General Questions regarding CTDA Registration
Q: What is the purpose of the Coronavirus Test Device Approvals (CTDA) Regulation?
A: The CTDA Regulation requires manufacturers or distributors of molecular and antigen tests for COVID-19 to apply for approval to market their test in the UK. The product must meet the requirements of The Medical Devices (Coronavirus Test Device Approvals) (Amendment) Regulations 2021.
Q: What type of tests does CTDA apply to?
A: CTDA applies to all molecular diagnostic or antigen tests, regardless of the detection technology used, sample type, or testing environment. Algorithms used to analyse test data are also within scope.
Q: What are molecular diagnostic tests?
A: Molecular diagnostic tests detect nucleic acids, such as RNA in the case of SARS-CoV-2. Examples include polymerase chain reaction (PCR), isothermal nucleic acid amplification, and loop-mediated isothermal amplification (LAMP) tests.
Q: What are antigen tests?
A: Antigen tests detect any other viral component or components, such as proteins, lipids, or whole virus. Examples include lateral flow tests, mass spectrometry, and microscopy.
Q: Are all COVID-19 molecular and antigen tests subject to approval?
A: Yes, all COVID-19 molecular and antigen tests are subject to approval, whether they are designed for use in a laboratory, at the point of care, near patient, or for home use (self-test).
Step 1 - Manufacturer and test information
Q: What is the desktop review process?
A: The desktop review is a systematic assessment of the evidence submitted by a supplier against a minimum required data set. The purpose of this step is to prevent tests that are below the expected standards from progressing to a technical validation in a laboratory. The information submitted will be reviewed, passed to a scientific advisor, peer-reviewed, and presented to the Desktop Review Assurance Group meeting for a recommendation on pass or fail. All decisions will be ratified by the Regulatory Approvals Committee.
Q: What documents are required to be submitted with the application?
A: As a minimum, the applicant must supply a Word or PDF document of the instructions for use (IFU) for the submitted test. The IFU must demonstrate the submitted test aligns with the intended use and evidence the stated performance characteristics of the test. Several supporting documents, in addition to the IFU, are also required. The submitted information will be assessed to ensure the key documents for the application are present.
Step 2 - Regulatory Status
Q: What is the regulatory status requirement for COVID-19 tests?
A: The minimum requirement for regulatory approval is either a UK Conformity Assessed (UKCA) or Certificate European (CE) mark. Alternatives, such as health institution exemptions or exceptional use authorization (e.g., MHRA derogation), may also be acceptable. From July 1, 2023, a UKCA mark will be required to place a device on the Great Britain market. The CE mark will continue to be accepted on the Great Britain market until June 30, 2023. For self-tests, the CE mark must be obtained through a third-party conformity assessment via a notified body within the EU and UK. A copy of the certificate and any exemption reports must be supplied.
Step 3 - Intended use case
Q: What information will the IFU be assessed for?
A: The IFU will be assessed for the intended use case, target population, sample collection type and requirements, target use setting, target user, and time to result.
Q: What documentation is required for intended use?
A: Relevant references in the IFU and publications must be attached and highlighted. If not supplied, the submission will be automatically rejected.
Q: What should be described for the target population?
A: The submission should describe if the test is intended for symptomatic and/or asymptomatic cases.
Q: What information is required for sample collection type and requirements?
A: The specifications and product reference numbers for collection devices (including swabs, media, and containers) that have been validated for use with the product must be stated.
Q: What information is required for target use setting?
A: The submission should state if the test is intended for self-test/point of care, near patient testing, and/or laboratory-based.
Q: Who is the target user for the submitted test?
A: The submission should state if the test can be used by a trained healthcare professional, member of the allied health professions, trained lay-person, and/or self-test.
Q: What is the time to result for the submitted test?
A: The time to result, excluding delivery and receipt of samples but including relaying of results into the LIMS system (where appropriate), must be stated.
Step 4 – Test Performance
Minimum evidence to support performance claim
Q: What is the minimum evidence required to support a performance claim for a CTDA application?
A: Essential evidence required is 100 clinical "positive" samples across the full dynamic range of viral loads and 150 clinical "negative" samples as determined by a comparator laboratory RT-qPCR. Desirable evidence is 150 clinical "positive" samples and 250 clinical "negative" samples. These sample numbers apply to each sample type, such as nasal, nasopharyngeal, throat, and saliva. Results for different sample types should not be combined and approval will only be provided for sample types with sufficient data demonstrating performance above the specified thresholds.
Q: Can samples from multiple studies be combined for the data set?
A: Yes, samples from more than one study can be combined, even if different comparators have been used. Samples from pre-identified participants, such as previously PCR or LFD positive, are also accepted if needed to gather data on the full range of viral loads.
Q: What should be done with discordant results?
A: Do not exclude discordant results. If a resolver assay has been used to explain the discordance, the data should be included.
Q: Can data from the Technologies Validation Group (TVG) be used for the CTDA application?
A: If a test has been validated by the TVG, the applicant can request to use the TVG data for the CTDA application by emailing TVGdata@ukhsa.gov.uk
Criteria for comparator method
Q: What is the criteria for the comparator method in COVID-19 testing?
A: The comparator method must be an RT-qPCR method that meets the diagnostic criteria from the Technologies Validation Group guidance "using tests to detect COVID-19." It should be CE-marked with a sensitivity of 97% or higher and a specificity of 99% or higher.
Q: Are clinical diagnosis or results from contrived samples accepted as comparator methods?
A: No, clinical diagnosis or results derived from contrived samples are not acceptable comparator methods.
Q: What raw data is required for the comparator method in COVID-19 testing?
A: The raw data (CT values or equivalent) from the comparator RT-qPCR method and the raw data for internal positive controls from the comparator RT-qPCR method are required in the supplementary evidence submitted through the portal. This is to ensure that the full dynamic range of clinically meaningful viral loads has been evaluated and negative comparator results are not due to assay failure.
Clinical Performance
Q: What is assessed for clinical performance?
A: The IFU, relevant raw data, and published supporting documents will be assessed for key requirements for evidence of clinical performance, including comparison with a RT-qPCR method that meets diagnostic criteria from the Technologies Validation Group: using tests to detect COVID-19.
Q: What is required for the comparator assays used in the assessment?
A: The comparator assays must meet the requirements of the ‘diagnostic criteria’ from the Technologies Validation Group: using tests to detect COVID-19. The name, test number, and IFU version of the comparator assays must be provided, and relevant reference must be attached and highlighted in the IFU and publications.
Q: What is the minimum sample size required for positive and negative clinical samples?
A: A minimum of 100 positive clinical samples and 150 negative clinical samples is required. A desired number is greater than or equal to 150 for positive clinical samples and greater than or equal to 250 for negative clinical samples.
Q: What information is required for the viral load or CT values of positive samples?
A: The CT or viral load of positive clinical samples as measured using the comparator RT-qPCR assays must be provided, and relevant reference must be attached and highlighted in the IFU and publications. The samples should span the dynamic range of clinically meaningful viral loads, including high, high-medium, low-medium, and low viral loads, and should represent the population the test is intended to be used in (such as symptomatic only).
Q: What is required to state the clinical sensitivity of the submitted test?
A: The clinical sensitivity of the submitted test must be determined by comparison with an RT-qPCR assay and raw data must be provided to evidence the statement, at the per sample level, across the dynamic range of clinically meaningful viral loads.
Q: What is required to state the clinical specificity of the submitted test?
A: The clinical specificity of the submitted test must be provided, and raw data must be provided to evidence the statement at the per sample level, compared to the comparator RT-qPCR for all negative samples.
Q: What evidence is required for the performance of the submitted test against contrived samples?
A: Raw data and relevant published papers for performance against contrived samples, such as diluted clinical samples or negative clinical samples spiked with positive control material, are desirable but not a requirement.
Q: What information is required for molecular assays?
A: For molecular assays, the number of SARS-CoV-2 targets in the submitted test and the genes they are associated with must be provided. Relevant reference must be attached and highlighted in the IFU and publications.
Analytical performance
Q: What will be assessed for key requirements of analytical performance?
A: The IFU, relevant raw data, and published supporting documents will be assessed.
Q: What must the analytical performance characteristics of the assay be based on?
A: The analytical performance characteristics must be based on comparison of the submitted test with results obtained using an RT-qPCR method that meets diagnostic criteria.
Q: What is required for the limit of detection (LOD) of the submitted test?
A: The LOD must be stated in copies per ml, and the reference must be attached and highlighted in the IFU and publications. A lack of LOD information will result in automatic rejection. Details of the materials and method used to determine the LOD must also be provided.
Q: What is required for in silico and in vitro testing exclusivity of the submitted molecular test?
A: Evidence of in silico and in vitro testing exclusivity must be provided, and the reference must be attached and highlighted in the IFU and publications. A lack of exclusivity information will result in automatic rejection. Details of in silico tests for primer and probe sequences and any subsequent in vitro testing must be provided.
Q: What is required for evidence of regular in silico analysis against SARS-CoV-2 variants of concern for molecular tests?
A: Evidence of regular in silico analysis against SARS-CoV-2 variants of concern must be provided. The applicant must inform the CTDA administration team within 48 hours of confirmation of a variant of concern affecting the assay target regions. This information is not a requirement but will aid the assessment of the test.
Q: What is required for antigen-based assays?
A: Information on protein targets and regions must be provided. A lack of this information will result in automatic rejection. Details of the test design and target regions, such as monoclonal, polyclonal, terminus, and target protein must be provided.
Q: What is required for in vitro or in silico cross reactivity with common respiratory targets?
A: Evidence of in vitro or in silico cross reactivity with common respiratory targets must be provided, and the reference must be attached and highlighted in the IFU and publications. A lack of this information will result in automatic rejection. Raw data of in silico or in vitro studies with clinical or contrived samples known to contain other respiratory viruses must also be provided.
Q: What is required for the in vitro effect of common interferents?
A: Evidence of the in vitro effect of common interferents must be provided, and the reference must be attached and highlighted in the IFU and publications. A lack of this information will result in automatic rejection. Raw data of any interfering substances tested in combination with the submitted test must also be provided.
Technology performance thresholds for approval under CTDA
Q: What is the CTDA Approval Process?
A: The CTDA Approval Process requires key mainstream technology groups to meet a minimum performance threshold set for the identified technology area. The process is designed to ensure that the government does not endorse substandard tests for their type.
Q: What are the minimum performance expectations for different types of tests?
A: The minimum performance expectations for different types of tests are:
- PCR and isothermal (extracted):
- Sensitivity with 95% 2-sided confidence interval entirely above 93%
- Specificity with 95% 2-sided confidence interval entirely above 97%
- PCR and isothermal (direct):
- Sensitivity with 95% 2-sided confidence interval entirely above 70%
- Specificity with 95% 2-sided confidence interval entirely above 93%
- Antigen:
- Sensitivity with 95% 2-sided confidence interval entirely above 60%
- Specificity with 95% 2-sided confidence interval entirely above 93%
Q: What is sensitivity and specificity in regards to coronavirus test devices?
A: Sensitivity in regards to a coronavirus test device means the percentage of coronavirus positive samples detected by the comparator RT-qPCR that are correctly identified by the test. Specificity in regards to a coronavirus test device means the percentage of coronavirus negative samples classified by the comparator RT-qPCR that are correctly identified as negative by the test.
Q: How is sensitivity calculated?
A: Sensitivity is calculated by dividing the number of true positives by the sum of the number of true positives and the number of false negatives, all multiplied by 100.
Q: How is specificity calculated?
A: Specificity is calculated by dividing the number of true negatives by the sum of the number of true negatives and the number of false positives, all multiplied by 100.
Q: How are the 95% confidence intervals calculated?
The 95% confidence intervals are calculated using the following formula:
Lower 95% CI = (2r + 1.96^2) - (1.96 * sqrt(1 - p) * (4r + 1.96^2)) / (n + 1.96^2) * 2 Upper 95% CI = (2r + 1.96^2) + (1.96 * sqrt(1 - p) * (4r + 1.96^2)) / (n + 1.96^2) * 2
Where:
- r = number of true positives (for sensitivity) or the number of true negatives (for specificity)
- n = number of positives on the comparator RT-qPCR (for sensitivity) or the number of negatives on the comparator RT-qPCR (for specificity)
- p = r divided by n (that is p is the sensitivity or specificity as a proportion)
Q: How is the rounded sensitivity and specificity compared to the thresholds?
A: The rounded sensitivity and specificity are compared to the thresholds by rounding to the nearest 0.1% and then determining if the lower 95% confidence interval is entirely above the threshold. For example, a test with a lower 95% confidence interval that rounds to 92.9% or 93.0% would fail against a threshold of 93%, as the requirement is that the lower 95% CI is entirely above 93%.
Q: What documentation is required for the CTDA Approval Process?
A: For the CTDA Approval Process, supplier confirmation or supporting documents are required to confirm that the submitted test meets the requirement.
Step 5 - Biosafety
Q: What are the biosafety containment requirements for my submission?
A: Please attach and highlight the relevant reference in the Instructions for Use (IFU) and publications. If not supplied, your submission will be automatically rejected. The biosafety of the submitted test will impact the use-case scenario in which it can be utilized.
Q: Does my submission include a viral inactivation step?
A: Please attach and highlight the relevant reference in the IFU and publications. If your submission includes a viral inactivation step, you must provide documented evidence of efficacy according to BSI standards. Viral inactivation statements are not acceptable without documented evidence.
Q: What data do I need to support the viral inactivation claim?
A: Please provide data to support the viral inactivation claim, such as equivalence to similar products or evidence that meets the British Standard for quantitative suspension tests for evaluation of virucidal activity, which requires a minimum titre reduction of 4 log (to base 10) in the virus titre.
Q: Can my submission be used outside of a laboratory setting if it does not include inactivation of clinical samples?
A: Please attach and highlight the relevant reference in the IFU and publications. If your submission does not include inactivation of clinical samples, you must provide evidence of the sample preparation and processing method, such as if it is non-aerosol creating and if full personal protective equipment (PPE) is needed.
Q: What are the regulatory requirements for manufacturers of IVDs for SARS-CoV-2?
A: Manufacturers of all in vitro diagnostic medical devices have responsibilities under UK legislation to undertake vigilance and post-market surveillance activities. In addition, the Medicines and Healthcare products Regulatory Agency (MHRA) also requires manufacturers of IVDs for SARS-CoV-2 to undertake diagnostic assurance with SARS-CoV-2 variants in circulation. See the MHRA guidance outlining the requirements.