Table 1– Evidence required by the World Health Organization (WHO) to enable tuberculosis (TB) diagnostic policy development and policy update
Phase 1: research and development
 Typically consists of upstream research and development to define and validate a prototype, followed by laboratory validation under international standards that culminate in a design-locked product
 WHO interacts with developers if requested to discuss end-user requirements such as biosafety, assay robustness and intended setting of use
Phase 2: evaluation and demonstration
 The performance of the new diagnostic product should be evaluated in controlled trials at three to five trial sites in high-burden TB and HIV countries, ideally using pre-specified and-user product specifications. These data are often used for product registration with global and/or regulatory authorities such as FDA and/or CE marking.
 Product specifications and performance should subsequently be validated in uncontrolled trials under field conditions in five to 10 trial sites in high-burden TB and HIV countries, and include cost-effectiveness studies.
Phase 3: WHO evidence assessment using GRADE
 For new technologies or new indications for use of technologies already approved by WHO
  Submission of dossier with phase 1 and 2 data to WHO
  Structured evidence assessment process (described in figure 3)
 For fast-follower or generic versions of technologies already approved by WHO
  Manufacture of the technology under ISO 13:485 standards; equivalent performance demonstrated in two to three independent supranational TB reference laboratories, to the reference technology already approved by WHO
  Structured evidence assessment process (described in figure 3)
 WHO is not a regulatory authority and does not recommend technologies for individual country use
Phase 4: phased uptake and collection of evidence for scale-up
 New diagnostic successfully implemented in routine diagnostic services by early implementers in high-burden TB and HIV countries; systemic assessment of proposed algorithms, laboratory workload, operational constraints, country by cost-effectiveness. Lessons learnt by early implementers used for country adaptation.
Phase 5: scale-up and policy refinement
 Scale-up of the new diagnostic, with subsequent data used to inform and refine WHO policy guidance in a dynamic and ongoing process
  • FDA: Food and Drug Administration; CE: Communauté Européenne (European Community); GRADE: Grades of Recommendations Assessment, Development and Evaluation; ISO: International Organization for Standardization.