
ed p
erfo
rman
ce, g
reat
er s
uita
bilit
y fo
r de
cent
raliz
atio
n, c
linic
al u
tility
(i.e
. aff
ects
dec
isio
n-m
akin
g) a
nd th
e nu
mbe
r of a
nti-T
B ag
ents
for w
hich
resi
stan
ce c
an b
e de
tect
ed.
The
add
itio
n o
f B
DQ
-res
ista
nce
det
ecti
on
to th
e te
st w
ould
requ
ire
spec
ial c
onsi
dera
tion
beca
use
new
type
s of
tech
nolo
gies
may
be
need
ed a
nd th
e m
olec
ular
bas
is o
f res
ista
nce
has
not b
een
fully
el
ucid
ated
; thu
s, a
n in
dica
tive
pric
e co
uld
not b
e de
term
ined
at t
his
time.
Fur
ther
mor
e, a
pric
e ra
nge
for t
ests
cov
erin
g th
e “o
ptim
al”
list
of p
riorit
ized
dru
gs c
ould
als
o no
t be
prov
ided
bec
ause
:
• th
e pr
ice
mig
ht v
ary
depe
ndin
g on
the
num
ber o
f dru
gs
cons
ider
ed; a
nd
• th
ere
are
no d
ata
for p
redi
ctin
g w
hat t
he c
ost o
f ass
ays
test
ing
for
new
dru
gs s
uch
as D
LM, L
ZD a
nd C
FZ w
ould
be.
(22–
28)
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
12
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
The
cost
of p
heno
typi
c D
ST fo
r firs
t-lin
e an
d se
cond
-line
dru
gs is
es
timat
ed to
be
in th
e ra
nge
of U
S$ 5
0–10
0 (±
30%
). A
new
test
sh
ould
idea
lly b
e pr
iced
low
er b
ased
on
evid
ence
of t
he c
ost o
f go
ods
and
estim
ated
vol
umes
, and
a re
ason
able
pro
fit; a
pric
e w
ithin
th
e sa
me
rang
e or
hig
her w
ould
nee
d to
be
evid
ence
-bas
ed a
nd
coul
d be
just
ified
thro
ugh
a co
st-e
ffec
tiven
ess
anal
ysis
.
Ensu
ring
acce
ss to
test
s w
hile
mai
ntai
ning
bus
ines
s in
tere
sts
can
be a
chie
ved
thro
ugh
fair
pric
ing,
whi
ch re
quire
s tr
ansp
aren
cy
of th
e co
st o
f goo
ds a
nd e
stim
ated
vol
umes
, with
a re
ason
able
pr
ofit m
argi
n.
Cap
ital
co
sts
for
the
inst
rum
ent
(Cei
ling
pri
ces)
Less
than
US$
20
000
(incl
udin
g w
arra
ntie
s,
serv
ice
cont
ract
s an
d
tech
nica
l sup
port
– a
t le
ast f
or 3
yea
rs)
Less
than
US$
500
0 (in
clud
ing
war
rant
ies,
ser
vice
con
trac
ts
and
tech
nica
l sup
port
– a
t le
ast f
or 3
yea
rs)
The
low
er th
e ca
pita
l cos
ts o
f the
inst
rum
ent a
re, t
he lo
wer
the
initi
al c
ost w
ould
be,
and
thus
the
barr
ier t
o im
plem
enta
tion
wou
ld a
lso
be lo
wer
, par
ticul
arly
sin
ce th
e vo
lum
e of
inst
rum
ents
th
at w
ould
be
dist
ribut
ed to
per
iphe
ral c
entr
es is
siz
eabl
e. T
he
cost
of t
he in
stru
men
t sho
uld
be e
vide
nce-
base
d an
d sh
ould
als
o in
clud
e w
arra
ntie
s, s
ervi
ce c
ontr
acts
and
tech
nica
l sup
port
. Cos
t–eff
ectiv
enes
s sh
ould
be
then
eva
luat
ed d
urin
g im
plem
enta
tion
acco
rdin
g to
the
num
ber o
f dru
gs a
nd ta
rget
s th
at a
giv
en
tech
nolo
gy c
an c
over
, the
ass
ay m
ultip
lexi
ng a
nd th
e m
ultip
urpo
se
optio
ns o
ffer
ed.
Add
ition
ally
, tes
t dev
elop
ers
and
man
ufac
ture
rs c
ould
con
side
r off
erin
g di
ffer
ent a
cqui
sitio
n m
odel
s, s
uch
as a
reag
ent r
enta
l or a
co
st-p
er-r
esul
t mod
el. T
he re
agen
t ren
tal a
gree
men
t wou
ld a
llow
fo
r cou
ntrie
s or
end
-use
rs to
pur
chas
e th
e te
st a
t a s
et c
ost p
er
test
, inc
ludi
ng th
e m
achi
ne, s
ervi
ce, m
aint
enan
ce a
nd te
chni
cal
supp
ort (
with
pric
e de
pend
ing
on v
olum
e of
test
s, in
clud
ing
test
s fo
r diff
eren
t ind
icat
ions
on
mul
tiple
inst
rum
ents
); w
here
as th
e co
st-p
er-r
esul
t mod
el in
clud
es th
e ab
ove
plus
any
test
s th
at d
o no
t pr
ovid
e an
act
iona
ble
resu
lt (e
.g. i
nval
id te
sts)
.
3 TPP: next-generation DST at peripheral centres 13
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Perf
orm
ance
Dia
gn
ost
ic
sen
siti
vity
fo
r TB
d
etec
tio
na
Sens
itivi
ty s
houl
d be
>8
0% fo
r a s
ingl
e te
st
whe
n co
mpa
red
with
2
liqui
d cu
lture
s; fo
r sm
ear-
nega
tive
TB it
sh
ould
be
>60%
and
fo
r sm
ear-
posi
tive
TB it
sh
ould
be
99%
Sens
itivi
ty fo
r det
ectin
g TB
sh
ould
be
>95%
for a
sin
gle
test
whe
n co
mpa
red
with
2
liqui
d cu
lture
s; fo
r sm
ear-
nega
tive
TB it
sho
uld
be >
68%
an
d fo
r sm
ear-
posi
tive
TB it
sh
ould
be
99%
The
sens
itivi
ty s
peci
fied
cons
ider
s th
e cu
rren
tly a
vaila
ble
tech
nolo
gies
as
base
line.
(2
9)
Dia
gn
ost
ic
spec
ifici
ty f
or
TB
det
ecti
on
a
Spec
ifici
ty s
houl
d be
>9
8% fo
r a s
ingl
e te
st
whe
n co
mpa
red
with
cu
lture
Spec
ifici
ty s
houl
d be
>98
% fo
r a
sing
le te
st w
hen
com
pare
d
with
cul
ture
(30–
32)
Lim
it o
f d
etec
tio
n
–fo
r D
ST≤1
04 CFU
/mL
of
sput
um (o
r clin
ical
ly
rele
vant
spe
cim
ens)
≤102 C
FU/m
L of
spu
tum
(or
clin
ical
ly re
leva
nt s
peci
men
s)A
s a
poin
t of r
efer
ence
for C
FU/m
L, th
e co
rres
pond
ing
smea
r sta
tus
for t
he m
inim
al re
quire
men
t is
a 1+
sm
ear-
posi
tive
spec
imen
and
fo
r the
opt
imal
requ
irem
ent i
s a
smea
r-ne
gativ
e bu
t TB-
posi
tive
spec
imen
(pau
ciba
cilla
ry s
peci
men
s).
Lim
it of
det
ectio
n te
stin
g sh
ould
be
perf
orm
ed, a
s ou
tline
d in
the
US
FDA
’s g
uida
nce
docu
men
t. Fo
r RIF
, IN
H a
nd F
Q, s
mea
r-ne
gativ
e sa
mpl
es s
houl
d al
so b
e de
tect
ed a
s a
min
imum
bec
ause
cur
rent
test
s al
read
y ac
hiev
e th
is.
(33,
34)
An
alyt
ical
se
nsi
tivi
ty f
or
DST
co
mp
ared
w
ith
gen
etic
se
qu
enci
ng
as
the
refe
ren
ce
stan
dar
da
Sens
itivi
ty s
houl
d be
>98
% fo
r det
ectin
g ta
rget
ed S
NPs
fo
r res
ista
nce
whe
n co
mpa
red
with
gen
etic
seq
uenc
ing
For N
GS
tech
nolo
gy-b
ased
ass
ays:
cur
rent
ly, t
here
are
no
clea
r gu
idel
ines
on
the
refe
renc
e st
anda
rd fo
r an
NG
S-ba
sed
diag
nost
ic
assa
y. In
gen
eral
, val
idat
ing
NG
S re
sults
usi
ng d
iffer
ent p
latf
orm
s pl
us d
iffer
ent a
naly
sis
pipe
lines
is c
onsi
dere
d ap
prop
riate
.
(30–
32)
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
14
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Dia
gn
ost
ic
sen
siti
vity
fo
r D
ST
com
par
ed w
ith
p
hen
oty
pic
DST
as
a r
efer
ence
st
and
ard
a
RIF:
>95
% s
ensi
tivity
for
dete
ctio
n of
phe
noty
pic
resi
stan
ce; I
NH
, FQ
: >90
%
sens
itivi
ty fo
r det
ectio
n of
phe
noty
pic
resi
stan
ce;
BDQ
, LZD
, CFZ
, DLM
, pr
etom
anid
, AM
K, P
ZA:
≥80%
sen
sitiv
ity fo
r de
tect
ion
of p
heno
typi
c re
sist
ance
RIF,
INH
, FQ
, BD
Q, L
ZD, C
FZ,
DLM
, pre
tom
anid
, AM
K, P
ZA:
>95%
sen
sitiv
ity fo
r det
ectio
n of
phe
noty
pic
resi
stan
ce
Mod
ellin
g da
ta s
ugge
st th
at fo
r rap
id D
ST to
be
mor
e co
st-e
ffec
tive
than
cul
ture
, on
a cu
rren
tly a
vaila
ble
plat
form
it m
ust a
ttai
n an
ag
greg
ated
sen
sitiv
ity o
f 88%
for a
ll cl
inic
ally
rele
vant
mut
atio
ns. A
lo
wer
sen
sitiv
ity c
ould
be
tole
rate
d fo
r a te
st w
ith h
igh
spec
ifici
ty,
part
icul
arly
if th
e pr
eval
ence
, and
thus
the
pret
est p
roba
bilit
y, is
hi
gh. T
he s
ensi
tivity
ach
ieve
d ag
ains
t a p
heno
typi
c in
tern
atio
nally
re
cogn
ized
refe
renc
e st
anda
rd (e
.g. W
HO
, Clin
ical
Lab
orat
ory
Impr
ovem
ent A
men
dmen
t) w
ill b
e on
ly a
s go
od a
s th
e m
utat
ions
th
at a
re ta
rget
ed (i
.e. e
ven
if al
l kno
wn
mut
atio
ns c
onfe
rrin
g IN
H
resi
stan
ce a
re d
etec
ted
with
100
% s
ensi
tivity
whe
n co
mpa
red
with
a
sequ
enci
ng re
fere
nce
stan
dard
, 100
% s
ensi
tivity
can
not b
e ac
hiev
ed
agai
nst a
phe
noty
pic
refe
renc
e st
anda
rd b
ecau
se th
e kn
owle
dge
of
all m
olec
ular
targ
ets
that
con
fer r
esis
tanc
e is
inco
mpl
ete)
.
Freq
uenc
y of
mut
atio
ns a
t diff
eren
t dru
g-re
sist
ant l
oci m
ay v
ary
depe
ndin
g on
var
ious
fact
ors
(e.g
. geo
grap
hica
l reg
ion,
loca
l ep
idem
iolo
gy a
nd o
utbr
eaks
); th
us, i
mpl
emen
tatio
n of
mol
ecul
ar
assa
ys s
houl
d ca
refu
lly c
onsi
der t
he lo
cal e
pide
mio
logy
in o
rder
to
achi
eve
the
requ
ired
sens
itivi
ty.
(30–
32)
An
alyt
ical
sp
ecifi
city
fo
r D
ST c
om
par
ed
wit
h g
enet
ic
seq
uen
cin
g a
s th
e re
fere
nce
st
and
ard
a
Spec
ifici
ty s
houl
d be
≥98
% fo
r any
ant
i-TB
agen
t fo
r whi
ch th
e te
st is
abl
e to
iden
tify
resi
stan
ce w
hen
com
pare
d w
ith g
enet
ic s
eque
ncin
g as
the
refe
renc
e st
anda
rd
If al
tern
ativ
e re
gim
ens
are
avai
labl
e, e
ffec
tive,
saf
e an
d no
t too
cu
mbe
rsom
e, th
en a
low
er P
PV m
ight
be
tole
rate
d.
Beca
use
the
pret
est p
roba
bilit
y is
low
whe
n in
divi
dual
s pr
esen
ting
with
out a
ny a
dditi
onal
risk
fact
ors
are
test
ed in
set
tings
with
a
low
pre
vale
nce
of re
sist
ance
, the
spe
cific
ity m
ust b
e ve
ry h
igh.
For
ex
ampl
e, if
the
prev
alen
ce o
f res
ista
nce
is a
bout
3%
acc
ordi
ng to
su
rvei
llanc
e da
ta, t
hen
a sp
ecifi
city
of 9
9% re
sults
in a
PPV
of o
nly
74%
. A v
ery
high
spe
cific
ity (e
.g. ≥
99.7
%) i
s th
us n
eces
sary
to re
ach
a PP
V o
f >90
%. I
f the
pre
vale
nce
of re
sist
ance
is ≥
20%
(e.g
. whe
n re
sist
ance
to R
IF is
use
d as
an
indi
cato
r or w
hen
test
ing
is o
nly
done
in
hig
h-ris
k pa
tient
s), a
spe
cific
ity o
f >97
% is
suffi
cien
t to
achi
eve
a PP
V o
f 90%
.
Som
e m
utat
ions
con
ferr
ing
resi
stan
ce a
re s
yste
mat
ical
ly m
isse
d
by c
urre
nt p
heno
typi
c re
fere
nce
stan
dard
met
hods
, and
som
e m
utat
ions
are
not
ass
ocia
ted
with
phe
noty
pic
resi
stan
ce (3
5).
(36,
37)
3 TPP: next-generation DST at peripheral centres 15
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Dia
gn
ost
ic
spec
ifici
ty f
or
DST
co
mp
ared
wit
h
ph
eno
typ
ic D
ST
as a
ref
eren
ce
stan
dar
da
Spec
ifici
ty fo
r mut
atio
ns in
clud
ed fo
r any
ant
i-TB
agen
t fo
r whi
ch th
e te
st c
an id
entif
y re
sist
ance
sho
uld
be ≥
98%
w
hen
com
pare
d w
ith th
e ph
enot
ypic
refe
renc
e st
anda
rd
reco
mm
ende
d fo
r eac
h an
ti-TB
age
nt
The
estim
ates
of s
peci
ficity
for m
olec
ular
test
s in
com
paris
on w
ith
phen
otyp
ic te
stin
g as
a re
fere
nce
stan
dard
mig
ht b
e fa
lsel
y lo
w
beca
use
the
refe
renc
e st
anda
rd h
as li
mite
d se
nsiti
vity
. The
refo
re, i
t is
impo
rtan
t to
use
the
optim
ized
qua
lity-
assu
red
phen
otyp
ic re
fere
nce
stan
dard
for a
dru
g in
com
paris
on.
Som
e m
utat
ions
con
ferr
ing
resi
stan
ce a
re s
yste
mat
ical
ly m
isse
d
by c
urre
nt p
heno
typi
c re
fere
nce
stan
dard
met
hods
, and
som
e m
utat
ions
are
not
ass
ocia
ted
with
phe
noty
pic
resi
stan
ce (3
5).
(30–
32)
Lim
it o
f d
etec
tio
n
of
min
or
vari
ants
≤20%
(i.e
. 20
resi
stan
t ba
cter
ia o
ut o
f 100
)≤3
% (i
.e. f
ewer
than
3
resi
stan
t bac
teria
out
of 1
00)
This
par
amet
er is
hig
hly
depe
nden
t on
the
baci
llary
load
. Clin
ical
re
leva
nce
of m
inor
var
iant
s is
not
fully
und
erst
ood
yet.
An
alyt
ical
sp
ecifi
city
fo
r TB
d
etec
tio
n
No
cros
s-re
activ
ity w
ith o
ther
org
anis
ms
incl
udin
g no
ntub
ercu
lous
myc
obac
teria
.
Ind
eter
min
ate
resu
lts
du
rin
g
DST
a
<10%
<3%
Inde
term
inat
e: in
conc
lusi
ve re
sults
that
are
val
id –
that
is, w
here
an
adeq
uate
test
resu
lt ha
s be
en o
btai
ned,
but
the
resu
lt is
not
cle
arly
po
sitiv
e or
neg
ativ
e.
Inva
lid: i
ncon
clus
ive
resu
lts th
at a
re in
valid
– th
at is
, the
key
di
agno
stic
feat
ure
cann
ot b
e in
terp
rete
d or
the
actu
al re
sult
is
mis
sing
.
Rep
rod
uci
bili
ty
for
DST
Inte
r-as
say
coeffi
cien
t of v
aria
nce
shou
ld b
e ≤1
0% a
t th
e hi
gh a
nd lo
w e
xtre
mes
of t
he a
ssay
for D
STTh
is a
pplie
s if
the
quan
titat
ive
outc
omes
of a
test
are
mea
sura
ble
(e.g
. lim
it of
det
ectio
n an
d cy
cle
thre
shol
d va
lues
).
Inte
rfer
ing
su
bst
ance
sN
o in
terf
eren
ce
shou
ld b
e ca
used
by
thos
e su
bsta
nces
kn
own
to o
ccur
in th
e hu
man
resp
irato
ry
and
pulm
onar
y tr
acts
, in
clud
ing
bloo
d th
at
coul
d po
tent
ially
inhi
bit
an a
ssay
(e.g
. a P
CR
reac
tion)
, and
sub
stan
ces
used
to tr
eat o
r alle
viat
e re
spira
tory
dis
ease
or
sym
ptom
s
No
inte
rfer
ence
sho
uld
be
caus
ed b
y di
ffer
ent m
ater
ial
for c
olle
ctin
g sw
ab-b
ased
an
d al
tern
ativ
e pa
edia
tric
sp
ecim
ens
(e.g
. sto
ol)
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
16
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Trea
tmen
t m
on
ito
rin
g
cap
abili
ty
Not
requ
ired
Pref
erab
le
A te
st th
at c
an re
plac
e sm
ear m
icro
scop
y fo
r tre
atm
ent m
onito
ring
(e.g
. by
dete
ctin
g vi
able
bac
teria
) is
mor
e lik
ely
to b
e ad
opte
d an
d
to c
ompl
etel
y re
plac
e sm
ear m
icro
scop
y; th
us, i
t wou
ld a
lso
have
a
larg
er m
arke
t.
Mu
ltiu
se p
latf
orm
Yes
(ach
ieva
ble)
Yes
(dem
onst
rate
d)A
ny te
chno
logy
ent
erin
g th
is m
arke
t sho
uld
be a
ble
to d
iagn
ose
rele
vant
dis
ease
s ot
her t
han
TB. T
he d
isea
ses
to b
e ta
rget
ed s
houl
d
be th
ose
amon
g th
e W
HO
list
of p
over
ty-r
elat
ed d
isea
ses;
for
exam
ple,
com
mun
icab
le d
isea
ses
such
as
SARS
-CoV
2, H
IV, m
alar
ia,
hepa
titis
C v
irus
infe
ctio
n an
d an
timic
robi
al re
sist
ance
act
iviti
es (i
.e.
prio
rity
path
ogen
s). O
f cou
rse,
pro
per i
mpl
emen
tatio
n st
rate
gies
sh
ould
be
in p
lace
to s
elec
t whi
ch a
dditi
onal
dis
ease
s sh
ould
be
targ
eted
alo
ng w
ith T
B in
any
giv
en s
ettin
g. Q
ualit
y-as
sura
nce
proc
edur
es w
ould
nee
d to
be
perf
orm
ed fo
r eac
h di
seas
e in
clud
ed in
th
e pl
atfo
rm; t
hus,
mul
tiple
x te
stin
g or
the
abili
ty to
use
a p
latf
orm
to
per
form
diff
eren
t tes
ts w
ill p
roba
bly
incr
ease
the
acce
ptab
ility
of
the
new
ass
ay.
Op
erat
ion
al c
har
acte
rist
ics
Sam
ple
typ
eSp
utum
and
oth
er
clin
ical
ly re
leva
nt
spec
imen
s fo
r TB,
in
clud
ing
(but
not
lim
ited
to
) gas
tric
asp
irate
, in
duce
d sp
utum
, na
soph
aryn
geal
asp
irate
, an
d st
ool.
Unp
roce
ssed
spu
tum
and
ad
ditio
nal c
linic
ally
rele
vant
sp
ecim
ens
for T
B or
oth
er
targ
eted
dis
ease
s (s
ee
“Mul
tiuse
pla
tfor
m”)
Add
ition
al c
linic
ally
rele
vant
spe
cim
ens
for T
B co
uld
be a
ltern
ativ
e sa
mpl
e ty
pes
that
can
eas
ily b
e co
llect
ed (e
spec
ially
for c
ateg
orie
s of
pat
ient
s w
here
spu
tum
is d
ifficu
lt to
obt
ain)
, and
spe
cim
ens
for
extr
apul
mon
ary
TB. T
here
sho
uld
be m
inim
al s
peci
men
pro
cess
ing
invo
lved
, if r
equi
red.
Sam
ple
vo
lum
e p
roce
ssed
by
the
test
0.5
–2 m
L 0.
1–10
mL
The
low
est v
olum
e po
ssib
le fo
r all
type
s of
sam
ples
idea
lly w
ould
be
0.1
mL,
esp
ecia
lly s
ince
HIV
-pos
itive
pat
ient
s an
d pa
edia
tric
po
pula
tions
may
hav
e di
fficu
lty p
rovi
ding
a s
ampl
e. S
imila
rly, i
f a
high
er v
olum
e is
ava
ilabl
e, th
e te
st s
houl
d be
abl
e to
use
that
hig
her
volu
me
if do
ing
so w
ould
incr
ease
sen
sitiv
ity. T
his
is e
spec
ially
re
leva
nt fo
r ext
rapu
lmon
ary
sam
ples
, whi
ch m
ay n
eed
an a
dditi
onal
3 TPP: next-generation DST at peripheral centres 17
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
conc
entr
atio
n st
ep b
efor
e te
stin
g. H
ow
ever
, in
bo
th h
igh
an
d
low
vo
lum
e sp
ecim
ens,
per
form
ance
sh
ou
ld n
ot
com
e at
th
e ex
pen
se o
f d
ecre
ased
sen
siti
vity
. At a
min
imum
, the
test
sho
uld
be
abl
e to
mee
t per
form
ance
requ
irem
ents
with
clin
ical
ly re
leva
nt
spec
imen
s w
ith v
olum
es o
f 0.5
–2 m
L, a
s us
ed b
y cu
rren
t tes
ts. T
he
test
sho
uld
need
onl
y 1
sam
ple.
Any
follo
w-o
n st
eps
or re
actio
ns
shou
ld n
ot re
quire
add
ition
al s
ampl
es.
Man
ual
p
rep
arat
ion
o
f sa
mp
les
(ste
ps
nee
ded
af
ter
ob
tain
ing
sa
mp
le)a
≤5 s
teps
≤1 s
tep
Ther
e sh
ould
be
no n
eed
for p
reci
se v
olum
e co
ntro
l and
pre
cise
tim
ing.
Onl
y te
sts
that
requ
ire b
asic
and
sim
ple
labo
rato
ry s
kills
ar
e su
ited
to p
erip
hera
l lev
el c
entr
es; n
o sp
ecifi
c an
alyt
ical
pr
oced
ures
bas
ed o
n ad
ditio
nal i
nstr
umen
ts s
houl
d be
requ
ired
(e
.g. D
NA
qua
ntifi
catio
n, g
el e
lect
roph
ores
is a
nd s
eria
l dilu
tions
). Th
e pr
oced
ure
shou
ld ta
ke a
dvan
tage
of a
utom
atio
n as
muc
h as
pos
sibl
e.
(18,
21)
Rea
gen
t in
teg
rati
on
No
spec
ific
indi
catio
ns,
but r
efer
to re
agen
t kit
st
orag
e an
d st
abili
ty fo
r re
stric
tions
All
reag
ents
sho
uld
be
cont
aine
d in
a s
ingl
e de
vice
Tim
e to
res
ult
a<6
hou
rs fo
r det
ectio
n an
d D
ST; a
chie
ve n
ext-
day
trea
tmen
t dec
isio
ns
<30
min
utes
for d
etec
tion
and
D
ST (<
2 ho
urs
acce
ptab
le);
achi
eve
sam
e-da
y tr
eatm
ent
deci
sion
s
The
need
for r
apid
turn
arou
nd is
aff
ecte
d by
thro
ughp
ut c
apac
ity
and
dura
tion
of te
stin
g. R
apid
turn
arou
nd ti
me
is c
ritic
al to
redu
cing
pr
etre
atm
ent l
oss
to fo
llow
-up.
A s
imila
r out
com
e ca
n be
ach
ieve
d in
di
ffer
ent w
ays;
for e
xam
ple,
thro
ugh
mat
chin
g of
mul
tiple
sam
ples
fo
r the
sam
e te
sts,
mul
tiple
sam
ples
for d
iffer
ent t
ests
or u
sing
ra
ndom
acc
ess
for t
estin
g. T
he ti
me-
to-r
esul
t (de
fined
as
time
for
sam
ple
proc
essi
ng th
roug
h te
st c
ompl
etio
n, e
xclu
ding
sto
ring
time
for b
atch
ing)
is p
roba
bly
the
mos
t im
port
ant p
aram
eter
bec
ause
ex
tend
ing
the
wai
t tim
e fo
r too
long
may
resu
lt in
pat
ient
loss
to
follo
w-u
p. T
he m
inim
al c
riter
ion
has
been
incr
ease
d, c
onsi
derin
g ne
wer
tech
nolo
gies
suc
h as
NG
S th
at a
re c
urre
ntly
una
ble
to m
eet
the
prev
ious
crit
erio
n of
<2
hour
s bu
t wou
ld p
rovi
de D
ST to
mul
tiple
dr
ugs
sim
ulta
neou
sly.
In c
omin
g ye
ars,
all
tech
nolo
gies
sho
uld
be
able
to p
rodu
ce te
st re
sults
in <
6 ho
urs,
whi
ch is
crit
ical
bec
ause
pe
riphe
ral s
ettin
gs u
sual
ly k
eep
6–8
hour
wor
k da
ys. F
inal
ly, a
s pa
tient
s ar
e un
likel
y to
wai
t lon
ger t
han
30 m
inut
es fo
r a te
st re
sult,
an
y w
ait l
onge
r tha
n th
at w
ill ty
pica
lly n
eces
sita
te re
sults
bei
ng
deliv
ered
the
follo
win
g da
y.
(38,
39)
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
18
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Dai
ly t
hro
ug
hp
ut
≥10
test
s≥2
5tes
tsTh
e da
ily th
roug
hput
nee
ded
in m
ost p
erip
hera
l cen
tres
is <
10
test
s pe
r day
. Dai
ly th
roug
hput
requ
irem
ents
mus
t be
cons
ider
ed
with
tim
e-to
-res
ult a
nd s
ampl
e ca
paci
ty in
min
d, b
ecau
se th
ese
char
acte
ristic
s ar
e al
l hig
hly
inte
rrel
ated
.
Sam
ple
cap
acit
y an
d t
hro
ug
hp
ut
Batc
hing
sho
uld
be
poss
ible
Mul
tiple
sam
ples
sho
uld
be
able
to b
e te
sted
at t
he s
ame
time;
rand
om a
cces
s sh
ould
be
poss
ible
Idea
lly, 1
sam
ple
shou
ld n
ot o
ccup
y th
e in
stru
men
t with
out t
hat
inst
rum
ent s
till b
eing
abl
e to
pro
cess
oth
er s
ampl
es (i
.e. r
ando
m
acce
ss o
r par
alle
l ana
lyse
s sh
ould
be
poss
ible
). If
the
plat
form
is
mul
tiple
xed,
then
runn
ing
diff
eren
t ass
ays
at th
e sa
me
time
shou
ld
be fe
asib
le.
Wal
k-aw
ay
op
erat
ion
No
mor
e th
an 1
ste
p of
op
erat
or in
terv
entio
n sh
ould
be
need
ed o
nce
the
sam
ple
has
been
pl
aced
into
or o
n th
e sy
stem
Ther
e sh
ould
not
be
a ne
ed fo
r op
erat
or in
terv
entio
n on
ce th
e sa
mpl
e ha
s be
en p
lace
d in
to
or o
n th
e in
stru
men
t
Onc
e th
e sa
mpl
e ha
s be
en lo
aded
into
an
inst
rum
ent,
then
furt
her
oper
ator
inte
rven
tion
shou
ld n
ot b
e re
quire
d un
til d
etec
tion
has
occu
rred
. Thi
s ch
arac
teris
tic is
rela
ted
to th
e ch
arac
teris
tics
for
sam
ple
prep
arat
ion
and
assa
y pr
oces
sing
(i.e
. the
ste
ps n
eedi
ng to
be
com
plet
ed a
fter
a s
ampl
e ha
s be
en o
btai
ned)
.
Bio
safe
tyRe
quire
men
ts a
re s
imila
r to
thos
e fo
r sm
ear m
icro
scop
y (lo
w-r
isk
TB la
bora
torie
s)To
be
feas
ible
to im
plem
ent a
t the
per
iphe
ral l
evel
, min
imal
in
fras
truc
ture
for b
iosa
fety
sho
uld
be re
quire
d. B
iosa
fety
cab
inet
s ar
e un
likel
y to
be
avai
labl
e. T
he te
chno
logy
mus
t pos
e a
low
saf
ety
risk
(com
para
ble
to th
at o
f mic
rosc
opy)
to h
ealth
wor
kers
and
oth
ers
with
in th
e fa
cilit
y.
Con
sult
the
min
imum
bio
safe
ty re
quire
men
ts a
s de
scrib
ed in
WH
O’s
Tu
ber
culo
sis
lab
orat
ory
bio
safe
ty m
anua
l (40
).
(41,
42)
Was
te d
isp
osa
l –
solid
Shou
ld re
quire
no
mor
e th
an c
urre
nt W
HO
-en
dors
ed T
B as
says
at t
he
perip
hera
l lev
el
Shou
ld re
quire
no
mor
e th
an
curr
ent r
apid
mol
ecul
ar te
sts
for T
B
Reus
able
, rec
ycla
ble,
or
non-
plas
tic a
ltern
ativ
es to
di
spos
able
mat
eria
ls
Furt
her i
nfor
mat
ion
is p
rovi
ded
in W
HO
’s T
uber
culo
sis
lab
orat
ory
bio
safe
ty m
anua
l (40
). In
crea
sing
the
amou
nt o
f was
te g
ener
ated
in
com
paris
on to
that
pro
duce
d by
sm
ear m
icro
scop
y sh
ould
idea
lly b
e av
oide
d. E
nviro
nmen
tally
frie
ndly
, sus
tain
able
pac
kagi
ng m
inim
izin
g th
e en
viro
nmen
tal i
mpa
ct o
f pac
kagi
ng s
houl
d be
con
side
red
for t
he
prod
uct’
s en
tire
lifec
ycle
.
(40)
Was
te d
isp
osa
l –
infe
ctio
us
Sim
ilar t
o th
ose
for s
mea
r mic
rosc
opy
(low
-ris
k TB
labo
rato
ries)
Low
-ris
k TB
labo
rato
ries
as d
escr
ibed
in W
HO
’s T
uber
culo
sis
lab
orat
ory
bio
safe
ty m
anua
l (40
). Th
e ba
selin
e bi
osaf
ety
risk
for
man
agin
g in
fect
ious
was
te a
t the
per
iphe
ral l
evel
sho
uld
not
be in
crea
sed.
(40)
3 TPP: next-generation DST at peripheral centres 19
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Inst
rum
ent
For i
nstr
umen
t-ba
sed
te
sts,
bui
ld o
n a
mod
ular
co
ncep
t allo
win
g ta
ilorin
g to
mee
t nee
ds
and
upgr
ade
addi
tiona
l fu
nctio
nalit
ies
at a
ny ti
me
For i
nstr
umen
t-ba
sed
test
s,
this
idea
lly w
ould
be
a si
ngle
in
tegr
ated
sys
tem
that
is
mod
ular
to a
llow
thro
ughp
ut
to b
e in
crea
sed
if ne
cess
ary
This
cha
ract
eris
tic o
nly
appl
ies
to in
stru
men
t-ba
sed
test
s. It
is n
ot a
re
com
men
datio
n th
at a
test
be
inst
rum
ent-
base
d. Id
eally
, a s
ingl
e de
vice
is p
refe
rred
but
mod
ular
sol
utio
ns w
ould
be
acce
ptab
le (e
.g.
for s
epar
ate
sam
ple
proc
essi
ng a
nd d
etec
tion)
.
Pow
er
req
uir
emen
tsa
Cap
able
of r
unni
ng o
n st
anda
rd e
lect
ricity
plu
s an
ad
hoc
cert
ified
UPS
un
it de
liver
ed w
ith th
e sy
stem
to e
nabl
e a
cycl
e to
be
com
plet
ed in
cas
e of
a p
ower
out
age;
a
circ
uit p
rote
ctor
mus
t be
inte
grat
ed w
ithin
the
syst
em; t
he U
PS s
houl
d
be in
tegr
ated
with
in th
e sy
stem
whe
re p
ossi
ble;
an
d th
e sy
stem
sho
uld
be
com
patib
le fo
r sw
itchi
ng
to a
bat
tery
-ope
rate
d
devi
ce w
ith th
e ab
ility
to
run
for a
t lea
st 1
day
on
the
batt
ery
and
to b
e re
char
ged
Cap
able
of r
unni
ng o
n st
anda
rd e
lect
ricity
plu
s an
ad
hoc
cer
tified
UPS
uni
t de
liver
ed w
ith th
e sy
stem
to
enab
le a
cyc
le to
be
com
plet
ed
in c
ase
of a
pow
er o
utag
e;
the
UPS
and
circ
uit p
rote
ctor
m
ust b
e in
tegr
ated
with
in th
e sy
stem
; and
the
syst
em s
houl
d
be c
ompa
tible
for s
witc
hing
to
a b
atte
ry-o
pera
ted
devi
ce
with
the
abili
ty to
run
for 1
da
y on
the
batt
ery
and
to b
e re
char
ged
(e.g
. sol
ar-p
ower
ed)
Con
tinuo
us p
ower
is n
ot a
lway
s av
aila
ble
at th
e le
vel o
f a p
erip
hera
l ce
ntre
, and
cur
rent
exp
erie
nce
with
the
use
of e
lect
rical
dev
ices
in
sett
ings
whe
re p
ower
sup
ply
can
be in
term
itten
t sho
wed
cha
lleng
es
in fi
ndin
g ap
prop
riate
UPS
sol
utio
ns s
uita
ble
for a
giv
en in
stru
men
t. U
PS s
houl
d co
me
toge
ther
with
the
inst
rum
ent,
and
man
ufac
ture
rs
mus
t pro
vide
UPS
cap
able
of m
eetin
g th
e go
al o
f ens
urin
g en
ough
po
wer
for a
cyc
le to
be
com
plet
ed. A
lso,
in th
e op
timal
situ
atio
n,
it sh
ould
be
poss
ible
to s
witc
h th
e sy
stem
into
a b
atte
ry-o
pera
ted
de
vice
that
can
be
rech
arge
d, p
ossi
bly
usin
g so
lar p
ower
(or a
noth
er
rene
wab
le s
ourc
e of
ene
rgy
whe
re a
pplic
able
).
(18,
21)
Mai
nte
nan
ce a
nd
ca
libra
tio
na
Prev
entiv
e m
aint
enan
ce
shou
ld n
ot b
e ne
eded
m
ore
than
onc
e a
year
Use
rs s
houl
d be
abl
e to
m
onito
r the
mac
hine
st
atus
inde
pend
ently
fr
om m
anuf
actu
rers
’ in
terv
entio
n by
usi
ng
appr
opria
te in
tern
al
Prev
entiv
e m
aint
enan
ce
shou
ld n
ot b
e ne
eded
mor
e th
an o
nce
ever
y 2
year
s
Use
rs s
houl
d be
abl
e to
m
onito
r the
mac
hine
st
atus
inde
pend
ently
from
m
anuf
actu
rers
’ int
erve
ntio
n by
usi
ng a
ppro
pria
te in
tern
al
or e
xter
nal c
ontr
ols;
resu
lts
Mai
nten
ance
and
cal
ibra
tion
repr
esen
t tw
o ch
alle
ngin
g po
ints
for
any
devi
ce to
be
plac
ed a
t the
per
iphe
ral l
evel
. A m
aint
enan
ce a
lert
is
nece
ssar
y to
ens
ure
prop
er fu
nctio
ning
in s
ettin
gs w
here
it is
unl
ikel
y th
at th
e sa
me
pers
on w
ill a
lway
s ha
ndle
the
devi
ce a
nd th
at re
cord
s w
ill b
e ke
pt a
bout
the
dura
tion
of u
se.
It is
ess
entia
l tha
t onl
y si
mpl
e to
ols
and
min
imal
exp
ertis
e ar
e ne
cess
ary
to p
erfo
rm m
aint
enan
ce, g
iven
the
num
ber o
f dev
ices
that
ar
e lik
ely
to b
e us
ed; a
dditi
onal
ly, s
ervi
ce v
isits
are
unl
ikel
y to
be
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
20
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
or e
xter
nal c
ontr
ols;
re
sults
for s
uch
cont
rols
can
be
shar
ed
with
man
ufac
ture
rs
or a
ppro
pria
te
cont
rol b
odie
s to
sc
hedu
le a
ppro
pria
te
on-d
eman
d in
terv
entio
n (m
aint
enan
ce o
r ca
libra
tion)
; an
aler
t sh
ould
be
incl
uded
to
indi
cate
whe
n m
aint
enan
ce is
ne
eded
acc
ordi
ng
to m
anuf
actu
rer’
s in
dica
tions
; sof
twar
e up
date
s sh
ould
be
prov
ided
rem
otel
y
for s
uch
cont
rols
can
be
shar
ed w
ith m
anuf
actu
rers
or
app
ropr
iate
con
trol
bod
ies
to s
ched
ule
appr
opria
te
on-d
eman
d in
terv
entio
n (m
aint
enan
ce o
r cal
ibra
tion)
; an
ale
rt s
houl
d be
incl
uded
to
indi
cate
whe
n m
aint
enan
ce
is n
eede
d ac
cord
ing
to
man
ufac
ture
r’s
indi
catio
ns;
soft
war
e up
date
s sh
ould
be
prov
ided
rem
otel
y
feas
ible
out
side
of u
rban
set
tings
. The
cos
t of m
aint
enan
ce s
houl
d
be lo
w a
nd s
ervi
ce a
gree
men
ts s
houl
d be
incl
uded
in th
e co
st.
Dat
a an
alys
isEx
port
ed d
ata
shou
ld b
e an
alys
able
on
a se
para
te
or n
etw
orke
d PC
Dat
a an
alys
is s
houl
d be
in
tegr
ated
into
the
devi
ce; a
PC
sho
uld
not b
e re
quire
d;
expo
rted
dat
a sh
ould
be
capa
ble
of b
eing
ana
lyse
d on
a
sepa
rate
or n
etw
orke
d PC
Res
ult
d
ocu
men
tati
on
, d
ata
dis
pla
y
An
inte
grat
ed re
sults
sc
reen
and
the
abili
ty
to s
ave
resu
lts s
houl
d
be in
clud
ed; t
he d
evic
e sh
ould
hav
e a
have
a
com
mon
ly-u
sed
in
terf
ace
port
(e.g
USB
or
USB
-c p
ort)
An
inte
grat
ed re
sults
scr
een
and
the
abili
ty to
sav
e an
d
prin
t res
ults
sho
uld
be
incl
uded
; the
dev
ice
shou
ld
have
a c
omm
only
-use
d po
rt
(e.g
USB
or U
SB-c
por
t)
Resu
lts s
houl
d be
sim
ple
to in
terp
ret (
e.g.
pos
itive
ver
sus
nega
tive
for T
B de
tect
ion,
or p
rese
nt v
ersu
s ab
sent
for d
rug
resi
stan
ce).
Info
rmat
ion
that
wou
ld a
llow
a m
ore
deta
iled
inte
rpre
tatio
n of
re
sults
sho
uld
be a
vaila
ble
(e.g
. inf
orm
atio
n on
the
mut
atio
ns
dete
cted
) for
sur
veill
ance
pur
pose
s or
mor
e di
ffer
entia
ted
clin
ical
de
cisi
on-m
akin
g; h
owev
er, i
t sho
uld
be p
ossi
ble
to h
ide
this
in
form
atio
n if
nece
ssar
y.
3 TPP: next-generation DST at peripheral centres 21
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Reg
ula
tory
re
qu
irem
ents
Man
ufac
turin
g of
the
assa
y an
d sy
stem
sho
uld
com
ply
with
ISO
1348
5 as
wel
l as
ISO
149
71 o
r hig
her s
tand
ards
or
regu
latio
ns, a
nd c
ompl
y w
ith IS
O IE
C 6
2304
(Med
ical
D
evic
e D
ata
Syst
ems)
; the
man
ufac
turin
g fa
cilit
y sh
ould
be
ass
esse
d at
a h
igh-
risk
clas
sific
atio
n an
d ce
rtifi
ed fo
r us
e by
one
of t
he re
gula
tory
aut
horit
ies
of th
e fo
undi
ng
mem
bers
of t
he In
tern
atio
nal M
edic
al D
evic
e Re
gula
tors
Fo
rum
(for
mer
ly k
now
n as
Glo
bal H
arm
oniz
atio
n Ta
sk
Forc
e); t
he a
ssay
mus
t be
regi
ster
ed fo
r in
vitr
o di
agno
stic
us
e
(43,
44)
Dat
a ex
po
rt
(co
nn
ecti
vity
an
d
inte
r-o
per
abili
ty)
Inte
grat
ed a
bilit
y fo
r al
l dat
a to
be
secu
rely
ex
port
ed fr
om th
e de
vice
in
a u
ser-
frie
ndly
form
at
(incl
udin
g da
ta o
n us
e of
the
devi
ce, e
rror
rate
s or
rate
s of
inva
lid te
sts,
an
d no
n-pe
rson
aliz
ed
resu
lts) o
ver a
USB
por
t;
Blue
toot
h co
nnec
tivity
sh
ould
als
o be
ava
ilabl
e,
and
it sh
ould
be
poss
ible
to
impo
rt d
ata
(e.g
. so
ftw
are
for u
pdat
ing
inte
rpre
tatio
n ru
les
or d
atab
ases
)
All
data
sho
uld
be a
ble
to b
e se
cure
ly e
xpor
ted
(incl
udin
g da
ta o
n th
e us
e of
the
devi
ce,
erro
r rat
es a
nd ra
tes
of in
valid
te
sts,
and
per
sona
lized
, pr
otec
ted
resu
lts) o
ver a
USB
po
rt a
nd n
etw
ork;
net
wor
k co
nnec
tivity
sho
uld
be
avai
labl
e th
roug
h an
eth
erne
t, w
i-fi a
nd G
SM/U
MTS
mob
ile
broa
dban
d m
odem
, or a
co
mbi
natio
n of
thes
e; re
sults
sh
ould
be
enco
ded
usin
g a
docu
men
ted
stan
dard
(e.g
. H
L7) a
nd b
e fo
rmat
ted
as
JSO
N te
xt; J
SON
dat
a
Mob
ile p
hone
cap
acity
is fr
eque
ntly
ava
ilabl
e ev
en a
t the
leve
l of
perip
hera
l cen
tres
. Thi
s co
uld
be le
vera
ged
for d
ata
expo
rt, q
ualit
y co
ntro
l, su
pply
-cha
in m
anag
emen
t and
sur
veill
ance
. As
the
syst
ems
will
be
impl
emen
ted
in p
erip
hera
l cen
tres
, dat
a co
nnec
tivity
sho
uld
be
ada
pted
to th
e ac
tual
situ
atio
n (d
ata
tran
sfer
can
not r
ely
on h
igh-
spee
d In
tern
et c
onne
ctiv
ity, a
nd th
e fo
rmat
of t
he d
ata
shou
ld b
e ad
apte
d ac
cord
ingl
y).
Dat
a ex
port
mus
t inc
lude
raw
dat
a an
d in
terp
rete
d re
sults
, al
low
ing
furt
her r
e-an
alys
is in
cas
e of
upd
ated
inte
rpre
tatio
n gu
idel
ines
. Con
nect
ivity
sol
utio
ns a
ssoc
iate
d w
ith in
stru
men
ts
shou
ld b
e no
npro
prie
tary
, so
that
ext
erna
l sol
utio
ns c
an b
e in
corp
orat
ed; w
here
clo
ud-b
ased
sto
rage
sol
utio
ns (o
r thi
rd-p
arty
ho
stin
g) a
re in
clud
ed, t
hey
shou
ld b
e co
mpl
iant
with
cou
ntry
re
gula
tions
and
mus
t be
able
to b
e tu
rned
off
with
out a
ffec
ting
inst
rum
ent f
unct
iona
lity.
(41,
45,4
6)
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
22
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
shou
ld b
e tr
ansm
itted
th
roug
h H
TTP(
S) to
a lo
cal o
r re
mot
e se
rver
as
resu
lts a
re
gene
rate
d; re
sults
sho
uld
be
stor
ed lo
cally
and
que
ued
du
ring
netw
ork
inte
rrup
tions
to
be
sent
as
a ba
tch
whe
n co
nnec
tivity
is re
stor
ed;
Blue
toot
h co
nnec
tivity
sho
uld
al
so b
e av
aila
ble;
and
it s
houl
d
be p
ossi
ble
to im
port
dat
a (e
.g. s
oftw
are
for u
pdat
ing
inte
rpre
tatio
n ru
les
data
base
s)
Elec
tro
nic
s an
d
soft
war
eSh
ould
be
inte
grat
ed in
to th
e in
stru
men
tIf
an e
xter
nal d
evic
e (e
.g. a
sep
arat
e PC
, tab
let o
r mob
ile) i
s ne
eded
, it
will
pro
babl
y lim
it th
e ab
ility
to u
pdat
e so
ftw
are,
bec
ause
not
all
perip
hera
l cen
tres
hav
e st
aff w
ith th
e sk
ills
need
ed to
ope
rate
a P
C.
Furt
herm
ore,
thef
t or m
ispl
acem
ent c
an b
e an
issu
e, a
nd s
epar
ate
PCs
shou
ld h
ave
a m
echa
nism
for s
ecur
e pl
acem
ent.
Op
erat
ing
en
viro
nm
ent,
te
mp
erat
ure
an
d
hu
mid
ity
leve
l
Betw
een
+5 °
C a
nd
+40
°C w
ith u
p to
70%
hu
mid
ity.
It is
impo
rtan
t to
adeq
uate
ly p
rote
ct
optic
s fr
om d
ust i
n th
ese
sett
ings
Betw
een
+5 °
C a
nd +
50 °
C
with
up
to 9
0% h
umid
ityH
igh
envi
ronm
enta
l tem
pera
ture
s an
d hi
gh h
umid
ity a
re o
ften
pr
esen
t in
coun
trie
s w
here
TB
is e
ndem
ic. T
ropi
caliz
ed in
stru
men
ts o
r de
vice
s sh
ould
be
avai
labl
e fo
r im
plem
enta
tion
in s
uch
sett
ings
.
(41,
47)
Rea
gen
t ki
t –
tran
spo
rtN
o co
ld c
hain
requ
ired;
sh
ould
be
able
to to
lera
te
stre
ss d
urin
g tr
ansp
ort f
or
at le
ast 7
2 ho
urs
at –
15 °
C
to +
40 °
C
No
cold
cha
in s
houl
d be
re
quire
d; s
houl
d be
abl
e to
to
lera
te s
tres
s du
ring
tran
spor
t fo
r at l
east
72
hour
s at
–15
°C
to
+50
°C
Refr
iger
ated
tran
spor
t is
cost
ly a
nd o
ften
can
not b
e gu
aran
teed
fo
r the
ent
ire tr
ansp
orta
tion
proc
ess.
Fre
quen
t del
ays
in tr
ansp
ort
are
com
mon
plac
e.
(18,
21,4
8)
3 TPP: next-generation DST at peripheral centres 23
Ch
arac
teri
stic
Min
imal
req
uir
emen
tsO
pti
mal
req
uir
emen
tsEx
pla
nat
ory
no
tes
Ref
eren
ces
Rea
gen
t ki
t –
sto
rag
e an
d
stab
ility
12 m
onth
s at
+5
°C to
+3
5 °C
with
up
to 7
0%
hum
idity
; sho
uld
be a
ble
to to
lera
te s
tres
s du
ring
tran
spor
t for
at l
east
72
hour
s at
+40
°C
; no
cold
ch
ain
shou
ld b
e re
quire
d
2 ye
ars
at +
5 °C
to +
40 °
C w
ith
up to
90%
hum
idity
; sho
uld
be
abl
e to
tole
rate
str
ess
durin
g tr
ansp
ort f
or a
t lea
st 7
2 ho
urs
at +
50 °
C; n
o co
ld c
hain
sh
ould
be
requ
ired
Hig
h en
viro
nmen
tal t
empe
ratu
res
and
high
hum
idity
are
oft
en
pres
ent i
n co
untr
ies
whe
re T
B is
end
emic
; the
y ar
e es
peci
ally
pr
oble
mat
ic d
urin
g th
e tr
ansp
ort o
f rea
gent
s an
d sy
stem
s. F
or n
ew
prod
ucts
, 12
mon
ths
is a
ccep
tabl
e, b
ecau
se e
vide
nce
to s
uppo
rt a
lo
nger
she
lf lif
e w
ill b
e un
avai
labl
e in
itial
ly.
(41,
47)
Ad
dit
ion
al
sup
plie
s (n
ot
incl
ud
ed in
kit
)
Non
eN
one
Inte
rnal
qu
alit
y co
ntr
ol
Full
cont
rols
for s
ampl
e pr
oces
sing
, am
plifi
catio
n an
d
dete
ctio
n of
TB
and
any
targ
et fo
r det
ectio
n of
resi
stan
ce
shou
ld b
e in
clud
ed; i
nter
nal c
ontr
ols
for a
naly
sis
and
re
port
ing
(e.g
. sof
twar
e ve
rsio
n) s
houl
d be
incl
uded
; a
mon
itor (
rem
ote)
sys
tem
for c
heck
ing
resu
lts o
n th
e co
ntro
ls s
houl
d be
als
o co
nsid
ered
The
syst
em s
houl
d be
com
plia
nt w
ith e
xter
nal c
ontr
ols.
(47,
49)
Trai
nin
g a
nd
ed
uca
tio
n3
days
(or 2
4 w
ork
hour
s)
for s
taff
at t
he le
vel o
f a
labo
rato
ry te
chni
cian
6 w
ork
hour
s fo
r sta
ff a
t th
e le
vel o
f a m
icro
scop
y te
chni
cian
Trai
ning
sho
uld
be d
evel
oped
acc
ordi
ng to
con
tinui
ng e
duca
tion
and
trai
ning
mod
els
and
indi
vidu
aliz
ed tr
aini
ng p
rogr
amm
es, t
o en
sure
that
onl
y pr
oper
ly tr
aine
d, a
ccre
dite
d pe
ople
can
per
form
th
e as
say.
Onl
ine
and
rem
ote
supp
ort s
yste
ms
shou
ld b
e av
aila
ble
for r
etra
inin
g, m
onito
ring
or e
valu
atin
g, a
nd u
pdat
ing
(“re
fres
her”
) tr
aini
ng. A
ll th
e ph
ases
of t
he tr
aini
ng s
houl
d be
pro
perly
do
cum
ente
d. A
ll tr
aini
ng a
nd in
stru
ctio
ns fo
r use
mus
t be
fully
av
aila
ble
at le
ast i
n En
glis
h, a
nd id
eally
in m
ultip
le o
ther
lang
uage
s as
wel
l.
AM
K: a
mik
acin
; BD
Q: b
edaq
uilin
e; C
FU: c
olon
y fo
rmin
g un
it; C
FZ: c
lofa
zim
ine;
DC
S: D
-cyc
lose
rine;
DLM
: del
aman
id; D
NA
: deo
xyrib
onuc
leic
aci
d; D
R-TB
: dru
g-re
sist
ant T
B; D
ST: d
rug
susc
eptib
ility
test
ing;
FD
A: F
ood
an
d D
rug
Adm
inis
trat
ion;
FQ
: fluo
roqu
inol
ones
; GSM
: Glo
bal S
yste
m f
or M
obile
Com
mun
icat
ions
; HIV
: hum
an im
mun
odefi
cien
cy v
irus;
htt
p: h
yper
text
tra
nsfe
r pr
otoc
ol; I
NH
: iso
niaz
id; J
SON
: Jav
aScr
ipt
Obj
ect
Not
atio
n; L
FX: l
evofl
oxac
in; L
MIC
: low
- and
mid
dle-
inco
me
coun
trie
s; L
ZD: l
inez
olid
; MD
R/RR
-TB:
mul
tidru
g-re
sist
ant o
r rifa
mpi
cin-
resi
stan
t TB;
MFX
: mox
iflox
acin
; NG
O: n
ongo
vern
men
tal o
rgan
izat
ion;
NG
S: n
ext-
gene
ratio
n se
quen
cing
; PC
: per
sona
l com
pute
r; P
a: p
reto
man
id; P
CR:
pol
ymer
ase
chai
n re
actio
n; P
PV: p
ositi
ve p
redi
ctiv
e va
lue;
PZA
: pyr
azin
amid
e; R
IF: r
ifam
pici
n; S
ARS
-CoV
2: s
ever
e ac
ute
resp
irato
ry s
yndr
ome
coro
navi
rus
2; S
NP:
sin
gle
nucl
eotid
e po
lym
orph
ism
; TB:
tub
ercu
losi
s; T
PP: t
arge
t pr
oduc
t pr
ofile
; UM
TS: U
nive
rsal
Mob
ile T
elec
omm
unic
atio
n Sy
stem
; UPS
: uni
nter
rupt
ed p
ower
sup
ply;
US:
Uni
ted
Stat
es; W
HO
: W
orld
Hea
lth O
rgan
izat
ion;
XD
R-TB
: ext
ensi
vely
dru
g-re
sist
ant T
B.a T
hese
cha
ract
eris
tics
wer
e co
nsid
ered
to b
e th
e m
ost i
mpo
rtan
t.
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
24
4 Conclusion
In recent years, there have been advances in the TB diagnostic pipeline and DST for M. tuberculosis. However, important gaps remain, requiring improvements to existing technologies or development of new technologies that can be used closer to the level of patient care, are priced affordably for LMICs and can provide an accurate, rapid and comprehensive DST solution. Furthermore, as new anti-TB medicines and regimens are developed, DST is playing a critical role in guiding the allocation of patients into specific regimens, and is thus improving treatment outcomes and preventing the amplification of drug-resistance patterns.
In an ideal scenario, tests for detecting drug resistance would meet all the defined needs; however, achieving such a level of alignment across multiple stakeholders and end-users is unrealistic. The update of this TPP is intended to guide test developers in identifying important test features and characteristics, and aligning these with patient and programmatic needs at the country level. Although it is expected that next-generation DST would meet all of the required minimum criteria, and as many of the optimal requirements as possible, potential trade-offs may be required; thus, the criteria are indicative rather than absolute.
References 25
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30 Nathavitharana RR, Hillemann D, Schumacher SG, Schlueter B, Ismail N, Omar SV et al. Multicenter noninferiority evaluation of Hain GenoType MTBDRplus Version 2 and Nipro NTM+MDRTB line probe assays for detection of rifampin and isoniazid resistance. J Clin Microbiol. 2016;54(6):1624–30 (https://www.ncbi.nlm.nih.gov/pubmed/27076658).
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38 Claassens MM, du Toit E, Dunbar R, Lombard C, Enarson DA, Beyers N et al. Tuberculosis patients in primary care do not start treatment. What role do health system delays play? Int J Tuberc Lung Dis. 2013;17(5):603–7 (https://www.ncbi.nlm.nih.gov/pubmed/23575324).
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42 Tuberculosis laboratory biosafety manual (WHO/HTM/TB/2012.11), Geneva, World Health Organization. 2012 (https://apps.who.int/iris/bitstream/handle/10665/77949/9789241504638_eng.pdf?sequence=1).
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Annexes 29
Annexes
Annex 1: List of participants to the stakeholder consultation
Stakeholder consultation on target product profile for next-generation drug-susceptibility testing at peripheral centres
10–12 & 30 March 2021
TB diagnostics experts, national and supranational reference laboratories
1. Fabiola AriasInstitute of Public Health of ChileTB Supranational Reference laboratorySantiago de Chile, Chile
2. Ramon P. BasilioNational TB Reference LaboratoryResearch Institute for Tropical MedicineMuntinlupa, Philippines
3. Daniela Maria CirilloEmerging Bacterial PathogensWHO Collaborating Centre and TB Supranational Reference laboratorySan Raffaele Scientific InstituteMilan, Italy
4. Eduardo De Souza AlvesLaboratory TechnicianPublic Health Laboratories, CGLABMinistry of HealthBrasilia, Brazil
5. Anzaan DippenaarPrince Leopold Institute of Tropical MedicineAntwerp, Belgium
6. Marjan FarzamiAssociate Professor of PathologyHead of Reference LaboratoryReference Health LaboratoryMinistry of Health and Medical EducationTehran, Iran (Islamic Republic of)
7. Patricia HallTB and Clinical Monitoring TeamInternational Laboratory Branch Division of Global HIV and TBCenter for Global HealthCenters for Disease Control and PreventionAtlanta, United States
8. Rumina HasanDepartment of Pathology and MicrobiologyAga Khan University Karachi, Pakistan
9. Farzana IsmailCentre for TuberculosisNational Institute for Communicable DiseasesJohannesburg, South Africa
10. Moses JolobaMakerere University College of Health SciencesDepartment of Medical MicrobiologyKampala, Uganda
11. S Siva KumarHead of Bacteriology DepartmentNational institute for Research in TuberculosisChennai, India
12. Paolo MiottoDivision of Immunology, Transplantation and Infectious DiseasesSan Raffaele Scientific InstituteMilan, Italy
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
30
13. NGUYEN Van HungHead of DepartmentNational TB Reference LaboratoryNational Lung HospitalHanoi, Viet Nam
14. PANG YuNational Clinical Center on TuberculosisBeijing, China
15. Zully Puyén-GuerraNational Reference Laboratory for MycobacteriaNational Institute of healthLima, Peru
16. Paulo REDNERLaboratory TechnicianNational TB Reference Laboratory, Oswaldo Cruz Foundation – FIOCRUZRio de Janeiro, Brazil
17. Andriansyah RukmanaHead of Microbiology DepartmentUniversity of Indonesia – National Reference Laboratory for Molecular TB and ResearchJakarta, Indonesia
18. Thomas ShinnickIndependent laboratory consultant Atlanta, United States
19. Tatyana SmirnovaHead of the Department of MicrobiologyCentral Tuberculosis Research Institute of the Russian Academy of SciencesMoscow, Russian Federation
20. Titiek SulistyowatiHead of Health Unit (TB Laboratory)BBLK Surabaya – National TB Reference LaboratorySurabaya, Indonesia
21. Sabira TahseenHead of National TB Reference LaboratoryMinistry of National Health Services, Regulations and CoordinationGovernment of PakistanIslamabad, Pakistan
National TB programmes and policy-makers
22. Ravindra Kumar DewanDirectorNational Institute of TB and Respiratory DiseasesNew Delhi, India
23. Fernanda Dockhorn CostaGeneral Coordination of Surveillance of Respiratory Transmission Diseases of Chronic ConditionsBrasilia, Brazil
24. Nishant KumarDeputy Additional Director GeneralCentral TB Division of the Directorate General of Health Services, under the Ministry ofHealth & Family WelfareNew Delhi, India
25. Endang LukitosariDeputy National TB Programme Manager for Drug-Resistant TBMinistry of HealthJakarta, Indonesia
26. Norbert NdjekaChair, AFR rGLC, Director, Drug-Resistant TB, TB&HIVNational TB Control & Management Cluster, Department of Health of South AfricaPretoria, South Africa
27. Alena SkrahinaRepublican Research and Practical Centre for Pulmonology and TuberculosisMinsk, Belarus
28. Irina VasilyevaChief TB expert of the Russian Ministry of HealthDirector of the National Medical Research Centre on Phthisiopulmonology and Infectious DiseasesMoscow, Russian Federation
Annexes 31
Clinicians and researchers
29. Kindi AdamResearcherCentre of Biomedical and Basic Health Technology Research and DevelopmentJakarta, Indonesia
30. Dina BisaraResearcherCentre of Community Health Effort Research and DevelopmentJakarta, Indonesia
31. Claudia DenkingerDirectorDivision of Tropical MedicineUniversity of HeidelbergHeidelberg, Germany
32. Keertan DhedaCentre for Lung Infection and ImmunityDivision of Pulmonology Department of Medicine University of Cape TownCape Town, South Africa
33. Camilla RodriguesHinduja HospitalMumbai, India
34. Timothy C. RodwellAssociate ProfessorDivision of Pulmonary, Critical Care and Sleep MedicineDivision of Global Public HealthUniversity of California San DiegoSan Diego, United States
35. Philip SupplyFrench National Center for Scientific ResearchCenter for Infection and Immunity of LilleLille, France
36. Diana VakhrushevaNational Research & Medical TB CentreMoscow, Russian Federation
37. Timothy WalkerCentre for Tropical Medicine and Global HealthOxford UniversityOxford, United Kingdom
Civil society organizations and patient representatives
38. David BraniganTreatment Action GroupNew York, United States
39. Ezio Távora Dos Santos Filho WHO Civil Society Task Force on TB Rio De Janeiro, Brazil
Implementing institutions and partners
40. Grania BrigdenDirectorDepartment of TuberculosisInternational Union Against Tuberculosis and Lung DiseaseGeneva, Switzerland
41. Roger Calderón-EspinozaLaboratory DirectorPartners in HealthLima, Peru
42. Martina CasenghiTechnical DirectorElizabeth Glaser Paediatric AIDS FoundationGeneva, Switzerland
43. Petra De HaasLaboratory AdvisorKNCV Tuberculosis FoundationThe Hague, The Netherlands
44. Cathy HewisonTB Advisor and TB Working Group LeaderMédecins Sans FrontièresOperational Section ParisParis, France
45. Brian KaiserTechnical OfficerGlobal Drug FacilityStop TB Partnership SecretariatGeneva, Switzerland
46. Troy MurrellGlobal Laboratory Services TeamClinton Health Access InitiativeBoston, United States
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
32
47. Sreenivas NairTechnical OfficerStop TB PartnershipGeneva, Switzerland
48. Diana VakhrushevaNational Research & Medical TB CentreMoscow, Russian Federation
Regulatory agencies
49. Lynnete BerkeleySenior MicrobiologistUS Food & Drug AdministrationMaryland, United States
50. Emma CherneykinaExpert on quality, effectiveness and safety of medical productsNational Quality InstituteFederal Service for Surveillance in Healthcare (Roszdravnadzor)Moscow, Russian Federation
51. Aihua ZhaoDivision of Tuberculosis Vaccine and Allergen, Institute for Biological Product ControlNational Institutes for Food and Drug ControlBeijing, China
Product development partnerships
52. Morten RuhwaldTB ProgrammeFIND, the global alliance for diagnosticsGeneva, Switzerland
53. Karishma SaranNew Diagnostics Working Group SecretariatFIND, the global alliance for diagnosticsGeneva, Switzerland
54. Samuel G SchumacherEvidence & PolicyFIND, the global alliance for diagnosticsGeneva, Switzerland
Global health initiatives and funding agencies
55. Draurio Barreira Cravo NetoTechnical Manager for TBStrategy teamUNITAIDGeneva, Switzerland
56. Fatim Cham-JallowTechnical Advice, DiagnosticsThe Global Fund to Fight AIDS, Tuberculosis and MalariaGeneva, Switzerland
57. Amy PiatekSenior Tuberculosis Technical AdvisorUnited States Agency for International Development Seattle, United States
Technical resource persons
58. Mikashmi KohliDepartment of Epidemiology, Biostatistics, and Occupational HealthMcGill International TB CentreMcGill UniversityMontreal, Canada
59. Emily MacleanDepartment of Epidemiology, Biostatistics, and Occupational HealthMcGill International TB CentreMcGill UniversityMontreal, Canada
WHO regional offices
60. Kenza BenaniMedical OfficerWorld Health Organization Regional Office for Eastern MediterraneanCairo, Egypt
61. Vineet BhatiaMedical Officer – MDR-TBDepartment of Communicable DiseasesWorld Health Organization Regional Office for South-East AsiaNew Delhi, India
Annexes 33
62. Jean de Dieu IragenaTechnical Officer Laboratory, HIV/TB and Hepatitis ProgrammeWorld Health Organization Regional Office for AfricaBrazzaville, Congo
63. Ernesto MontoroAdvisor, Laboratory IntegrationHIV, Hepatitis, Tuberculosis and Sexually Transmitted InfectionsPan American Health Organization/ World Health Organization Regional Office for the AmericasWashington, United States
64. Kalpeshsinh RahevarMedical OfficerETB and Leprosy UnitDivision of Communicable DiseasesWorld Health Organization Regional Office for the Western PacificManila, Philippines
WHO headquarters
65. Lice González A, UCN/GTB/PCI
66. Alexei Korobitsyn, UCN/GTB/PCI
67. Nazir Ismail, UCN/GTB/PCI
68. Corinne Merle, TDR/IMP
69. Carl-Michael Nathanson, UCN/GTB/PCI
70. Matteo Zignol, UCN/GTB/PCI
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
34
Annex 2: Overview of results of the WHO public comment process
To finalize the revised target product profile (TPP) document, in January 2021, the World Health Organization (WHO) launched an online public comment process to obtain feedback from a large array of stakeholders. The process aimed to ensure that proposed changes were objective and balanced, in terms of the needs and values of patients and other end-users, and of industry.
Through this process, stakeholders were invited to comment and share their views on the scope, target users or use setting, pricing, test performance and operational characteristics. Stakeholders were also invited to provide additional comments and questions on the proposed, updated TPP. A total of 128 individuals accessed the call for public comment and 82 agreed to participate. Fig. A1 provides an overview of the sectors represented by participants.
Fig. A1 Distribution of responses by sector (n=82)
NRL: national reference laboratory; SRL: supranational reference laboratory; TB: tuberculosis.
Summary of comments
Overall, the survey comments did not differ widely from the proposed TPP, and most were relatively minor. For a few specific areas in the TPP, divergent views were expressed by multiple respondents; these areas were as follows:
• giving higher priority to new drugs, particularly pyrazinamide (PZA), because the TPP is meant to provide guidance for the coming 5 years;
• expanding the target population to include children, using paediatric-friendly samples such as stool if needed; and
• lowering pricing criteria to levels that are more realistic for low-income countries (LICs).
Finally, there were some specific comments on diagnostic performance that also require attention.
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Annexes 35
Major comments
Priority of anti-TB agents for testing (Scope)
Five respondents stated that PZA must be assigned higher importance, given its role in many regimens, including for people living with HIV (PLHIV). One respondent stated that the “optimal requirements” (optimal) first level should also include bedaquiline (BDQ), linezolid (LZD), clofazimine (CFZ) and PZA. Two respondents stated that pretomanid (Pa) should replace CFZ on the optimal second level, whereas three respondents said it should be added. One respondent suggested including delamanid (DLM) with BDQ, LZD and CFZ on the optimal second level, given its role in shortened paediatric regimens; another suggested adding D-cycloserine to the optimal third level. For the “minimal requirements” (minimal), one respondent stated that first level should include fluoroquinolones (FQ), four respondents stated that BDQ ± LZD should replace amikacin (AMK) on the third level, and one stated that BDQ, CFZ ± LZD must be included.
Target population and sample type (scope)
Four respondents stated that the target population must be expanded to include children, noting that stool works well as a sample. Five respondents suggested that stool and other WHO-recommended extrapulmonary samples be included and mentioned in explanatory notes.
Pricing and costs for individual tests and instrument (pricing)
Individual test pricing was thought to be too high for low- and middle-income countries (LMIC) by six respondents from India, Japan, Netherlands and the United States of America (USA), representing academia, advocacy, implementing partners and industry. Pricing should be based on cost of goods sold and volume, not on ability to pay or value (two respondents from academia and advocacy). Suggested minimal prices for rifampicin (RIF) and isoniazid (INH) were less than US$ 10–15 (one respondent, advocacy) and US$ 18–25 (one respondent, industry). Suggested optimal prices for RIF/INH were less than US$ 5 (two respondents, advocacy and industry) and less than US$ 5 (one respondent, industry). Optimal pricing suggestions for RIF/INH/FQ/AMK were less than US$ 10 (two respondents, advocacy and industry) and US$ 15–20 (one respondent, industry).
One industry respondent disagreed with the approach of setting minimum prices, because this may stifle innovation. An advocacy respondent stated that basing non-culture drug susceptibility testing (DST) pricing on culture is unreasonable; instead, pricing should be based on existing molecular testing costs.
Considering LICs’ limited ability to pay, four respondents (from academia, government, industry and implementing partners) stated that instrument costs must decrease, and three stressed that generic or universal instruments that will only require limited updating must be prioritized. New service and delivery models could be considered; for example, reagent rental models that include instrument and maintenance spread over a large volume of tests. One industry respondent noted that costs are both unrealistically low and high when considering equipment, maintenance and warranties.
Target Product Profile for Next-Generation Drug-Susceptibility Testing at Peripheral Centres
36
Cost with respect to daily throughput (pricing and operational characteristics)
Five respondents (from academia, implementing partners and professional medical societies) raised concerns about the possibility of high costs if daily throughput is low, and suggested that distinct options for low and high incidence settings should be specified. The definition of optimal should decrease to fewer than 10 tests, and for minimal should be changed to 11–25. Three implementing partner respondents did not want batching considered, citing concerns about waiting to test.
Limits of detection, diagnostic accuracy, indeterminate results (performance)
Three respondents suggested changing the optimal limit of detection to 10 colony forming units (CFU)/mL to align with Xpert Ultra, while one noted that a limit of detection of 104 is too high for many PLHIV.
Regarding TB detection sensitivity, stated criteria were generally seen as too low. Separately, respondents stated that sensitivity must be equal to Xpert Ultra, higher than existing tests, and much higher in smear-negative cases. However, one respondent suggested that the criteria for minimal smear-positive should be at least 95%. DST sensitivity compared with a sequencing reference standard will differ for each drug, so a uniform requirement may be unrealistic. Compared with a phenotypic reference standard, DST sensitivity of more than 95% for all drugs is probably not feasible; instead, it would be acceptable to update targets as genetic information is elucidated (two respondents). Exceptionally, RIF sensitivity should be more than 98% and PZA minimal sensitivity should be more than 90%.
Regarding DST specificity, performance criteria is needed for the case of composite reference standards (phenotypic and sequencing combined). For analytical specificity, respondents were both appreciative and ambivalent that nontuberculous mycobacteria were mentioned.
The optimal limit of detection for minor variants should decrease to 1%, aligning with the mycobacterial growth indicator tube (MGIT), and decrease to less than 5% for minimal, because this is critical for understanding treatment success (three respondents).
Concerning indeterminant DST results, one respondent stated that the optimal value must decrease to less than 1%, while another believed that these stringent values would stifle test development. One respondent suggested including distinct values for smear-positive and smear-negative cases. Three respondents stated that reproducibility criteria should decrease to less than 5%.
Minor comments
The minimal target user was considered both underqualified and overqualified with respect to interpretation of results and clinical decision-making. Two respondents stated that treatment monitoring capability was unnecessary. Separately, respondents asked that distinct performance specifications be made for asymptomatic and symptomatic patients, and that the list of interfering substances be expanded to include other respiratory pathogens and flora, transport media and stool. One respondent suggested adding guidelines regarding product longevity. Another suggested that the instrument should run in non-air-conditioned temperatures, while another stated that it must be able to withstand high levels of ambient dust. One respondent stipulated that minimal battery power should be 24 hours.
Annexes 37
Turnaround time should be decreased, and a rapid test format that could be performed at the point of care or bedside should be the goal. Five respondents considered the minimal time to results as being too long, with 4–6 hours (one respondent) and less than 2 hours (three respondents) suggested; also, optimal timing should decrease to less than 30 minutes.
Respondents separately noted that maintenance should be inexpensive, achievable by local staff and included in the cost of equipment; also, that manufacturers should have at least one support person available per WHO region. Another thought these criteria were not feasible. Regarding training, three respondents suggested reducing the minimal time to 2 days or less, and one mentioned the need for training for maintenance and software updates.
Four respondents mentioned a desire for reusable, recyclable or non-plastic alternatives to disposables. One respondent suggested changing biosafety and all waste disposal requirements to those of rapid molecular tests instead of microscopy. Another suggested referencing basic laboratory supplies (e.g. pipettes and a timer), which may be unavailable at peripheral settings. One respondent suggested adding a data export criterion for reporting results to client, while two respondents suggested adding requirements for virus or malware protection and data security.
For further information, please contact:
World Health Organization20, Avenue Appia CH-1211 Geneva 27 SwitzerlandGlobal TB ProgrammeWeb site: www.who.int/tb
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