Step 2.1 – Determine importation requirements
Step 2.2 – Conduct country validation and verification studies, as required
Step 2.3 – Complete national regulatory processes
Step 2.1 – Determine importation requirements
National authorities should be consulted to determine relevant processes to be followed for importation. Countries should work closely with manufacturers and authorized providers of equipment and consumables, to determine importation and registration requirements, and to initiate country verifications, if required.
Step 2.2 – Conduct country validation and verification studies, as required
Validation includes conducting large-scale evaluation studies to measure the performance of the test if there is any possibility that country-specific factors (e.g. prevalence of different mutations or microorganism strains) may cause performance to deviate substantially from the manufacturer’s results or other evaluation studies. Validation is also required before commencing testing of clinical specimens in cases where laboratories perform non-standard or modified methods, use tests outside their intended scope (e.g. on specimens for which the test has not been validated) or use methods developed in-house. These studies, in addition to testing a well-characterized panel of known positive and negative samples, may include prospectively testing the current gold standard and the new test in parallel on clinical specimens (36).
Verification includes small-scale method evaluation studies in cases where commercial tests are used according to the manufacturer’s intended use. This usually involves testing a well-characterized panel of known positive and negative samples (in a blinded fashion), in line with requirements for national or international accreditation schemes (37). Validation studies are an essential part of the WHO review process and the development of recommendations for the use of a new test. Once large-scale validation studies have been published and a test’s target performance characteristics have been established, laboratories that are implementing the method do not need to repeat such large-scale studies. Instead, implementing laboratories should conduct small-scale verification studies to demonstrate that the laboratory can achieve the same performance characteristics that were obtained during the validation studies when using the test as described in those validation studies, and establish that the method is suitable for its intended use in the population being tested. Countries must make their own determination on the need for verification, based on national guidelines and accreditation requirements.
For example, when planning a targeted NGS verification study (38), the following should be considered:
- A detailed protocol is required, outlining the number and types of samples to be tested and defining the criteria that must be met to demonstrate that the laboratory can achieve the targeted performance characteristics. Samples should be chosen to assess the performance of the entire NGS process, from DNA isolation to interpretation of results.
- If targeted NGS is to be implemented in several laboratories, a more extensive verification study may be done at the NTRL (e.g. 30–50 samples that cover all drugs to be verified and contain a balance of susceptible and resistant isolates), with limited verification studies done at the other laboratories, for cost saving and efficiency.
- For verification, a mix of samples should be selected that will give results at test thresholds (e.g. a mix of positive and negative results) and will give a variety of semiquantitative results. Samples for verification could be leftover sputum or frozen sputum samples with known results, stored clinical isolates or proficiency testing panels. Countries should select a variety of strains for verification, based on their local epidemiology.
- Reproducibility and repeatability could be assessed by testing three reference samples, three to five times each.
- A verification report should be compiled, the observed performance parameters compared with the published performance and a determination of acceptance made.
Step 2.3 – Complete national regulatory processes
Countries should work closely with the relevant government authorities, manufacturers and authorized service providers to meet the requirements of the national regulatory authority. Sufficient time must be allowed to submit the application and provide any required supplementary evidence.