New and emerging diagnostic tests for screening of ...€¦ · Screening Programme, all women are...

New and emerging diagnostic tests for screening of infections during

pregnancy

March 2009

The National Horizon Scanning Centre Research Programme is part of the

National Institute for Health Research

Acknowledgements

The author would like to thank the internal review team at the National Horizon Scanning Centre for their input into planning and writing the report. The author would also like to extend their thanks to the project external advisors: Professor Catherine Peckham, Institute of Child Health, London, Dr Penny Wilson, Technology Strategy Board, and Dr John Marshall, National Screening Committee; and experts and organisations contacted during this review.

The National Institute for Health Research’s National Horizon Scanning Centre Research Programme is funded by the Department of Health.

The views expressed in this publication are those of the author and not necessarily those of the NHS,

the NIHR or the Department of Health

Copyright ©2010‐2011 University of Birmingham.

Author:

Dr Sara Trevitt, Senior Horizon Analyst, National Horizon Scanning Centre

Customer:

UK National Screening Committee

Report effective from:

16th March 2009

The National Horizon Scanning Centre

Department of Public Health, Epidemiology and Biostatistics University of Birmingham, Edgbaston, Birmingham B15 2TT England

www.nhsc‐healthhorizons.org.uk

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Introduction In early 2009, the National Horizon Scanning Centre (NHSC) conducted a review of new and emerging diagnostic tests for the screening of infections during pregnancy, on behalf of the United Kingdom National Screening Committee (UK NSC). Current antenatal screening practice Around 700,000 women become pregnant in the UK every year1. Under the National Screening Programme, all women are offered testing for a range of maternal diseases, including a number of infectious diseases. According to current UK practice, between 8‐12 weeks’ gestation, women presenting for antenatal care are routinely offered screening tests for syphilis, Hepatitis B Virus (HBV), Human Immunodeficiency Virus (HIV) infection and rubella susceptibility. Samples of blood are taken, generally at antenatal clinic visits, and sent off for analysis at centralised laboratories. The test results come back to the patient’s record some days or weeks later, and are provided to the woman at her next clinic visit (usually the 20 week scan) if no issues are identified. Tests that are positive or uncertain at this initial screening stage are confirmed by subsequent diagnostic testing and the patient recalled if necessary. Service delivery issues The current system of antenatal screening for infections can be inefficient for several reasons:

a) sampling and testing take place in separate locations (clinic and laboratory respectively), giving rise to the potential for samples and/or results to become mislaid;

b) the sample volume taken may be insufficient for analysis, requiring patient recall; c) samples may be stored incorrectly, invalidating the results; d) there may be problems with test accuracy (especially the occurrence of false

negative results) and quality assurance (QA); e) there is considerable geographical variation in practice.

Point of care testing Point of care (POC) testing (also known as near‐patient testing), in which both sampling and analysis take place in a clinic or primary care setting and the results are available then and there, could alleviate some of these service delivery problems. At present, only a handful of POC tests (POCT) are in clinical use in the UK, predominantly in sexually transmitted disease (STD) clinic and outreach settings. POC testing is not currently part of routine practice in NHS antenatal clinics. This is largely due to concerns over test accuracy and reliability, and well as resource issues such as extra costs and staff training requirements, and reluctance from central laboratories. The UK NSC is interested in knowing about any new tests that may be capable of providing rapid and accurate results during a single routine antenatal visit, thereby avoiding the need

1 Source: NHS Clinical Knowledge Summaries http://www.cks.library.nhs.uk/patient_information_leaflet/antenatal_screening accessed 12 February 2009

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to send samples away ‐ in space and time ‐ for laboratory analysis. The adoption of such a point of care screening strategy within the NHS could offer significant advantages in service delivery and patient care. Clinical issues The use of rapid antenatal testing is of clinical significance for HIV and syphilis infection, as measures can be taken immediately to prevent the baby becoming affected. In the case of HBV infection in the mother, precautions can be taken during delivery and the baby vaccinated after birth, and in cases of rubella the mother can be offered the MMR vaccine after the baby is born to protect any future pregnancies. Although most testing for infections takes place by the end of the first trimester, women at high risk for HIV present for antenatal care as late as 18 weeks on average, and in these cases rapid testing is particularly important. Current technology Rapid diagnostic tests relevant to this review are based on one of three existing methods:

1. Particle agglutination tests: these are based on a simple one‐step antigen/antibody reaction procedure that requires no special equipment, and typically produce results in 10‐60 minutes.

2. Immunoconcentration tests, also known as ‘flow through’ devices. These typically produce results in 5‐15 minutes.

3. Immunochromatography assays using ‘lateral flow’ strips. This is the most recent technological development, and results are generally available within 20 minutes.

In order to sell diagnostic products for clinical use in the United Kingdom, companies must obtain an indication‐specific CE marking2 for each product. HIV and Hepatitis B tests are subject to particularly stringent licensing regulations, and for this reason companies tend to be less proactive in this area of in vitro diagnostics (IVD)3. Unlike for pharmaceutical products, there is no comprehensive database of diagnostic products that are CE marked, so information on CE marking status must be obtained directly from the company concerned. Aims The aim of this review is to identify new and emerging diagnostic screening technologies that may be of interest to the UK NSC in its future planning of antenatal screening services in the UK. The NHSC had four weeks (extended to six) in which to identify, research and compile a table containing basic information on technologies which met the review criteria.

2 The CE (Conformité Europea) mark is the declaration made by the manufacturer that a product meets the requirements in the IVD Medical Devices Directive (98/79/EC), necessary for the product to be sold legally in the European Union (EU). 3 In vitro diagnostic (IVD) tests are carried out on specimen samples taken from the body, e.g. blood, urine and saliva, as opposed to testing carried out directly on or inside the body.

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Review criteria Diagnostic screening technologies developed by selected companies4 that are:

• Indications ‐ for the routine detection of rubella susceptibility, and/or syphilis, and/or HBV and/or HIV infection during pregnancy.

• Timeframe ‐ (i) up to 18 months prior to CE marking, or (ii) CE‐marked but currently

only in limited research use in the UK (i.e. at only a few UK centres)*.

• Speed/efficiency ‐ intended to provide a time from sampling to results (turnaround time, or TAT) of 2 hours or less and/or may confer significant improvements in efficiency to the screening process, e.g. greater test reliability.

* In practice it proved difficult to obtain information on how widely used tests were in the UK, and as a surrogate indicator, tests were included if they had been CE marked recently (i.e. within the last 12 months).

Of particular interest to the UK NSC was intelligence on emerging ‘combination’ rapid POC tests capable of performing multiplex testing (i.e. able to run related tests in parallel on a single integrated system) for syphilis, HBV and HIV in an antenatal clinic setting.

Methods The central strategy of the review was to identify companies active in this field of in vitro diagnostics, and to interrogate their websites and contact them directly to obtain information on their relevant new and emerging products. The review criteria were then applied to the technologies identified, in order to create a table of those that met the criteria. This process was conducted in four steps. Step 1: identification of active companies The first step was to compile a list of relevant existing rapid POC tests, in order to identify those companies that are producing them and may therefore have relevant tests in development. This was done in two ways: 1.1 Intelligence on relevant technologies and companies active in this field was sought

through direct communications with: a) individual POCT experts b) professional organisations, such as the Royal College of Pathologists c) IVD trade associations in the UK and Europe.

Emails were sent to enquire if these individuals and organisations were aware of any relevant tests or could suggest any companies that might be developing such tests. Experts and organisations that did not respond were contacted at least twice more. A

4 Four companies were not included in the NHSC review: Inverness Medical, Philips, Roche Diagnostics and GE Healthcare, since their products were to be investigated by Dr Penny Wilson of the Technology Strategy Board.

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full list of organisations and individual experts approached, and the emails sent to them, are at Annex 1.

1.2 Online sources (listed at Annex 2) were searched using predetermined search terms

(listed at Annex 3) to identify relevant tests (both existing and in development) and active companies. These sources included: a) diagnostic product listings b) technology databases of horizon scanning and health technology assessment

organisations c) licensing organisations outside the EU: list of products approved by the United States

(US) Food and Drugs Administration (FDA) d) clinical trial databases of ongoing research of investigational products e) Medline, Cochrane library and Google.

Step 2: researching company portfolios Once a list of potentially relevant companies had been drawn up we researched their product portfolios by examining their websites for technical information and pipeline intelligence. Any relevant information on technologies that may fit any of the review criteria was identified. Step 3: company engagement Those companies who appeared to have relevant products and/or seemed likely to have active development pipelines were contacted by email to enquire if they had any tests relevant to the review. Companies that did not respond were contacted at least three times in total. Step 4: compiling a technology table Product information obtained from company websites (Step 2) and company correspondence (Step 3) was used to progressively populate a table of technologies. Step 2 was an iterative process because most of the companies needed to be contacted several times to obtain information required for filtering against the review criteria (e.g. the TAT, CE status/plans, and suitability for POC diagnostic screening use). Step 5: filtration of technologies The review criteria were applied to the technologies identified. To be classified as POC, tests were either described as such in company literature or be confirmed as being such by the company through direct correspondence. Some tests could be eliminated with certainty if one or more of the criteria were definitely not met, for example if the company confirmed that the test was not for POC use, or was intended for blood screening rather than diagnostic screening. The remaining technologies were divided into two groups. Those that fully met the review criteria were placed on an ‘A‐List’. Those that met some but not all of the criteria were placed on a ‘B‐List’, if information on the unmet criteria was unavailable (e.g. the company did not reply with required information).

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Results During the period of the review, three of the six experts approached responded to our request for information, as did four of the eight professional organisations, and one of the five trade associations. We identified 39 potentially active companies (Table 1). Thirty‐one responded to our requests for information and eight did not, despite chasing. Table 1. Companies identified and contacted

Company name Abbott Diagnostics Beckman Coulter Biokit SA BioLytical Laboratories Bio‐Rad Laboratories Bioscience Calypte Biomedical Corporation Cambridge BioScience ChemBio Diagnostic Systems Inc Chemtron Biotech Inc CTK Biotech Inc DiaSorin SpA Diesse Diagnostica FIND Diagnostics (Foundation for Innovative New Diagnostics)Fujirebio Diagnostics Inc (aka FDI) Gen‐Probe Inc Healthcare Providers Direct Inc Human Diagnostics Worldwide (aka Human GmBH)IND Diagnostics Inc (International Newtech Development)InnoGenetics InTec Products Inc IQuum Inc J Mitra & Co Pvt Ltd (Embee Diagnostics) Lobeck Medical Ltd LumiQuick MedMira Laboratories Inc MP Biomedicals LLC (subsidiary = Genelabs Diagnostics Ltd)Novartis Vaccines and Diagnostics Inc Omega Diagnostics Ltd OraSure Technologies Inc Orgenics (brand name of Inverness Medical Innovations)Ortho‐Clinical Diagnostics (J&J)/ Veridex Qualpro Diagnostics (Tulip Group) Randox Laboratories Ltd Roche Diagnostics Siemens Healthcare Diagnostics Span Diagnostics Inc Standard Diagnostics Inc Trinity BioTech plc

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Seventy‐seven technologies were identified, of which 34 did not meet one or more review criteria and were eliminated. The remaining 43 technologies were filtered according to the review criteria into two groups: 1. A‐List: 31 technologies that met all of the review criteria (Table 2)

Disease A‐List technologies (see Table 2 for details) HIV 11HBV 5Syphilis 10Rubella 2Combined/multiplex 3Total 31

The A‐List included three emerging combination tests (also known as ‘multiplex’ tests):

a) INST HIV1/2 & Syphilis (60 second) Combo Rapid test from BioLytical Laboratories (CE marking December 2009)

b) Multiplo Rapid HBV/HIV/HCV Antibody test from MedMira Laboratories (CE marking imminent)

c) QuickProfile Blood Screen Panel (HIV/HBsAg/Syphilis) from LumiQuick (fully developed but CE plans undecided).

2. B‐List: 12 technologies that met most of the review criteria, but for which some key

information was not forthcoming from the company (Table 3).

Disease B‐List technologies (see Table 3 for details) HIV 4HBV 2Syphilis 3Rubella 3Combined/multiplex 0Total 12

Table 4 shows three further technologies that did not meet the review criteria but might nonetheless be of interest to the NSC.

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Table 2. A‐List technologies (commercially sensitive information has been removed)

Disease Test name

Company Description and cost

Setting for use Sample type Time to

results CE marking/ availability

HIV INSTI HIV‐

1/HIV‐2 Antibody Test

BioLytical Laboratories http://www.biolytical.com

Rapid in vitro qualitative flow‐through test for the detection of antibodies to HIV Type 1 and 2 Cost: in Europe USD $7‐10 per test

Point of care, inc. antenatal clinic. Can be performed by a nurse/trained personnel

Whole blood (50 µg capillary blood), serum or plasma

60 seconds

CE marked (2006) and available, but not yet in routine use in the UK Research ongoing5

HIV MiraCare Rapid HIV Antibody Test.

MedMira Laboratories http://www.medmira.com

Flow through device. Single use qualitative immunoassay to detect antibodies to HIV type 1 and 2.

Point of care or near patient settings

1 drop of whole blood, serum and plasma

3 minutes CE marked and available in parts of the EU: Spain, Portugal, Germany, Romania + Greece. Not yet being sold in the UK

HIV Capillus HIV‐1/HIV2

Trinity BioTech plc http://www.trinitybiotech.com

Rapid qualitative assay based on latex aggregation, for the detection of antibodies to HIV 1 and 2. Some manual preparation and additional equipment required

Initial screening in low volume testing facilities and in emergency situations

Whole blood, plasma and serum

3‐7 minutes (after some manual preparatory steps)

Available but not widely used in the UK

HIV Hexagon HIV Human Diagnostics Worldwide http://www.human.de

Immunochromatographic rapid test for antibodies against HIV 1 and 2 (3rd generation)

Point of care Whole blood, serum, plasma

5‐20 minutes

Recently CE marked and available

HIV SD Bioline HIV 1/2 3.0

Standard Diagnostics Inc http://www.standardia.com

Immunochromatographic rapid test for the qualitative detection of anitbodies to all isotopes specific to HIV 1 and 2.

Whole blood (20 µg), plasma and serum (both 10 µg needed)

5‐20 minutes

CE marked Oct 2008 and available

HIV Signal HIV test Span Diagnostics Ltd Rapid screening test, based on Point of care Serum and 10 minutes

5 Phase III trial in the United States started July 2007 (n=2,500), comparing reliability and accuracy with existing standard. See http://clinical trials.gov/ct2/show/record/NCT00514605 for details

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http://www.span.co.in lateral flow immunochromato‐graphy, for the early qualitative detection of antibodies to HIV 1 and 2

plasma (after some manual preparatory steps)

HIV One Step HIV test

Chemtron Biohttp://www.chemtron.bio.com

Lateral flow, immunochromatographic test Cost: in Europe €0.60 (approx)

Point of care, inc clinics: performed by doctor, nurse, or technician

Whole blood,plasma or serum

10 minutes In development

HIV Dual Path Platform Technology (DPP) HIV 1‐2 rapid test

ChemBio Diagnostic Systems Inc http://www.chembio.com

Rapid chromatographic lateral flow immunoassay. Company says that this dual path platform system can achieve greater sensitivity than conventional single path lateral flow assays

Point of care Whole blood, serum, plasma oral fluid

≤20 minutes In development

HIV OraQuick ADVANCE® HIV‐1/2 Antibody Test Trade name: 'Advance Awareness'

OraSure Technologies Inc http://www.orasure.com

Single‐use qualitative immunoassay to detect antibodies to HIV 1/2. Manually performed and visually read

Point of care, e.g. outreach programme and mobile testing clinics

Oral fluid, plasma, whole blood (finger stick and venipuncture)

20 minutes CE marked June 2007 and available, but not widely used and research is ongoing6

HIV OnSite HIV 1 + 2 Ab Combo Rapid Test

CTK Biotech Inchttp://www.ctkbiotech.com

Two‐line lateral flow rapid test Point of care Whole blood, serum and plasma

20 minutes Not yet CE marked but available elsewhere

HIV Liat HIV Assay

IQuum Inc http://www.iquum.com

Viral load test to determine disease prognosis and monitor antiretroviral therapy. Fully automated, sensitive and fast quantitative HIV assay for near

Point of care, e.g. emergency room, AIDS clinic. Use by doctor, nurse

200 µl plasma. The use of whole blood is currently under development

<1 hour In development (market research being conducted) Studies of clinical

6 Pilot observational study of use in United States emergency departments started 2007. See http://clinical trials.gov/ct2/show/record/NCT00548041 for details (last updated November 2007)

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patient application. Is performed on IQuum's ‘Lab‐in‐a‐tube' (Liat) system

technician utility planned

HBV INSTI Hep B (60

sec) Surface Antigen Rapid Antibody Test


Rapid in vitro qualitative flow‐through test for the detection of antibodies to HBV Cost: estimated cost in Europe USD $8‐10 per test

Point of care, inc. antenatal clinic. Can be performed by a nurse/trained personnel

Whole blood (finger stick), plasma or serum

60 seconds

In development

HBV Crystal HBsAg test (device or dipstick)

Span Diagnosticshttp://www.spandiag.com

One‐step flow through immunochromatographic visual qualitative test for the detection of Hepatitis B Surface Antigen. Available in a device or dipstick format

Point of care Plasma or serum 15 minutes

HBV OnSite HBsAb Rapid Test

CTK Biotech Inc http://www.ctkbiotech.com

Lateral flow chromatographic immunoassay for the qualitative detection of antibodies including IgG, IgM and IgA to Hepatitis B Surface Antigen. Intended for screening purposes

Point of care Plasma and serum

15 minutes

In development

HBV SD Bioline Hepatitis tests (HBsAg, Anti‐HBs, HBeAg/HBsAg)


One step immunochromato‐graphic assays

Point of care Serum and plasma, and blood (only for HBsAG)

20 minutes Available but not widely used in the UK

HBV One Step HBsAg test

Chemtron Biohttp://www.chemtron.bio.com

Lateral flow, immunochromatographic test Cost: in Europe €0.32 (approx)

Point of care, inc clinics: performed by doctor, nurse, or technician


20 minutes In development

Syphilis INSTI Syphilis

(60 sec) Rapid Antibody Test


Rapid in vitro qualitative flow‐through test for the detection of antibodies to Treponema pallidum

Point of care, inc. antenatal clinic. Can be

Whole blood (finger stick), plasma or serum

60 seconds

In development

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Cost: estimated cost in Europe USD $8‐10 per test

performed by a nurse/trained personnel

Syphilis Signal TP device

Span Diagnosticshttp://www.spandiag.com

Flow through immunochromatographic test for the qualitative detection of antibodies to Treponema pallidum

Point of care Serum or plasma 10 minutes CE marked recently (2008)

Syphilis SD Bioline Syphilis 3.0


One‐step qualitative immunochromatographic screening assay for the detection of antibodies to all isotopes against Treponema pallidum (IgG, IgM and IgA). Lateral flow test, cassette‐mounted (extra supplied needed)

Point of care Whole blood, plasma and serum

5‐20 minutes

CE marked but not widely used in the UK Evaluated by WHO SDI: ‘excellent performance’

Syphilis Syph‐Check POC (also known as SyphPoc)

Healthcare Providers Direct Inc http://www.healthcareprovidersdirect.com

Immunochromatographic colloidal gold anti‐IgG/IgA/IgM conjugate and using recombinant capture antigens. Benefits: company comments that recombinant antigens make the test highly specific, and detection of IgG and IgM allows for detection of all stages of infection.

Point of care (clinic or GP’s surgery). Company intends to seek an FDA CLIA waiver so untrained personnel can perform the test

2 drops of whole blood (finger stick), or 1 drop of either serum, plasma

10‐15 minutes

CE marked and available, but not widely used and research is ongoing7

Syphilis Syphicheck‐WB

Qualpro Diagnostics http://www.tulipgroup.com

Modified TPHA for the detection of Treponema specific IgG and IgM antibodies, self‐performing, double antigen sandwich immunoassay. Cassette‐mounted lateral flow device (no extra supplied needed)

Point of care Whole blood, serum and plasma

15 minutes

CE marked recently (2008)

Syphilis ESPLINE TP Fujirebio Diagnostics Manual cassette‐mounted rapid Antenatal clinic. Serum or plasma 15 minutes Available but not yet

7 The company has informed us of a clinical study (n=1,200) just started at 3 centres, that is due to complete May/June 2009. Preliminary results on >200 patient samples tested by RPR, TPPA, TPHA and FTA yielded a collective sensitivity of 97.6% and specificity of 98.3% versus treponemal tests. Searching online trial databases found a study of validity: sensitivity and specificity in progress (n=600), started Oct 08, completing June 2009. See http://clinical trials.gov/ct2/show/record/NCT00732355 for details. This maybe the same study.

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Syphilis test

Inc http://www.fujirebio.co.jp

membrane lateral flow test (extra supplies may be needed)

Can be performed by doctor/nurse/technician

widely used in the UK

Syphilis OnSite Syphilis Ab Combo Rapid Test


Lateral flow chromatographic immunoassay for the qualitative detection of antibodies including IgG, IgM and IgA for Treponema pallidum. Intended for screening purposes

Point of care Whole blood, plasma and serum

15 minutes

CE marked and ‘new’

Syphilis QuickView Syphilis Antibody Test

LumiQuick http://www.lumiquick.com

Immunochromatographic lateral flow rapid test device for the detection of antibodies to Treponema pallidum

Hospital, clinical laboratory, blood station

120‐150 µl (3 drops) of whole blood, serum or plasma

20 minutes

In development

Syphilis Serodia‐TP.PA Syphilis test

Fujirebio Diagnostics Inc http://www.fujirebio.co.jp

Rapid manual qualitative gelatin particle agglutination assay for the detection of antibodies to Treponema pallidum

Antenatal clinic. Requires a technician to perform it

Serum and plasma

2 hours Available but not yet widely used in the UK

Syphilis Hexagon Syphilis (3rd generation)

Human Diagnostics Worldwide (Human GmbH) http://www.human.de http://www.human‐de.com

Immunochromatographic rapid lateral flow test for Treponema pallidum IgG, IgM, IgA antibodies

Point of care Whole blood, serum and plasma

5‐20 minutes

Recently CE marked and available

Rubella QuickView

Rubella IgG test


Immunochromatography, lateral flow test. Co plan to combine the QuickView Rubella IgG and IgM tests in one single device

Point of care, professional use


20 minutes

In development Clinical trials ongoing

Rubella QuickView Rubella IgM test


Immunochromatography, lateral flow test. Co plan to combine QuickView Rubella IgG and IgM tests in one single device

Point of care, professional use


20 minutes

In development Clinical trials ongoing

Combi HIV/

INSTI HIV 1/2 & Syphilis (60

BioLytical Laboratories http://www.biolytical.c

Rapid in vitro qualitative flow‐through test for the simultaneous

Point of care, e.g. antenatal

Whole blood (50 µg capillary),

60 seconds

In development

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Syphilis sec) Combo Rapid Test

om

detection of antibodies to HIV 1/2 and Treponema pallidum Cost: estimated cost in Europe USD $12‐15 per test

clinic. Can be performed nurse/trained personnel

plasma and serum

Combi HBV/HIV/HCV

MultiPlo Rapid HBV/HIV/HCV Antibody Test.

MedMira Laboratories http://www.medmira.com

Flow through technology Point of care or near patient settings


3 minutes Fully developed; available in Russia

Combi HIV/HBsAg/Syphilis

QuickProfile Blood Screen Panel


Immunochromatographic lateral flow through test

Point of care, performed by technician or nurse


20 minutes In development (evaluation phase). CE marking plans undecided

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Table 3. B‐List technologies (may meet the review criteria, but information incomplete)

Disease Test name

Company Description and cost

Setting for use Sample type Time to

results CE marking/ availability

HIV Rapid Anti‐HIV (1&2) Test

InTec Products Inchttp://www.intecasi.com

Colloidal gold enhanced, rapid immunochromatographic assay for the qualitative detection of antibodies to HIV. Intended for screening purposes

Point of care Whole blood, plasma or serum

15 minutes

Details requested

HIV Advanced Quality Rapid Anti‐HIV (1&2) Test

InTec Products Inchttp://www.intecasi.com

Colloidal gold enhanced, rapid immunochromatographic assay for the qualitative detection of antibodies to HIV. Intended for screening purposes

Point of care Urine 15 minutes Details requested

HIV Biorapid HIV 1&2


Immunochromatographic screening test for the detection of antibodies to HIV type 1 /2

Details requested

Whole blood, serum, plasma

20 minutes

CE marked and available

HIV Aware HIV‐1/2 OMT

Calypte Biomedical Corporation http://www.calypte.com

Single‐use qualitative, visually‐read in vitro immunoassay for the detection of antibodies to HIV type 1 and type 2 in oral fluid specimens (oral mucosal transudate).

Point of care use: doctor’s office, test centres

Oral fluid, plasma, whole blood (finger stick + veni‐puncture)

20 minutes

Details requested

HBV Hexagon

HBsAg 1‐Step Human Diagnostics Worldwide (aka Human GmbH) http://www.human.de and http://www.human‐de.com

Immunochromatographic 1‐step lateral flow test for Hepatitis B surface antigen (HBsAg)

Point of care. Can be performed by a doctor, nurse or technician

Serum and plasma

20‐30 minutes

Not yet CE marked.

HBV MiraWell HBV Rapid Test, Point‐of‐Care Format

MedMira Laboratorieshttp://www.medmira.com

Rapid diagnostic test for the detection of Hepatitis B core antibody

Point of care, e.g. clinical laboratories, mobile testing

Whole blood, plasma or serum

3 minutes Not yet CE marked.

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clinics Syphilis Assure Syphilis

rapid test MP Biomedicals (subsidiary = Genelabs Diagnostics) http://www.mpbio.com

Rapid chromatographic membrane based immunoassay for the qualitative detection of antibodies (IgG and IgM) to Treponema pallidum

Point of care Serum or plasma

10 minutes

CE marked and available

Syphilis One‐Step Syphilis Test

IND Diagnostics Inc http://www.ind.ca

Qualitative immunoassay for detecting antibodies specific to Treponema pallidum antigens

Details requested

Whole blood, serum or plasma

10‐20 minutes

Available

Syphilis LIAISON Treponema screen

DiaSorin SpA http://www.diasorin.com

Fully automated chemiluminescent based test

Details requested

Serum or plasma

40 minutes

Details requested

Rubella LIAISON

Rubella IgG DiaSorin http://www.diasorin.com

Fully automated quantitative chemiluminescent test for the determination of IgG

Details requested

Serum or plasma

35 minutes

FDA approved Q4 2008.

Rubella LIAISON Rubella IgM

DiaSorin http://www.diasorin.com

Fully automated quantitative chemiluminescent test for the determination of IgM

Details requested

Serum or plasma 45 minutes

FDA approved Q4 2008.

Rubella OnSite Rubella Rapid Test


Lateral flow chromatographic immunoassay, intended for screening purposes

Point of care Details requested Details requested

In development.

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Table 4. Technologies not within remit but that may be of interest

Disease Test name

Company Description Setting

for use Sample type

Time to results

CE marking/ availability

Comment

Syphilis (combi with other STDs)

Multiplex test in development that includes Syphilis (also herpes simplex I/II, chlamydia trachomatis, Neisseria gonorrhoea, Trichomonas vaginalis)

Randox http://www.randox.com

PCR‐based detection array. Single multiplex biochip, runs on their Multitstat platform. Automated DNA extraction followed by single tube PCR and an automated biochip assay

Blood, urine, swab

4‐6 hours

In develop‐ment (entering a validation studies) CE expected within 18 months

HIV Determine HIV 1/2 Ag/Ab Combo test

Inverness Medical Available

Expert says: this is the most popular test in the UK, and quite widely used in outreach testing venues. A 4th generation is coming out that should improve sensitivity at the time of primary infection

Rubella Rapid rubella test

Inverness Medical Available

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Discussion A POCT is defined as ‘an analytical test undertaken by a member of the healthcare team or by a non‐medical individual in a setting distinct from a normal hospital laboratory’ (Royal College of Pathologists, 2004). This term encompasses tests requiring varying degrees of manual versus automated processing, but what we were looking for primarily were fully automated ‘black box’ systems, which require just the addition of the sample and a result reading a specific time later. However, it was often unclear from company literature whether tests were suitable for this kind of minimal‐handling POC use, or what kind of personnel were intended to perform them. Tests that run on plasma or serum samples were included, although they require some processing of whole blood. Achieving company engagement in the first instance proved problematic in several cases. Eight of the 39 companies approached did not respond, despite repeated requests for information. Of the 31 companies that did communicate with us, several requests were needed to obtain as much of the required information as possible. The B‐List technologies could not be eliminated or transferred to the A‐List because key information could not be obtained from the company. This was partly due to a lack of time, but not entirely. For example, one question that many companies were unable to answer was whether an existing test was widely used in the UK or not. Several tests remain on the B‐List for this reason, and more time would not have helped. Instead, consulting a UK pathology expert/s might resolve the question. Methods used This report provides a summary of the intelligence gathered during the review. The review acted as a pilot and some useful methodological findings emerged from the process, including: • The central strategy developed in this review of identifying active companies and then

engaging with them directly was effective and considered to provide the best means of obtaining good quality current intelligence.

• The most useful information sources for the initial identification of active companies

were online product listings. • Consulting POCT experts was valuable. • Approaching trade associations and professional organisations for advice did not prove

to be very useful. • In vitro diagnostics is a fast moving field. Product lines are constantly evolving and

technical specifications and evaluative data therefore become rapidly out of date. For this reason general internet searching (e.g. Google) should be concentrated on information that is less than one year old.

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• Searching the clinical trial databases was time consuming and not productive: only three technologies were found, and these had already been more readily identified from other sources.

• Searching databases of published primary and tertiary research such as Medline and

Cochrane reviews was attempted, but the volume of information generated was too great to process productively and the information was often insufficiently current.

The review was conducted over six weeks, by the equivalent of one full‐time NHSC Horizon Scanner. The original deadline of four weeks was unrealistic in view of the extensive company engagement involved, and was extended to six weeks. However, in view of the time lags inherent in communications with companies, a longer timescale such as 3‐6 months would have been more productive. Conclusion Thirty‐one new and emerging rapid tests for the point of care diagnostic screening of HIV, Hepatitis B, and or syphilis infection and/or rubella susceptibility were identified, including three combination tests. These may provide future options for national POC antenatal screening for infectious diseases. Twelve further technologies that may also be relevant were identified, but further information from the companies is required.

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Annexes Annex 1 Experts and organisations contacted Annex 2 Online sources Annex 3 Search terms Annex 1 Experts and organisations contacted

Experts contacted

Professor John Parry, Health Protection Agency (HPA). Microbiologist with expertise in the evaluation of rapid tests for HIV Dr Keith Perry, Director of the HPA Microbiological Diagnostic Assessment Service (MiDAS) Dr Laura van Dommelen. Expert on evaluating rapid syphilis tests Dr Tim Wreghitt, Vice‐President of the College of Pathologists, and a virologist Dr Stephen Gillespie, Chair of Microbiology SAC, Royal College of Pathologists Dr Rosanna Peeling. Head of WHO/TDR STD Diagnostics Initiative (SDI) Dr Cathy Ison, HPA expert on syphilis tests

Professional organisations contacted

Microbiological Diagnostic Assessment Service, MiDAS (Health Protection Agency) Royal College of Pathologists, RCPath Infectious Disease Research Network, IDRN Association of Clinical Biochemists, ACB (consulted via their online chat room by Dr Penny Wilson) European Centre for Disease Prevention and Control, ECDC International Federation of Clinical Chemistry and Laboratory Medicine, IFCC World Association of Societies of Pathology and Laboratory Medicine, WASPaLM American Association of Clinical Biochemists, AACC

Trade Associations contacted

European Diagnostic Manufacturers’ Association, EDMA German IVD trade association, VDGH Irish Medical Devices Association, IMDA Irish Medical & Surgical Trade Association, IMSTA Netherlands IVD trade association, Diagned

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Annex 2 Online sources 2.1 Diagnostic product listings

• RDT Info, http://www.http://www.rapid‐diagnostics.org • Point of Care.net, http://www.pointofcare.net • WHO website, http://www.who.int/std_diagnostics • Lab Tests Online, http://www.labtestsonline.org • Biokits, http://www.biokits.com/list‐Diagnostics 2.2 Horizon Scanning and Health Technology Assessment organisation technology databases

• NHSC in‐house technology database • HTA Programme, http://www.ncchta.org • International Network Association for Health Technology Assessment (INAHTA),

http://www.york.ac.uk • ECRI, http://www.ecri.org • Euroscan, http://www.euroscan.bham.ac.uk • CADTH, Canada, http://www.cadth.ca • Australia and New Zealand Horizon Scanning Network (ANZHSN), http://www.horizon

scanning.gov.au • Medica, http://www.medica.de • IVD Technology, http://www.devicelink.com 2.3 Licensing organisation outside of the EU

• FDA Office of In Vitro Diagnostic Device evaluation and safety (OIVD), http://www.fda.gov/CDRH/oivd

2.4 Clinical trial databases • WHO International Clinical Trials Registry, http://www.who.int/trialsearch • Current Controlled Trials, http://www.controlled‐trials.com • ClinicalTrials.gov, http://www.clinicaltrials.gov • UKCRN Portfolio Database, http://www.public.ukcrn.org.uk/search

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Annex 3 Search terms

Test terms Disease terms Point of care HIV Point‐of‐care Syphilis POCT pallidum POC Rubella Rapid test German measles Rapid Hepatitis B Investigational Hep B New test HBV New HBsAg The test and disease terms were combined using ‘and/or’ instructions to build up search queries.

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Bibliography • Barbara J, Ramskill S, Perry K et al. The National Blood Service (England). Approach to evaluation

of kits for detecting infectious agents. Transfusion Medicine Reviews 2006,21: 147–58. • Branson BM. Point‐of‐care rapid tests for HIV antibodies. Journal of Laboratory Medicine

2003;27(7/8|):288‐295. • British Association for Sexual Health and HIV (BASHH) Clinical Governance Committee. Guidance

on the appropriate use of HIV Point of Care Tests. June 2006. • http://www.http://www.bashh.org/committees/cgc/reports/final_hiv_point_of_care_tests_guid

ance_rev080606.pdf • Celentano DD. Is HIV screening in the labor and delivery unit feasible and acceptable in low‐

income settings? PLoS Medicine 2008;5(5):0693‐0694. • Centers for Disease Control and Prevention (CDC). Revised recommendations for HIV testing of

adults, adolescents, and pregnant women in health‐care settings. MMWR 2006;55(RR14):1–17. • Department of Health. Screening for infectious diseases in pregnancy: standards to support the

UK antenatal screening programme. DH; London: August 2003. http://www.http://www.doh.gov.uk/antenatalscreening

• Greenwald JL, Burstein JL, Pincus J et al. A rapid review of rapid HIV antibody tests. Current Infectious Disease Reports 2006;8:125‐141.

• Hammers RL, de Beer IH, Kaura H et al. Diagnostic accuracy of 2 oral fluid‐based tests for HIV surveillance in Namibia. Journal of Acquired Immune Deficiency Syndrome 2008;48:116‐118.

• Herring AJ, Ballard RC, Pope V et al. A multi‐centre evaluation of nine rapid, point‐of‐care syphilis tests using archived sera. Sexually Transmitted Infections 2006;82:v7‐v12.

• Kendrick SR, Kroc KA, Couture E et al. Comparison of point‐of‐care rapid HIV testing in three clinical venues. AIDS 2004;18(16):2208‐2210.

• National Institute for Health and Clinical Excellence. Antenatal care: routine care for healthy pregnant women. NICE Clinical Guideline CG62. London: NICE; March 2008.

• Pai NP, Barick R, Tulsky JP et al. Impact of round‐the‐clock, rapid oral fluid HIV testing of women in labor in rural India. PLoS Medicine 2008;5(5):e92:0768‐0776.

• Pai NP, Tulsky JP Cohan D et al. Rapid point‐of‐care HIV testing in pregnant women: a systematic review and meta‐analysis. Tropical Medicine and International Health 2007;12(2):162‐173.

• Roberts KJ, Grusky O & Swanson AN. Outcomes of blood and oral fluid rapid HIV testing: a literature review, 2000‐2006. AIDS Patient Care and STDS 2007;21(9):621‐617.

• Royal College of Pathologists. Guidelines on point‐of‐care testing. London: October 2004. http://www.http://www.rcpath.org/resources/pdf/Point‐of‐CareTesting‐updatedOct04.pdf

• UK National Guidelines for HIV testing 2008. British HIV Association, British Association of Sexual Health and HIV British Infection Society. September 2008.

• van Dommelen L, Smismans A, Goossens VJ et al. Evaluation of a rapid one‐step immunochromatographic test and two immunoenzymatic assays for the detection of anti‐Treponema pallidum antibodies. Sexually Transmitted Infections 2008;84:292‐296.

• Weatherburn P, Hickson F, Reid D et al. Evaluation of the Department of Health funded fasTest HIV testing in the community pilots. London: Sigma Research, 2006. http://www.sigmaresearch.org.uk/go.php/projects/project42

• World Health Organisation (WHO) Sexually Transmitted Diseases Diagnostics Initiative (SDI). The use of rapid Syphilis tests. WHO/TDR 2006.

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