Guidance

Target Product Profile: Point of Care SARS-CoV-2 detection tests

Updated 8 August 2023

Target Product Profile: Point of Care SARS-CoV-2 Detection Tests

Version control

Version

1.0

Date issued

15th June 2020

Description

Initial document

The purpose of a Target Product Profile (TPP)

Target product profiles (TPP) outline the desired ‘profile’ or characteristics of a target product that is aimed at a particular disease or diseases. TPPs state intended use, target populations and other desired attributes of products, including safety and performance-related characteristics. They help guide industry development towards desired characteristics. A TPP provides a common foundation for the development of tests and contains sufficient detail to allow device developers and key stakeholders to understand the characteristics a test must have to be successful for the particular intended use. Included is a description of (1) the preferred and (2) the minimally acceptable profiles based on the intended use, setting of use, and intended user, with respect to the performance and operational characteristics expected of the target products. As new scientific evidence is generated, this TPP may require further review and revision.

TPPs for COVID-19

These product profiles have been developed to assist manufacturers to design and deliver tests that might be useful in support of the UK COIVD-19 testing strategy. How closely a product matches the profile may inform procurement and regulatory decision making. Any deviation from existing standards must be fully justified. Production lead time may also factor into decision making. Implementation of the testing strategy will be enhanced by parallel testing capability offered through the availability of point of care tests (POCT) that can quickly detect the SARs-CoV-2 virus in a near patient setting, allowing health and care professionals to efficiently triage patients depending on their likelihood of being infected.

Such tests require taking a small sample of bodily fluid and looking for the presence of viral nucleic acids or antigens specific to SARS-CoV-2, the causative agent of COVID-19. When available these tests could be used across the broad spectrum of health and care settings and eventually in non-healthcare contexts, such as schools, airports and prisons. They should thus be safe, simple, robust and have a rapid time to test result.

Point of Care SARS-CoV-2 tests for other purposes are not part of this profile and might include:

• to provide a confirmatory diagnosis of patient’s current SARS-CoV-2 infection status
• to prognose a patient’s likely outcome, including disease severity or survival
• to predict or monitor a patient’s likely response to treatment
• to differentially diagnose SARs-CoV-2 from other common febrile or influenzalike disease pathogens, through the use of a multiplex assays
• rapid laboratory tests to augment clinical laboratory capacity and turn around time
• self-tests to be performed by a lay individual

It should be noted that for each of these intended use scenarios, a different TPP could apply. As such the contents of the TPPs in this document are restricted. These TPPs are profiles based on our best information, but the science and use requirements are rapidly evolving. Manufacturers should ensure they are working to the most recent TPP and the most recent science

Clinical performance requirements

This is a specification of the clinically acceptable performance requirements for point of care SARS-CoV-2 viral detection tests. It sets out the clinical requirements based on the consensus of what is ‘minimally acceptable’ in the opinion of UK IVD industry, healthcare professionals and medical device regulators given the emergency situation. A test kit with other specifications than this may not be suitable to support the UK testing strategy.

The intended use of assays that match these profiles (or one that does not yet meet the specifications but looks promising) is to aid in the triage of patients with a current SARS-CoV-2 infection by detection of SARS-CoV-2 nucleic acids or antigens in human samples.

The acceptable criteria for clinical sensitivity and specificity are an initial estimate of minimally acceptable performance based on current expert opinion in a potentially limited number of use cases. Examples of potential use cases of such devices from FIND.

To ensure ongoing public safety and value for money, procurement and deployment of tests should take into account consideration of the specific clinical decision and pathway changes the test is being used to make, the current and future prevalence of SARS-CoV-2 within the intended test population, as well as the potential consequences of false positives and false negatives. For example, the acceptable clinical sensitivity and specificity may need to be higher for some uses of the tests. For example, in populations with a low prevalence of COVID-19 even higher specificity may be needed to prevent the probability that a positive test result is a true positive (positive predictive value) from being unacceptably low.

Annex 2 provides tables which may be useful in supporting decision making, by demonstrating the impact of changing sensitivity, specificity and prevalence on the numbers of false positives and negatives. For example, tests with a low sensitivity may have limited utility in ruling-out SARS-CoV-2 in patients, especially if rule-out may expose others to infection. Similarly, tests with a low specificity may have limited utility in ruling-in SARS-CoV-2 in patients, especially if this may expose uninfected patients to infection, for example by being transferred to a COVID ward.

When used for triage, it may be possible to reduce the potentially harmful consequences of an insensitive or unspecific test, by confirming negative or positive POC results using a more accurate, but slower diagnostic test, such as conventional lab based methods. The advantage of the POC test here could be that at least a proportion of people with, or without, COVID-19 can be managed faster than relying on conventional lab based testing alone.

These specification criteria are based on similar Target Product Profiles published by the World Health Organisation, PATH, and FIND for IVDs to other diseases. Each of these organisations has extensive experience with establishing TPPs for simple, rapid diagnostic tests.

Future developments

These profiles are subject to review and change, as we gain a greater knowledge of the virus, the disease and our needs for an effective response. They may need to be updated at short notice.

As our knowledge and understanding of the disease changes and the UK clinical needs change, so will the specifications. A test that meets this version of the TPP may not meet future versions. When assessing options of available test refer to the latest version of TPP published.

As the market matures, it is expected that test formats will adapt – for example, SARS-CoV-2 may be included in respiratory panels or the target user may include people other than healthcare professionals or tests requiring less maintenance may become available.

It is also expected that as more well curated and well characterised samples become available, then test performance can be established on higher numbers of samples.

Other solutions

Ideally, products should be designed to achieve as many of the optimal characteristics as are feasible, while still satisfying the minimal criteria for all defined features. However, a test that does not yet meet all these profiles may still have a role in supporting the UK testing strategy.

Access to a UK-wide, sufficiently constituted panel of samples (saliva, urine, blood) would be helpful in delivering evaluations.

This could mean either 1. sufficient samples to assess analytical performance – including highly characterised SARS-CoV-2 calibration and control materials and samples containing likely interferent or cross-reactants. 2. a standard set of samples to validate the clinical performance of a test, selected to represent a UK population that the test will be used in.

Target Product Profile: Point of Care SARS-CoV-2 Detection Tests

Key to Table

Acceptable: Defines the minimum acceptable feature

Desired: Highly desirable features of considerable benefit. As time is of the essence, if omitting one of these features significantly accelerates development and production it can be considered.

Scope

Intended use

Desired

Aid in triage of current SARS-CoV-2 infection by detection of SARS-CoV-2 nucleic acids or antigens in samples from people of all ages at any point during active infection.

Acceptable

Aid in triage of current SARS-CoV2 infection by detection of SARSCoV-2 nucleic acids or antigens in samples from people of all ages during the acute phase of infection.

Target population

Desired

People with or without clinical signs and symptoms associated with SARS-CoV-2 infection, if testing is appropriate.

Acceptable

People with clinical signs and symptoms associated with SARS-CoV-2 infection.

Target user

Desired

Trained healthcare professional (i.e. one of the 10 health and social care professional bodies that are overseen by the professional standards authority)

Acceptable

Trained healthcare professional (i.e. one of the 10 health and social care professional bodies that are overseen by the professional standards authority)

Comment

A healthcare professional will select the right test to use with the patient, perform the test and then interpret and communicate the results. There may be some scope for supervised self-sampling where the sample collection device is CE marked for this purpose (eg. saliva samples). Full training appropriate to the intended user is required.

Target use setting

Desired

At the point of care in secondary, primary and community healthcare settings. Non-healthcare settings (e.g. schools, airports, prisons).

Acceptable

At the point of care in secondary, primary and community healthcare settings. Non-healthcare settings (e.g. schools, airports, prisons).

Test design characteristics

Test format

Desired

A standardised kit that contains all materials required for the procedure in a self-contained kit that includes controls, reagents and Instruction for Use. All accessories needed to perform the assay and sample collection included.

Acceptable

A standardised kit that contains all materials required for the procedure in a self-contained kit that includes controls, reagents and Instruction for Use. Accessories needed to perform the assay provided separately (eg. sample collection).

Comment

All accessories need to be validated for use in combination with the test as part of the CE marking.

Target analyte

Desired

Dual (or more) SARS-CoV-2 RNA or antigen targets

Acceptable

Single SARS-Cov-2 RNA or antigen target

Sample type

Desired

Sputum, saliva or other method not using invasive swab

Acceptable

Nasopharyngeal or oropharyngeal swabs, lower respiratory tract aspirates, bronchoalveolar lavage, nasopharyngeal wash/aspirate or nasal aspirate

Comment

Methods not using invasive swabs are desirable due to patient discomfort, pre-analytical errors and issues with supply chain.

Result output

Desired

Semi quantitative

Acceptable

Qualitative

Comment

Reference RNA materials are now available from NIBSC. This may be revised when an International Standard becomes available.

Size

Desirable

Handheld

Acceptable

Desktop, portable

Power requirement

Desirable

No power source needed, or a rechargeable and replaceable battery

Acceptable

Standard mains power supply

Internal controls

Desirable

Required to confirm validity of test and any processing and clearly identify invalid results as invalid

Acceptable

Required to confirm validity of test and any processing and clearly identify invalid results as invalid

Comment

Invalid results may be due to sampling technique

Technical failure rate

Desirable

Less than 1%

Acceptable

Less than 5%

Comment

Demonstrated through post market surveillance. Higher failure rates can lead to delays and lack of confidence with end users. Low test failure rates are more important in settings where users have difficultly repeating tests.

Ease of use and result interpretation

Desirable

Suitable for target user groups (i.e. trained healthcare professionals)

Acceptable

Suitable for target user groups (i.e. trained healthcare professionals)

Need for calibration

Desirable

No calibration required

Acceptable

Remote or auto-calibration

Identification capability

Desirable

Unique barcode or equivalent for integration into electronic systems

Acceptable

Labelling of the device with the patient/donor identification must be feasible.

Performance characteristics

Clinical (diagnostic) sensitivity (or Positive Percent Agreement)

Desirable

Greater than 97% (within confidence intervals of 93-100%)

Acceptable

Greater than 80% (within 95% confidence intervals of 70-100%)

Comment

At least 150 positive clinical samples. The samples should cover a clinically meaningful range of viral loads (i.e. should be from people with high, medium and low viral load) that represents the population the test is intended to be used in. For tests with lower sensitivity, it is envisaged that when used in practice people with negative results will need confirmatory checking by an additional test.

Clinical (diagnostic) specificity (or Negative Percent Agreement)

Desirable

Greater than 99% (within confidence intervals of 97-100%)

Acceptable

Greater than 95% (within 95% confidence intervals of 90-100%)

Comment

At least 250 negative clinical samples. For tests with lower specificity, it is envisaged that when used in practice people with positive results will need confirmatory checking by an additional test.

Comparison method

Desirable

A composite clinical reference standard or dPCR reference method.

Acceptable

A validated CE marked laboratory method in current clinical use, against which the Negative/Positive Percent Agreement is calculated.

Comment

For samples in which the POC test is positive and comparison method is negative, further testing should be done to try and explain the discordant result (for example, repeating the sample run on both tests or using a third method, if available).

Analytical specificity

Desirable

No clinically relevant cross reactivity or interference

Acceptable

No clinically relevant cross reactivity to other Coronavirus species. Minimal interference caused by common interferents at clinically relevant concentrations (dependant on sample type and analyte).

Comment

See Annex 1 for list

Analytical sensitivity (Limit of Detection)

Desirable

Fewer than 100 SARS-CoV-2 copies/mL

Acceptable

Fewer than 1000 SARS-CoV-2 copies/mL

Comment

Positive samples for which the quantity value and measurement uncertainty have been assigned (i.e. by dPCR) should be used to characterize the true positive detection rate. Where a different unit of measurement is used (eg copies/swab, ng/ml) equivalence must be demonstrated.

Clinical utility

Desirable

Evidence that using the test improves system and patient outcomes (for example, time to diagnosis, patient experience, use of pre-cautionary COVID-19 isolation facilities).

Acceptable

Evidence that using the test improves system and patient outcomes (for example, time to diagnosis, patient experience, use of pre-cautionary COVID-19 isolation facilities).

Comment

Refer to NICE evidence standards for further information.

Turn-around time

Desirable

Less than 30 minutes from sample to result

Acceptable

Less than 2 hours from sample to result

Throughput

Desirable

More than 100 tests per unit per 12 hours

Acceptable

More than 6 tests per unit per 12 hours

Test procedure characteristics

Hands-on time

Desirable

Less than 2 minutes

Acceptable

Less than 20 minutes

Sample collection equipment

Desirable

Included with the test

Acceptable

Uses standard NHS consumables

Comment

All accessories need to be validated for use in combination with the test as part of the CE marking.

Sample processing and handling

Desirable

No sample processing steps required

Acceptable

Up to 2 standardised sampleprocessing steps, but these must not take longer than 15 minutes or require additional laboratory equipment (centrifuge, vortex, pipette etc).

Biosafety

Desirable

Standard PPE and safety procedures need to be followed. No need for BSL 2 or 3 laboratory facilities. Evidence that live virus is deactivated early in the process.

Acceptable

Standard PPE and safety procedures need to be followed. No need for BSL 2 or 3 laboratory facilities. Evidence that live virus is deactivated early in the process.

Risk in use

Desirable

Risks have been managed according to ISO 14971.

Acceptable

Risks have been managed according to ISO 14971.

Operational characteristics

Test kit storage and stability conditions

Desirable

No cold chain (15 to 30° C).

Acceptable

Storage of kit and reagents at 2-8° C for at least 12 months. Stable for 12 hours once removed from cold storage.

Assay end point stability (time window during which signal remains valid)

Desirable

Up to 1 hour

Acceptable

Up to 30 minutes

Comment

In a busy testing environment, the need for a stable end point is imperative.

Operating conditions

Desirable

15 to 30° C

Acceptable

15 to 30° C

Connectivity

Desirable

Wireless connectivity into NHS LIMS systems

Acceptable

Not required

Presentation of results

Desirable

Human readable, easy to capture and able to record public health data

Acceptable

Human readable, easy to capture and able to record public health data

Reader to reader variation

Desirable

Doesn’t require reading

Acceptable

Readers should be able to correctly interpret true positive results near the limit of detection

Reproducibility

Desirable

More than 95% between repeats at LoD. More than 99% at higher concentrations.

Acceptable

More than 95% between repeats at LoD. More than 99% at higher concentrations.

Comment

Manufacturers should consider ISO 20395:2019 and ISO 5725-1 when evaluating reproducibility.

Volume of sample

Desirable

Depends on the sample type, but no more than 0.5mL

Acceptable

Depends on the sample type, but no more than 0.5mL.

Disposal requirements

Desirable

No additional disposal requirements.

Acceptable

No additional disposal requirements.

Training needs (Time dedicated to training session for end users)

Desirable

No additional training needed

Acceptable

Less than half day of training needed

Other

Immediate supply volumes (Tests per week, within 4 weeks)

Desirable

5000 tests per day

Acceptable

1000 tests per day

Label and Instructions for Use

Desirable

Conforms to IVD Directive and relevant harmonised standards

Acceptable

Conforms to IVD Directive and relevant harmonised standards

Regulatory status

Desirable

CE marked

Acceptable

Exempt according to Article 9 para 12 or para 13 of IVD Directive

Maintenance

Desirable

Preventive maintenance should not be needed until after 2 year or >5000 samples; an alert should be included to indicate when maintenance is needed.

Acceptable

Preventive maintenance should not be needed until after 1 year or 1000 samples; an alert should be included to indicate when maintenance is needed.

Design and manufacturing environment

Desirable

ISO 13485:2016

Acceptable

ISO 13485:2016

Annex 1: Assay validation

Establishing performance characteristics

It is recommended that the following aspects are considered when designing and validating the assay.

• Reference material should be used to establish performance, including standard validation panels, quality control materials and proficiency testing materials
• When establishing analytical specificity, the following should be considered:
  • Prepandemic samples,
  • other coronavirus, SARS-CoV-1,
  • hCoV 229E, OC43, HKU1, NL63 epitopes
  • Adenovirus (e.g. C1 Ad. 71)
  • Human Metapneumovirus (hMPV)
  • Parainfluenza virus 1-4
  • Influenza A & B
  • Enterovirus (e.g. EV68)
  • Respiratory syncytial virus
  • Rhinovirus
  • Chlamydia pneumoniae
  • Haemophilus influenzae
  • Legionella pneumophila
  • Mycobacterium tuberculosis
  • Streptococcus pneumoniae
  • Streptococcus pyogenes
  • Bordetella pertussis
  • Mycoplasma pneumoniae
  • Pneumocystis jirovecii (PJP)
• Potential interferents may originate from the following endogenous and exogenous sources and may be more relevant to ligand-binding based antigen tests than conventional PCR based assays.

Endogenous substances

• Hemoglobin
• Bilirubin
• Protein
• Triglycerides
• Hematocrit
• Rheumatoid Factor
• Antibodies developed against protein expression system used to generate recombinant antigens

Exogenous substances

• Medications most often prescribed in the patient population for which the test is ordered
• Recommended anticoagulants e.g. EDTA

Annex 2: Diagnostic accuracy considerations

When considering procurement and deployment of devices for any given clinical usecase, it is recommended to consider the maximum number of false positives and false negatives that would be acceptable for the new test based on the possible consequences of these misdiagnoses.

The table below presents the numbers of false positves and negatives in a cohort of fixed size (10,000) with varying prevalence of COVID-19 (NPV/PPV rounded to nearest whole number). Therefore, for a test with a sensitivity of 80% and specificity of 95%:

COVID-19 prevalence	False positives	Positive predictive value (proportion of people with positive results who have COVID-19)	False negatives	Negative predictive value (proportion of people with negative results that don’t have COVID-19)
1%	495	14%	20	100%
5%	475	46%	100	99%
10%	450	64%	200	98%
50%	250	94%	1000	83%

It should also be noted that sensitivity and specificity values estimated in a particular population (i.e. intensive care patients) may not be generalisable to other populations (i.e. general practice) with a different prevalence of COVID-19, if these populations are made up of people with less or more severe COVID-19. For example, accuracy estimates generated in a population of people with early symptoms of COVID-19 may be higher, due to viral load, than a test would achieve in a population of people with no symptoms of the condition.

Prevalence 1%

Numbers per 10,000 tested

		Sensitivity
Specificity	Test result	98%	95%	90%	85%	80%	75%
98%	False +ves False -ves	198 2	198 5	198 10	198 15	198 20	198 25
95%	False +ves False -ves	495 2	495 5	495 10	495 15	495 20	495 25
90%	False +ves False -ves	990 2	990 5	990 10	990 15	990 20	990 25
85%	False +ves False -ves	1,485 2	1,485 5	1,485 10	1,485 15	1,485 20	1,485 25
80%	False +ves False -ves	1,980 2	1,980 5	1,980 10	1,980 15	1,980 20	1,980 25
75%	False +ves False -ves	2,475 2	2,475 5	2,475 10	2,475 15	2,475 20	2,475 25

Prevalence 5%

Numbers per 10,000 tested

		Sensitivity
Specificity	Test result	98%	95%	90%	85%	80%	75%
98%	False +ves False -ves	190 10	190 25	190 50	190 75	190 100	190 125
95%	False +ves False -ves	475 10	475 25	475 50	475 75	475 100	475 125
90%	False +ves False -ves	950 10	950 25	950 50	950 75	950 100	950 125
85%	False +ves False -ves	1,425 10	1,425 25	1,425 50	1,425 75	1,425 100	1,425 125
80%	False +ves False -ves	1,900 10	1,900 25	1,900 50	1,900 75	1,900 100	1,900 125
75%	False +ves False -ves	2,375 10	2,375 25	2,375 50	2,375 75	2,375 100	2,375 125

Prevalence 10%

Numbers per 10,000 tested

		Sensitivity
Specificity	Test result	98%	95%	90%	85%	80%	75%
98%	False +ves False -ves	180 20	180 50	180 100	180 150	180 200	180 250
95%	False +ves False -ves	450 20	450 50	450 100	450 150	450 200	450 250
90%	False +ves False -ves	900 20	900 50	900 100	900 150	900 200	900 250
85%	False +ves False -ves	1,350 20	1,350 50	1,350 100	1,350 150	1,350 200	1,350 250
80%	False +ves False -ves	1,800 20	1,800 50	1,800 100	1,800 150	1,800 200	1,800 250
75%	False +ves False -ves	2,250 20	2,250 50	2,250 100	2,250 150	2,250 200	2,250 250

Prevalence 50%

Numbers per 10,000 tested

		Sensitivity
Specificity	Test result	98%	95%	90%	85%	80%	75%
98%	False +ves False -ves	100 100	100 250	100 500	100 750	100 1,000	100 1,250
95%	False +ves False -ves	250 100	250 250	250 500	250 750	250 1,000	250 1,250
90%	False +ves False -ves	500 100	500 250	500 500	500 750	500 1,000	500 1,250
85%	False +ves False -ves	750 100	750 250	750 500	750 750	750 1,000	750 1,250
80%	False +ves False -ves	1,000 100	1,000 250	1,000 500	1,000 750	1,000 1,000	1,000 1,250
75%	False +ves False -ves	1,250 100	1,250 250	1,250 500	1,250 750	1,250 1,000	1,250 1,250

Annex 3: Glossary

POC/POCT: point of care/point of care tests

RNA: Ribonucleic acid

dPCR: Digital polymerase chain reaction

LoD: Limit of Detection

PPE: Personal Protective Equipment

BSL: Biological Safety Level

LIMS: Laboratory Information Management System

Point of care test (also known as near patient test)

An in vitro diagnostic medical device that is not intended for self-testing but is intended to perform testing outside a laboratory environment, generally near to, or at the side of, the patient by a health professional

Self-test

An in vitro diagnostic medical device intended to be used by a layperson

Analytical sensitivity

Sensitivity of a measurement procedure. Quotient of the change in a measurement indication and the corresponding change in a value of a quantity being measured

Analytical specificity

Selectivity of a measurement procedure capability of a measuring system, using a specified measurement procedure, to provide measurement results for one or more measurands which do not depend on each other nor on any other quantity in the system undergoing measurement.

Clinical (Diagnostic) Sensitivity

Ability of an IVD examination procedure to identify the presence of a target marker associated with a particular disease or condition

Clinical (Diagnostic) Specificity

Ability of an IVD examination procedure to recognise the absence of a target marker associated with a particular disease or condition

The above definitions of performance characterisitics taken from BS EN ISO 18113-1:2011, In vitro diagnostic medical devices — Information supplied by the manufacturer (labelling): Terms, definitions and general requirements.

Positive Percent Agreement

Calculated in the same way as Clinical (Diagnostic) Sensitivity, but indicate that a non-reference standard was used

Negative Percent Agreement

Calculated in the same way as Clinical (Diagnostic) Specificity, but indicate that a non-reference standard was used