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

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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

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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).

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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.

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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).

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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).

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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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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

xing

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

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ongo

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ext-

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: pyr

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rus

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sin

gle

nucl

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lym

orph

ism

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ercu

losi

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arge

t pr

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nive

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: W

orld

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lth O

rgan

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R-TB

: ext

ensi

vely

dru

g-re

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B.a T

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nsid

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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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24 Dowdy DW, Hoog AV, Shah M, Cobelens F. Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis. Int J Tuberc Lung Dis. 2014;18(6):647–54 (http://www.ncbi.nlm.nih.gov/pubmed/24903933).

25 Murray M, Cattamanchi A, Denkinger C, Van’t Hoog A, Pai M, Dowdy D. Cost-effectiveness of triage testing for facility-based systematic screening of tuberculosis among Ugandan adults. BMJ Glob Health. 2016;1(2):e000064 (https://www.ncbi.nlm.nih.gov/pubmed/28588939).

26 Padmasawitri TIA, Frederix GW, Alisjahbana B, Klungel O, Hövels AM. Disparities in model-based cost-effectiveness analyses of tuberculosis diagnosis: a systematic review. PLOS One. 2018;13(5):e0193293 (https://www.ncbi.nlm.nih.gov/pubmed/29742106).

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28 Van’t Hoog AH, Bergval I, Tukvadze N, Sengstake S, Aspindzelashvili R, Anthony RM et al. The potential of a multiplex high-throughput molecular assay for early detection of first and second line tuberculosis drug resistance mutations to improve infection control and reduce costs: a decision analytical modeling study. BMC Infect Dis. 2015;15:473 (https://www.ncbi.nlm.nih.gov/pubmed/26503434).

References 27

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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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36 Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 2012;380(9851):1406–17 (https://www.ncbi.nlm.nih.gov/pubmed/22938757).

37 Horne DJ, Pinto LM, Arentz M, Lin SY, Desmond E, Flores LL et al. Diagnostic accuracy and reproducibility of WHO-endorsed phenotypic drug susceptibility testing methods for first-line and second-line antituberculosis drugs. J Clin Microbiol. 2013;51(2):393–401.

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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47 Banoo S, Bell D, Bossuyt P, Herring A, Mabey D, Poole F et al. Evaluation of diagnostic tests for infectious diseases: general principles. Nat Rev Microbiol. 2010;8(12 Suppl):S17–29 (https://www.ncbi.nlm.nih.gov/pubmed/21548184).

48 Kuupiel D, Bawontuo V, Mashamba-Thompson TP. Improving the accessibility and efficiency of point-of-care diagnostics services in low- and middle-income countries: lean and agile supply chain management. Diagnostics. 2017;7(4):58 (https://www.ncbi.nlm.nih.gov/pubmed/29186013).

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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