National Hepatitis C Testing Policy May 2007

Appendix 6 The Regulation of hepatitis C Testing and Mechanisms for Quality Assurance

Page last updated: July 2007

1. Assuring the Quality of the HCV Test

The TGA has the regulatory responsibility for ensuring the quality, performance and safety of hepatitis C test kits and other IVDs through the Therapeutic Goods Act 1989 and its associated regulations. The objective of the TGA is to assure the safety, quality, performance and timely availability of all test kits available in Australia at a standard at least equal to that of comparable countries. The TGA has the authority to remove from the market any test that does not perform to the expected standard or that is known or demonstrated to be defective.

The TGA is responsible for the pre-market evaluation and post-market monitoring of HCV assays. Under the regulatory framework, pre-market assessment includes a review of evidence of the manufacturer’s quality management system, kit performance, kit presentation, labelling and promotional material and reagent safety and stability.

The TGA currently contracts evaluation of an assay’s performance to the NRL, to ensure it will be suitable for the Australian population. The level and depth of an evaluation is governed by, and commensurate with the risks associated with failure in their use. The evaluation is designed to ensure that the performance is acceptable for the intended use or category of the IVD.

If the performance and other regulatory issues are deemed acceptable, the test kits are included on the Australian Register of Therapeutic Goods (ARTG) as ‘registered’ goods.

The NRL is subcontracted by the TGA to monitor HCV assays in the post-market setting. Participants’ HCV results in external quality assessment schemes provide information about an assay’s ongoing performance during use. Any observed deficiencies are reported to the TGA.

The TGA has mechanisms for the investigation and recall of faulty IVDs. This includes the Incident Report Investigation Scheme (IRIS) for the investigation of all reports submitted to the TGA on adverse events or problems associated with the use of medical devices, including HCV tests. IRIS can be utilised by the laboratories noting performance and safety issues with an assay.

The TGA Recalls Coordinator has the power to withdraw faulty HCV assays, and in the extreme case, to cancel product registration.

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2. Assuring the Quality of hepatitis C Testing

Ongoing quality of testing is best achieved when quality management systems are implemented to ensure good laboratory practice is enforced. Good laboratory practice is supported and defined by relevant industry standards. For Australian medical laboratories, these standards are identified or authored by the National Pathology Accreditation Advisory Council (NPAAC).

ISO 15189 is recognized as the quality management system to be used by medical laboratories. The standard describes, amongst other aspects, the requirement for ongoing monitoring of the laboratory’s performance. Use of quality control (QC) testing and enrolment in External Quality Assessment Schemes are mandated. These tools provide internal and external comparative data to monitor performance. Each is discussed in more detail below.

NPAAC has developed many standards that describe a minimal requirement for good laboratory practice, covering general issues such as laboratory supervision, retention times for records and samples, as well as specific discipline standards. Two standards of this latter group are highly relevant for laboratories testing for hepatitis C. They are "Standards and Guidelines for Laboratory Testing of Antibodies to the Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV)" 2006 and "Laboratory Accreditation Standards and Guidelines for Nucleic Acid Detection and Analysis" 2006.

Evidence of ongoing compliance with these standards can be demonstrated by successful NATA/RCPA Medical Accreditation. Hepatitis C testing should only be performed in laboratories that hold this accreditation as evidence that laboratory practice is of a high standard.

Quality Assurance Programs

Quality Assurance programs (QAPs) provide a means of assessing the successful implementation of effective laboratory management, and in the case of hepatitis C testing, a means of demonstrating ongoing quality of the test and the testing process. Evaluations of HCV tests are conducted before registration and provide base-line information on how a test kit should perform. In Australia, QAPs are used by the NRL to monitor both post-market kit performance and competence of laboratory process using the kits. Providers of QAPs for HCV testing in Australia include the NRL and the RCPA QAP P/L SQAP. The role of different types of QA monitoring tools are described below.

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External Quality Assessment Schemes (EQAS)

EQAS are designed to assess the accuracy of the laboratory testing process, from receipt of the specimen to release of the analysed test result. EQAS usually consists of a panel of specimens sent to participating laboratories for testing at regular intervals. The panels are constructed so that aspects of the testing process and the kit in use can be assessed. The laboratories are able to compare their results with reference results and with the results of similar laboratories. This allows problems to be identified and follow-up provides for resolution of the problems, particularly those that are kit-based. It also creates a networking ability across laboratories so performance evaluation is enhanced. Both Australian QAP providers offer this form of QAP.

Quality Control Samples

Laboratories use quality control samples to continuously monitor the accuracy of HCV antibody and nucleic acid tests. When used in every assay run, the samples allow for confirmation that the test results are reproducible and reliable. Monitoring the reactivity of a quality control sample, which should deliver consistent results across runs and batches, means that intra-laboratory and batch-to-batch variability can be tracked and abnormalities in performance can be assessed as laboratory or test based.

Specificity Monitoring

Ongoing performance of testing can be reviewed through specificity monitoring. If the level of false reactivity in tests in large numbers of samples is monitored, both assay and laboratory problems can be detected. There is usually a low rate of false reactivity, therefore a sudden increase in the false reactivity rate could suggest that the assay’s performance is unsuitable.

Reference Testing

Reference testing serves as a reference point for HCV samples whose status cannot be resolved at the standard or reference laboratory level. Specialised testing strategies are used, among them selected tests not used by other laboratories. This provides an extra layer of testing for samples that are difficult to diagnose using screening laboratories’ usual methods. It is also a base for testing the integrity of samples to be used in quality programs to assure their sameness and stability.

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3.Categorisation

As discussed in Chapter 9, HCV test kits are categorised according to the manufacturer’s assigned intended use. These categories are described in the following table (Table 1).

Table 1: Categorisation of HCV test kits for regulatory evaluation and use

Test categoriesA
Purpose or uses of kits StandardB ReferenceC
Donor Testing – screening of blood and tissue donations. Enzyme immunoassay
Particle agglutination assay
Machine-based immunoassay
NAT screening tests
Level 1*
Enzyme immunoassay
Western blot
Line assay
Rapid assays
Antigen enzyme immunoassay
Discriminatory NAT assay
Qualitative amplification assay
Quantitative amplification assay
Level 3 *
Diagnostic Testing – to determine the infection status of a sample for clinical purposes e.g. diagnosis, antenatal screening, pre-operative, visa, insurance, emergency, testing and supplemental and confirmatory purposes.
Enzyme immunoassay
Particle agglutination assay
Machine-based immunoassay
Rapid test
Alternative sample assay
Level 2*
Unlinked epidemiological surveillance – or definition of infection status of a population where no results are conveyed to individuals from whom samples are taken.
Rapid test
Alternative sample assay
Level 3*
Monitoring and management – quantifies or characterises the virus for clinical management.
Amplification assay
Antigen enzyme immunoassay
Typing assays
Assay for the detection of drug-resistant types of virus
Level 4*


* Denotes the minimum level of evaluation (see below). The levels do not relate to the Classes of kits defined in the IVD regulations to be implemented in 2007.

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  1. Test categories: Laboratories perform standard and/or reference testing.
  2. Standard tests: Standard tests may be used by laboratories performing diagnostic or screening testing to identify the HCV negative antibody status of samples using screening or standard assays. Any test may be used for screening purposes provided it is evaluated to the appropriate level and shown to be appropriately sensitive and specific and approved by the TGA for that use. Those samples yielding non-reactive results do not need to be further tested unless clinical considerations demand it. Reactive samples must be subjected to supplemental testing to distinguish true reactivity from false reactivity. The reference testing must confirm the presence of specific antibody or virus before the result is accepted as a true positive.
  3. Reference tests: Reference tests are used by laboratories to conduct confirmatory or additional special testing. This testing is conducted to confirm true positive status by distinguishing true from false reactivity. Usually this testing is conducted within a diagnostic strategy and an immunoblot is often used; but other reference testing situations occur (e.g. in a setting of possible seroconversion illness) when the first-used reference tests may include a nucleic acid test. Other reference tests may be used once the HCV status is confirmed to quantify viral load, characterise the virus or predict treatment response. These tests may be conducted outside reference laboratories as long as any TGA conditions for the kit registration are met.

Test kit performance evaluations (indicated by Levels 1, 2, 3, 4 in Table 1)

The level of evaluation for any test is commensurate with the risk of delivering a false result associated with its use:

Level 1: Number of samples selected to fully determine all characteristics of the assay in a statistically valid manner and within narrow confidence limits. A full scale Level 1 evaluation involves estimation of sensitivity and specificity in sufficient samples to yield statistically valid assay comparison. Samples for estimation of sensitivity include samples from infected people through the entire course of infection including seroconversion.

Level 2: Full evaluation of sensitivity often within a multi-site protocol and with more limited determination of specificity (i.e. in fewer samples and therefore with a wider confidence interval around the estimation).

Level 3: Evaluation only in a characterised sensitivity panel, with testing in a limited number of negative samples which have potential for or established false reactivity. Rapid test or alternative sample assays, if used for screening, should be evaluated as screening tests (i.e. at Level 1 or 2).

Level 4: Evaluation protocol designed on submission of the assay. Post-market monitoring or collection of data that indicate how the test is performing as it is used will be required as a condition of supply of the kits. The conditions will be indicated on the TGA registration certificate.