New drugs uptake in WHO EURO - KNCV Tuberculosefonds · • Automated real-time nucleic acid...

New drugs uptake in WHO EURO

Dr Ogtay Gozalov,

Medical officer,

WHO EURO

[email protected]

Dr Maya Kavtaradze,

Regional Technical Adviser,

Stop TB Partnership's GDF

[email protected]

Dr Elmira Gurbanova,

rGLC/Europe consultant,

[email protected]

Dr Gunta Dravniece,

Senior TB Adviser, KNCV

[email protected]

18th Wolfheze Workshops and 15th WHO National TB Programme Managers’ Meeting

The Hague, Netherlands

June 2017

mailto:[email protected]




Analysis of rGLC/Europe reports on

new drugs / new treatment regimens

Methodology

18 regional GLC mission reports from 15 sites were analyzed

against elements needed to be addressed for introduction of

new TB drugs (Bdq and Dlm), as per the Policy

Implementation Package

Year

of

the

asse

ssm

ent

Arm

enia

Aze

rbai

jan

Bel

aru

s

Geo

rgia

Kaz

akh

stan

Serb

ia (

UN

AT

Ko

sovo

)

Kyr

gyzs

tan

FYR

Mac

ed

on

ia

Mo

ldo

va

Ro

man

ia

Rep

ub

lic o

f M

old

ova

(T

ran

stri

stri

a)

Taji

kist

an

Turk

men

ista

n

Ukr

ain

e

Uzb

ekis

tan

2016

2017

Availability of Bdq and/or Dlm in the country

101

4

Available in Armenia, Belarus, Georgia,Kazakhstan, Serbia (UN AT Kosovo),Moldova, Romania, Moldova(Transnistria), Ukraine, Uzbekistan

No information on Tajikistan

Not available in Azerbaijan, FYRMacedonia, Kyrgyzstan, Turkmenistan

Out of 15 countries assessed, 10 introduced Bdq

and/or DlmNumber of countries that introduced

new TB drugsCumulative number of patients receiving new TB drugs

2013 2014 2015 2016

2 2

810

845

137

33 Bdq-basedtreatment

Dlm-basedtreatment

Bdq+Dlm-basedtreatment

National implementation plan for introduction of new TB

drugs

7

3

5

Availability of the National Implementation Plan

Available in Armenia, Belarus,Georgia, Kyrgyzstan, Moldova,Tajikistan, UzbekistanNo information on Kazakhstan,Turkmenistan, Ukraine

Not available in Azerbaijan, Serbia(UN AT Kosovo), FYR Macedonia,Romania, Moldova (Transnistria)

Minimum requirements for country preparedness and

planning: National health context

14

1

Availability of the National Strategy to fight TB up to 2020

Available in Azerbaijan, Armenia, Belarus,Georgia, Kazakhstan, Serbia (UN ATKosovo), Kyrgyzstan, FYR Macedonia,Moldova, Romania, Tajikistan,Turkmenistan, Ukraine, Uzbekistan

No information on Moldova (Transnistria)


planning: Laboratory

Drug susceptibility testing (DST) to first-line drugs (FLD) Quality assurance for DST to FLD

14

1

Available in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan,Serbia (UN AT Kosovo), FYR Macedonia, Moldova, Romania,Moldova (Transnistria), Tajikistan, Turkmenistan, Ukraine,Uzbekistan

No information on Kyrgyzstan

9

5

1

Passed in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, FYRMacedonia,Tajikistan, Ukraine, UzbekistanNo information on Kyrgyzstan, Moldova, Romania, Moldova (Transnistria),TurkmenistanNot passed in Serbia (UN AT Kosovo)


planning: Laboratory

Drug susceptibility testing (DST) to second-line drugs (SLD)

Quality assurance for DST to SLD

12

1

2

Available in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan,Moldova, Romania, Moldova (Transnistria), Tajikistan, Turkmenistan,Ukraine, UzbekistanNo information on Kyrgyzstan

Not available in Serbia (UN AT Kosovo), FYR Macedonia

12

21

Passed in Azerbaijan, Armenia, Belarus, Georgia, Moldova,Kazakhstan, Romania, Tajikistan, Moldova (Transnistria),Turkmenistan, Uzbekistan, Ukraine

Not passed in Serbia (UN AT Kosovo), FYR Macedonia



planning: Drug supply and management

• Registration of Clofazimin (Cfz) is problematic at all countries.

• Bdq and Dlm are imported based on one-time license, mainly

because these drugs are still on a clinical trial

• TB drugs procured with the support from the Global Fund are

quality assured.

• However, drugs procured through local budget, mainly do not

hold GMP or WHO-prequalification


planning: Drug supply and management

9

1

5

Shortage of TB drugs reported during the last 2 years

No shortage reported in Armenia,Georgia, Kazakhstan, Serbia (UN ATKosovo), FYR Macedonia, Moldova,Tajikistan, Turkmenistan, Uzbekistan


Shortage reported by Azerbaijan,Belarus, Romania, Moldova(Transnistria), Ukraine


planning: Case management

3

1

11

National guidelines for the programmatic management of drug-resistant TB is updated as per the latest WHO recommendations

Updated in Belarus, Kazakhstan, Ukraine


Not updated in Azerbaijan, Armenia, Georgia, Serbia (UNAT Kosovo), FYR Macedonia, Moldova, Romania,Moldova (Transnistria), Tajikistan, Turkmenistan,Uzbekistan


planning: Monitoring and evaluation

• All countries use updated WHO definitions for TB (2013 update)

• Some countries still do not have functional electronic TB database

and execute paper-based reporting (Azerbaijan, Tajikistan,

Turkmenistan, Uzbekistan, Kyrgyzstan)

• Supportive supervisions in majority countries are performed by the

National TB Programs, but are heavily relying on the Global Fund

support


planning: Pharmacovigilance

• Armenia, Belarus and Georgia established:

– Active pharmacovigilance (PV)

– Centralized PV data collection

– Cohort-event monitoring used as PV method

• In remaining 12 countries the PV is not duly implemented

New and companion drugs via

GDF

Access to New TB tools via Global Drug Facility

and reporting requirements

www.stoptb.org

Global Drug Facility (GDF)

An enterprise of the Stop TB Partnership, mainly funded by USAID, hosted in UNOPS and managed by the Partnership secretariat

GDF began supplying FLDs in 2001, and in 2007 added the supply of SLDs, pediatric TB medicines and diagnostics and is a major source for GeneXpert™

137 countries benefited from GDF procurement / bundled mechanism

> 27 M Adult FLDs treatments> 1,59 M pediatric treatments> 239,321 SLDs patient treatments

US$ 1.63 billion of TB commodities procured since GDF inception in 2001

GDF Goal: Facilitate equitable and timely access to affordable, quality-assured, medicines and diagnostics, including new tools.

(as of December 2016)

GDF order placed by Product Line

www.stoptb.orgwww.stoptb.org

The Product List and Catalogue http://www.stoptb.org/gdf/drugsupply/drugs_available.asp

New Diagnostics

http://www.stoptb.org/gdf/drugsupply/drugs_available.asp


Equipment and accessories, diagnostics and consumables, microbiological tests and test systems for:

• Equipment Kit for Microscopy laboratory Diagnostics and consumables kits for ZN or Auramine staining techniques

• Liquid Culture and DSTs Becton Dickinson BACTEC MGIT 960 system MGIT Tubes, OADC Supplement, SIRE Kits and Rapid Diagnostic Test SD BIOLINE TB Ag MPT64

• Lyophilized drug for laboratory use (Amikacin, Capreomycin, Kanamycin, Moxifloxacin, Ofloxacin)

• Solid culture and DST Loewenstein-Jensen-Medium

• Molecular line probe assays for 1st-line anti-TB drugs HAIN LifescienceGT-Blot 48, Twincubator, GenoType MTBDRplus and services

• Automated real-time nucleic acid amplification - Xpert MTB/RIF system

• Laboratory instruments, consumables, chemicals and personal protective equipment

Access to Laboratory and Diagnostic Products All products for WHO’s recommended techniques including New rapid diagnostic and DST tests!

Product coming to GDF portfolio in 2017 • TB LAMP (LoopampTM technology)• Digital X-Ray• DNA Genotek - OMNIgene•SPUTUM (OM-SPD)• Quiagen - QuantiFERON-TB Gold Plus (QFT®-Plus)

GDF diagnostics catalogue


Repurposed medicines with increasing demand: Clofazimine, linezolid, amoxicillin clavulanate, imipenem/cilastatin

Substantial price decrease for: Linezolid

Price decrease for: Amoxicillin Clavulanate, Capreomycin,Imipenem/Cilastatin, Levofloxacin, Moxifloxacin and PAS Sodium Salt

Clofazimine 100mg from Novartis

Off label use in TB - disclaimer and quarterly A second manufacturer is expected in 2017

Application for inclusion in the WHO EML -March 2017

Access to WHO-recommended medicines

Full range of medicines for any type of TB treatment regimens available from the GDF!

Products price list online

New dispersible pediatric formulations2-FDC/RH-75/50; 3-FDC/RHZ-75/50/150 Treatment of Latent Tuberculosis Infection

Priftin® (rifapentine 150 mg tablet) from Sanofi

www.stoptb.org

Improve the service level to GDF clients:

• Decrease lead time between the countries’ orders and delivery by serving countries from available stock

• Ensure flexibility of supply in case of over stocking or stock-out situations in countries: Adapt client orders with consumption by pre or postponement of deliveries

Improve the service level to GDF suppliers :

• Improve the GDF order cycle by a better scheduling of orders to suppliers

• Adapt replenishment orders and production capacity to smooth peaks in the ordering pattern

• Provide to suppliers more reliable forecast and information on the market especially on policy changes

New GDF Strategic Rotating Stockpile (SRS): aimed to SRS Product Name

Amikacin 500mg/2ml injectable

Amoxicillin 500mg+Clavulanic acid 125mg

Amoxicillin 875mg+Clavulanic acid 125mg

Bedaquiline 100mg tablet

Clofazimine 100mg capsule

Capreomycin 1gram powder for injectable

Cycloserine 250mg capsule

Delamanid 50mg tablet

Ethionamide 250mg tablet

Kanamycin 1g injectable solution

Levofloxacin 250mg tablet

Levofloxacin 500mg tablet

Linezolid 600mg tablet

Moxifloxacin 400 mg tablet

PAS sodium sachet

Prothionamide 250 mg tablet

Pyrazinamide 400 mg tablet

Pyrazinamide 500 mg tablet

Syringe & needle (auto-disabling)

Water for injections

Isoniazid 300mg tablet

Ethambutol HCI 400 mg tablet

www.stoptb.org

Delivering-only does not work any more

GDF value-adding package of services

The Goal of the GDF Technical Assistance and Capacity Building Strategy is twofold

• To strengthen priority countries capacity to ensure timely equitable access to the GDF-supplied quality-assured medicines and products, including new TB products

• To provide country information and evidence on TB product demand and country TB control trends for the GDF strategic procurement planning and decision-making, and global forecasting exercises


GDF TA and Capacity Strengthening

GDF tier 1 countries with core USAID support

Full package TA for expedited uptake of new TB tools managed by Regional Technical Advisors

• Development of Transition PSM plans• Assistance with functional EWS for monitoring uptake• Ongoing focused technical assistance and capacity

building for PSM systems strengthening • PSM tools implementation: QuanTB (quantification,

planning, Early Warning), data collection tools

Tier 2 countries with additional USAID support

Managed by GDF HQ and RTAsImplemented by pool of GDF-trained consultants

• Targeted TA for PSM plans of the Global Fund proposals

• Development of Transition PSM plans for new TB tools• Regional capacity building for forecasting and

quantification• Assistance with functional Early Warning System• Joint missions: rGLC, TGF, WHO, partners (e.g. KNCV,

UNION, etc.)• Best practices and knowledge sharing

GDF Regional Technical Advisers:Zaza Munez – SE Asia and W.Pacific [email protected]

Salama Mwatawala – Africa [email protected]

Maya Kavtaradze – Europe/CAR [email protected]

Erulappa Thanaraj – India [email protected]

Two additional RTAs to be hired forAfrica (Anglophone/Francophone)

SE Asia

Pool of trained regional consultants





www.stoptb.org

New TB tools

Shorter MDR-TB treatment regimen

New Paediatric Formulations

New and repurposed drugs

New diagnostics


Sirturo by J&J, Kemwell Biopharma, USFDA/EMAPacking size: HDPE container(s) of 188Shelf life: 36 months

USAID Bedaquiline Donation Program: free-of-charge to eligible countries following WHO interim recommendations

Bedaquiline 100 mg tablest As of April 2017: 10 705 treatment courses globally including MSF projects (delivered, orders placed withsuppliers or in process)Of which in Europe and CAR countries: 2 944 courses without MSF projects

Countries can request Technical Assistance from USAID and GDF ([email protected] ; [email protected]; [email protected])

Adverse events reported directly to Janssen or via GDF: [email protected]

Country BDQ Order Completed

BDQ Order placed with

supplier BDQ Total

Armenia 69 69

Azerbaijan 91 91

Belarus 386 139 525

Georgia 341 60 401

Kazakhstan 390 332 722

Kosovo 2 2

Kyrgyzstan 25 110 135

Republic of Moldova 89 67 156

Tajikistan 50 70 120

Turkmenistan 40 40

Ukraine 200 200

Uzbekistan 90 393 483

Grand Total 1440 1504 2944






Deltyba by Otsuka, EMA/JapanPacking size: Box(s) of 672Shelf life: 60 monthsCountries eligible for TB Financing by The Global Fund and following WHO interim recommendations can access Delamanid via the GDFPrice USD 1,700 for a full treatment course (6 months)

Adverse events reported to Otsuka via the GDF: [email protected]

Delamanid 50mg tablets As of April 2017: 2 448 treatment courses globally including MSF projects (delivered, orders placed withsuppliers or in process)Of which in Europe and CAR countries: 626 courses without MSF projects

Country DLM Order Completed

DLM Order placed with supplier

DLM Total

Armenia MSF

Azerbaijan

Belarus 144 193 337

Georgia 35 35

Kazakhstan 130 80 210

Kosovo

Kyrgyzstan 8 8

Republic of Moldova 25 25

Tajikistan MSF

Turkmenistan

Ukraine

Uzbekistan 11 11 + MSF

Grand Total 309 317 626


www.stoptb.org

A. Countries/programs should ensure they follow the five WHO recommendations for optimal introduction of BDQ and DLM:

Effective treatment and monitoring Proper patient inclusion Informed consent Adherence to WHO recommendations Active pharmacovigilance and management of adverse events aDSM

─ Active and systematic clinical and laboratory assessment of patients on treatment with new anti-TB drugs, novel MDR-TB regimens or XDR-TB regimens to detect, manage and report suspected or confirmed drug toxicities and adverse events;

─ Systematic and standardized recording and reporting at least Serious Adverse Events (may also monitor other AEs that are of clinical significance or of special interest to the program and can be expanded to eventually cover TB patients on treatment with any second-line drugs)

aDSM is intended

─ to be an integral component of the programmatic management of drug-resistant TB(PMDT) and

─ to complement current capacities of national pharmacovigilance.

How to Access Bedaquiline and Delamanid via GDF (1)


B. Review the background documentation on the program and the order form from the GDF (http://www.stoptb.org/gdf/drugsupply/procurement_forms.asp)

Annex: Adverse Drug Reaction / Serious

adverse event forms • BDQ Adverse events reported to Janssen via GDF: [email protected]

• DLM Adverse events reported to Otsuka via the GDF:

[email protected]

System for systematic and standardized

recording and reporting of AEs is required


http://www.stoptb.org/gdf/drugsupply/procurement_forms.asp



www.stoptb.org

D. Review the need for other second-line drugs that are needed to treat patients who will be receiving BDQ or DLM ─ data-driven need-based approach to forecasting /

quantification for all medicines (not cohort-based)─ Phase-in / phase-out planning: scenarios and

estimation of volumes and values of obsolete medicines for withdrawal and destruction

E. Review needs based on the above descriptions


C. Estimate the number of patients who will benefit from the medicines:─ Planning and executing the supply for multiple concurrent new and

old regimens of different duration and at various implementation start dates

─ Mixed supply medicines in countries graduating from the GF support: maintaining quality and access

Out- and in-coming medicines

Increased individualization and number of treatment regimens

Standard M/XDR 20 month:

8Cm70%Km30%Lfx50% Mfx50% Pto90%Cs90% PAS60%Z100%/12Lfx50%

Mfx50% Pto90%Cs90% PAS60%Z100%

With new and repurposed drugs 20 months:

6Bdq90%/6Dlm30%/8Cm65%Imp\Cls35%Amx\Clv35%Cfz90%Lnz90%Mfx50%Lfx10% Pto30%Cs30%PAS4% Z50% /12Cfz90%Lnz90%Mfx50%Lfx10%

Pto30%Cs30%PAS4% Z50%

STR 9 - 12 months (composition and duration may vary):

(4-6)Km10% Cm80% Am10%Mfx20% Pto100% Cfz100% Hh100% Z100% E100% /(5 -6) Mfx100% Pto100% Cfz100% Z100% E100%

Forecasting and quantification for multiple regimens become too complex for the existing level of expertise

Lack of data-driven rational phase-in / phase-out transition planning with scenarios and cost estimations

Need for functional Early Warning System including patient data collection to manage transition without treatment interruptions

Km Mfx

Pto

PAS

Z

Cm

Lfx

EtoCs

AmCfz

AmCl

Bdq Dlm

Imp

Lnz


Benefits from EWS (quarterly QuanTB reports):• Proactively monitor TB medicines supply and medicines orders: Early

action to prevent stock-out/overstock• Streamline medicine orders: Firm order schedules, streamlined supply to

countries • Ensure uninterrupted supply for smooth transition to new medicines and

regimens• Play scenarios for rational introduction of new TB tools• Reduce wastage of medicine: in-country reallocation of medicines where

possible and changing delivery schedule - GDF needs advance notification!• GDF will improve global and strategic procurement forecasting (Cheaper

medicines for countries)• Reports will also serve as foundation for evidence-based technical

assistance to countries for rapid and rational transition to new medicines and regimens

Quantification and Early Warning System


F. Place order for new and other second-line drugs as the turn-around time is

likely to be several months, and TA activities can be carried out while awaiting

drug arrival:

─ Need to capacitate laboratories to conduct SL DST (LPA, automated,

conventional)

─ Development, approval and introduction of new treatment guidelines and

training of staff at all levels

─ Need for approved policy for expedited uptake of new medicines and

regimens, including for withdrawal and destruction of obsolete sub-optimal

medicines

G. Explore options to import new medicines in the country if they are not

registered yet:

─ Registration/waivers and importation approvals (Donor and Domestic

funded)

H. Review clinical cases and patient histories to see who would benefit from new

medicines.

How to Access Bedaquiline and Delamanid

via GDF (4)

• Delays in initiating orders…• Delays in approving quotes…• Delays in country to grant

dispatch authorization…• Last minute changes in

required shipping documents....

• Delays in country to import through customs, stock and deliver…

www.stoptb.org

1. All Medicines and diagnostic tools recommended by WHO, including STR and new drugs are available in GDF

2. Technical assistance and capacity strengthening for the introduction of new TB tools are available through the GDF and USAID-funded projects

3. NTPs should use current opportunities and should not delay the transition of use of new TB drugs, STR and new pediatric formulations

4. NTPs are requested to follow reporting requirements including ADRs and EWS reports

Message from WHO and GDF to NTP’s:

Introduction of new drugs and shorter DR-TB treatment regimen

KNCV’s approach

Gunta Dravniece, Michael Kimerling

KNCV

Wolfheze conference, May 31-June 2 2017

KNCV supports

programmatic introduction and evaluation of any innovation

• Diagnostics

• Regimen design

• Monitoring of safety

and efficacy

• Drug management

• Patient support

• Infection control

• Recording & reporting

• Digital health

Monitoring

Patient with presumptive TB

Standard TB treatment with First

Line Drugs

No TB

Rapid molecular test (e.g. Xpert MTB/RIF)

Rif susceptible TB Rif resistant TB

Appropriate referral/ treatment

Shorter DR-TB treatment regimen

Eligible

Individualized DR-TB treatment

regimen

Ineligible

START TREATMENT AFTER EVALUATION OF ELIGIBILITY FOR SHORTER REGIMEN

KNCV’s patient triage approach allows initiation of the most effective treatment regimen for

any TB patient in <5 days

Patient Triage Approach

Linking the

Bdq donation program

with introduction of the

STR

KNCV’s support in WHO Euro

Through USAID Challenge TB project (CTB)

Four countries in the region

• Ukraine (PATH and KNCV)

• Uzbekistan (WHO and KNCV)

• Kyrgyz Republic (KNCV)

• Tajikistan (KNCV)

Generic documents developed and adapted for country needs

1. Implementation planning tool 2. Programmatic and clinical guide3. Job aids (Use of Bdq; QTE)

4. Generic SOPs (under development)5. Generic Training materials (under development)

COUNTRY SUPPORT:EXAMPLE FROM KYRGYZ

REPUBLIC

Regulatory environment and policy I

1.Advocacy work resulted in support from MoH

2. Use of new drugs included in national guidelines

3. National plan for new drugs and regimens

developed and endorsed by MoH

Regulatory environment and policy II

4. Triage approach and implementation of proposed regimens

supported by inter-/national partners

5. Adverse event monitoring within MDR-TB program was revised

and linked with PV authority

Site preparation I

1. One functional diagnostic algorithm designed

and includes Xpert and HAIN SL tests

2. Specimen transportation, procurement of

consumables supported by other partners considering

KNCV approach

3. UNDP/GF supports triage approach – drugs for

shorter and individualized regimens procured

Site preparation II

1. Clinical guide and SOPs developed

2. Access to all necessary monitoring tests

supported by UNDP/GF in coordination with KNCV

3. Electronic data base developed

4. Training for clinical and laboratory staff provided

5. Patients’ enrolment for shorter regimen and regimen with

new drugs started in January 2017

6. Continuous on job training and supervision provided

Introduction timelines in Kyrgyz Republic

44

Q3 2015

Q4 2015

Q1 2016

Q2 2016

Q3 2016 Q4

2016

• Finalization of guide and SOPs• Training of clinical and

laboratory staff

• Site selection/assessment

• Development of National

plan

• Estimation of drug needs

• On job training

• Patient enrollment

• Adjustment of guidelines

• Design of diagnostic algorithm and treatment regimens

• Development of SOPs

• Endorsement of National plan

Development of guide

Enrollment started in January 2017

Short treatment regimen is introduced starting from two sites

(Bishkek city, Chui oblast)

• 58 patients enrolled, including 3 children and 7 adolescents

Individualized regimen containing new and repurposed drugs

is provided for patients from whole country.

• 58 patients enrolled, majority from the waiting list, many of them in

severe condition at the time of enrollment

Progress in other countries

Tajikistan

• Enrollment started in December 2016

• By the end of April 2017 24 patients enrolled in shorter regimen and 24 in individualized regimen

Ukraine

• Bdq ordered for 200 patients

• Enrollment will be started in June 2017

Uzbekistan

• CTB project just started

• Guidelines adjusted

• National plan developed

Lessons learned from CTB countries I

Treatment regimen

Treatment

monitoring

Diagnostics

1. Treatment regimen is only one of components in patient

management. TA should address the essential PMDT elements

2. Many PMDT components were not ready in countries

therefore preparation takes longer (around 12 months).

3. TA on ND&R provides an opportunity to strengthen MDR

program.

4. Political support is crucial

Treatment regimen

Treatment

monitoring

Diagnostics

Lessons learned from CTB countries II

5. Preparing national plan helps to identify all components and

dividing tasks among partners

6. Preparation of introduction sites should be simultaneous

with preparations at national level

7. Specific needs for children and adolescents with TB should be

considered

8. Coordination with partners is essential

• Common approach

• Coordinated procurement

• Complementary activities

Acknowledgements

KNCV

• Susan van den Hof

• Agnes Gebhard

• Ieva Leimane

• Nick Blok

• Maria Idrissova

• Bakyt Myrzaliev

• Sandra Kik

• Edine Tiemersma

• Fraser Wares

• Job van Rest

• Hadi Qawasmeh

• Marcela Tommasi

• Michael Kimerling

PATH

• Katya Gamazina

• Olga Pavlova

• Nina Zherebko

• Aleksey Bogdanov

Acknowledgements• rGLC/Europe

members and consultants

• NTP’s of Member States

• Stop TB partnership GDF

• KNCV and Challenge TB Project

• MSF

New drugs uptake in WHO EURO - KNCV Tuberculosefonds · • Automated real-time nucleic acid...

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