Tests in the Essential Diagnostics List (EDL) William Sewell WHO Consultant A/Prof University of NSW & St Vincent’s Hospital Sydney Australia 13 Dec 2018 Adriana Velazquez Berumen | Senior advisor on medical devices, EMP, Geneva www.who.int

Drug-related reasons for Diagnostics Tests Screening Detection of disease in asymptomatic individuals Diagnosis Identification of disease in patients with symptoms Treatment Selection Antimicrobial resistance testing Companion diagnostics in cancer management Check for G6PD deficiency before prescribing certain anti-malarials Monitoring HIV viral load monitoring INR for Warfarin Therapeutic drug monitoring Measuring adverse effects e.g. CBC for toxic effects of chemotherapy The EDL is not intended to be prescriptive and member states will need to take various local factors into consideration as they develop their national EDL’s. More about that in the next workshop. While the EDL provides a list of important tests required at various levels of the health care system, it is important to note that the EDL itself cannot have an impact without an integrated, connected, tiered laboratory system, with adequate, well qualified human resources, laboratory infrastructure, and regulatory/quality assurance systems. Impact also requires Member States to adopt and adapt the EDL and develop national and regional EDLs, as well as to implement the selection and supply mechanisms necessary to ensure access to the IVDs. This will be discussed further in the next workshop. 14/04/2019

Content of the first edition of the EDL Published in May 2018 Section I & II.a Section I & II.b General IVDs Disease Specific IVDs 12 Test Categories 11 Test Categories 23 Test Categories 16 Test Categories 62 Test Categories Section I Primary Care (No lab available) The EDL is arranged to divide test categories between those for use in the Primary Care setting where laboratory trained personnel are not available, and those that require laboratory facilities. In each of those settings, the test categories are arranged in General Laboratory Tests and Disease Specific tests You can see that there are a total of 62 test categories listed in the first edition of the EDL We talk about “TEST CATEGORIES” because each category may include several individual tests on the market for that application, and we do not refer to test brand names in the EDL. ADVANCE SLIDE: The General Laboratory Tests are organized by discipline as shown and further disciplines such as Anatomical Pathology will be added in future editions The Disease specific tests are arranged by disease You can see that the first edition covers WHO high priority disease areas, and this will be expanded in future editions to cover non-communicable diseases as well as neglected tropical diseases. Section II Facilities with Laboratories 14/04/2019

Content of the first edition of the EDL Published in May 2018 Section I & II.a Section I & II.b General IVDs Disease Specific IVDs 12 Test Categories 11 Test Categories 23 Test Categories 16 Test Categories 62 Test Categories Organised by Disease: HBV HCV HIV Malaria Tuberculosis HPV Syphilis Organised by Discipline: Clinical Chemistry and Immunology Blood Transfusion Serology Microbiology, Mycology and Parasitology Haematology Section I Primary Care (No lab available) The EDL is arranged to divide test categories between those for use in the Primary Care setting where laboratory trained personnel are not available, and those that require laboratory facilities. In each of those settings, the test categories are arranged in General Laboratory Tests and Disease Specific tests You can see that there are a total of 62 test categories listed in the first edition of the EDL We talk about “TEST CATEGORIES” because each category may include several individual tests on the market for that application, and we do not refer to test brand names in the EDL. ADVANCE SLIDE: The General Laboratory Tests are organized by discipline as shown and further disciplines such as Anatomical Pathology will be added in future editions The Disease specific tests are arranged by disease You can see that the first edition covers WHO high priority disease areas, and this will be expanded in future editions to cover non-communicable diseases as well as neglected tropical diseases. Section II Facilities with Laboratories 14/04/2019

Example of an EDL Entry General In Vitro Diagnostic Tests I.a General IVDs for primary health care Diagnostic test Test purpose Assay format Specimen type Haematology Haemoglobin (Hb) Diagnosis and monitoring of anaemia Key clinical marker for severe infections (i.e. malaria, dengue, VHFs) Safety monitoring when using certain drugs (e.g. zidovudine for HIV) Haemoglo- binometer Capillary whole blood Venous whole blood Diagnostic Test: The analyte being measured Test Purpose: Brief outline of the common reasons for performing the test Assay format: Recommended method(s) for performing the test (no brand names) Specimen type: Typical specimens used for this test 14/04/2019

Example of an EDL entry Disease Specific In Vitro Diagnostic Tests I.a Disease-specific IVDs for primary health care Diagnostic test Test purpose Assay format Specimen type WHO prequalified or endorsed products WHO supporting documents Hepatitis B Hepatitis B surface antigen (HBsAg) Screening for acute and chronic hepatitis B (HBV) infection: infants over 12 months of age, children, adolescents, adults RDT Oral fluid Capillary whole blood http://www.who.int/diagnostics_laboratory/evaluations/pq-list/hbsag/public_report/en/ Guidelines on hepatitis B and C testing (February 2017): http://apps.who.int/iris/bitstream/handle/10665/254621/9789241549981-eng.pdf?sequence=1 WHO prequalified or endorsed products: Where products have been prequalified, the link to relevant documents is provided WHO Supporting Documents: Links to WHO supporting evidence, guidelines or manuals 14/04/2019

Primary care tests in EDL 1.0 Nearly all blood tests can be performed on capillary whole blood Other specimens are urine (urinalysis & microscopy), stool (microscopy), oral fluid (microbiological RDT) and sputum (TB). The blood-based general laboratory tests are listed on a variety of simple devices. Most disease-specific assays are RDTs or microscopy Section I & II.a Section I & II.b General IVDs Disease Specific IVDs The EDL is arranged to divide test categories between those for use in the Primary Care setting where laboratory trained personnel are not available, and those that require laboratory facilities. In each of those settings, the test categories are arranged in General Laboratory Tests and Disease Specific tests You can see that there are a total of 62 test categories listed in the first edition of the EDL We talk about “TEST CATEGORIES” because each category may include several individual tests on the market for that application, and we do not refer to test brand names in the EDL. ADVANCE SLIDE: The General Laboratory Tests are organized by discipline as shown and further disciplines such as Anatomical Pathology will be added in future editions The Disease specific tests are arranged by disease You can see that the first edition covers WHO high priority disease areas, and this will be expanded in future editions to cover non-communicable diseases as well as neglected tropical diseases. 12 Test Categories 11 Test Categories 23 Test Categories 16 Test Categories 62 Test Categories Section I Primary Care (No lab available) Section II Facilities with Laboratories 14/04/2019

Laboratory-supported tests in EDL 1.0 Assay formats are more complex Assay formats include chemistry and haematology analyzers, bacterial culture, immunoassay, nucleic acid tests (NAT), flow cytometry (for CD4 T cell count in HIV) and interferon-gamma release assays (for TB). Section I & II.a Section I & II.b General IVDs Disease Specific IVDs The EDL is arranged to divide test categories between those for use in the Primary Care setting where laboratory trained personnel are not available, and those that require laboratory facilities. In each of those settings, the test categories are arranged in General Laboratory Tests and Disease Specific tests You can see that there are a total of 62 test categories listed in the first edition of the EDL We talk about “TEST CATEGORIES” because each category may include several individual tests on the market for that application, and we do not refer to test brand names in the EDL. ADVANCE SLIDE: The General Laboratory Tests are organized by discipline as shown and further disciplines such as Anatomical Pathology will be added in future editions The Disease specific tests are arranged by disease You can see that the first edition covers WHO high priority disease areas, and this will be expanded in future editions to cover non-communicable diseases as well as neglected tropical diseases. 12 Test Categories 11 Test Categories 23 Test Categories 16 Test Categories 62 Test Categories Section I Primary Care (No lab available) Section II Facilities with Laboratories 14/04/2019

General IVDs in EDL 1.0 As mentioned earlier, the General Laboratory Tests are arranged according to their disciplines The total of 35 test categories listed, provide basic diagnostic support for a wide range of diseases WHO documentation supporting General Laboratory Tests are presented at the end of the EDL Section I & II.a Section I & II.b General IVDs Disease Specific IVDs The EDL is arranged to divide test categories between those for use in the Primary Care setting where laboratory trained personnel are not available, and those that require laboratory facilities. In each of those settings, the test categories are arranged in General Laboratory Tests and Disease Specific tests You can see that there are a total of 62 test categories listed in the first edition of the EDL We talk about “TEST CATEGORIES” because each category may include several individual tests on the market for that application, and we do not refer to test brand names in the EDL. ADVANCE SLIDE: The General Laboratory Tests are organized by discipline as shown and further disciplines such as Anatomical Pathology will be added in future editions The Disease specific tests are arranged by disease You can see that the first edition covers WHO high priority disease areas, and this will be expanded in future editions to cover non-communicable diseases as well as neglected tropical diseases. 12 Test Categories 11 Test Categories 23 Test Categories 16 Test Categories 62 Test Categories Section I Primary Care (No lab available) Section II Facilities with Laboratories 14/04/2019

Disease Specific IVDs in EDL 1.0 Disease-specific tests in EDL1 focus on high priority infectious diseases: Hep B, Hep C, HIV, malaria, TB, syphilis and HPV. Tests include multiple formats e.g. antigen, antibody, nucleic acid, flow cytometry, microscopy, culture, and others Many disease specific tests are WHO pre-qualified, and all have WHO supporting documents. Section I & II.a Section I & II.b General IVDs Disease Specific IVDs The EDL is arranged to divide test categories between those for use in the Primary Care setting where laboratory trained personnel are not available, and those that require laboratory facilities. In each of those settings, the test categories are arranged in General Laboratory Tests and Disease Specific tests You can see that there are a total of 62 test categories listed in the first edition of the EDL We talk about “TEST CATEGORIES” because each category may include several individual tests on the market for that application, and we do not refer to test brand names in the EDL. ADVANCE SLIDE: The General Laboratory Tests are organized by discipline as shown and further disciplines such as Anatomical Pathology will be added in future editions The Disease specific tests are arranged by disease You can see that the first edition covers WHO high priority disease areas, and this will be expanded in future editions to cover non-communicable diseases as well as neglected tropical diseases. 12 Test Categories 11 Test Categories 23 Test Categories 16 Test Categories 62 Test Categories Section I Primary Care (No lab available) Section II Facilities with Laboratories 14/04/2019

Approach for EDL 2.0 Principles of EDL1 continue: General IVDs plus disease specific IVDs Tests for primary health care and laboratory facilities Requirement for devices to have regulatory approval Improve General IVD section: Flag tests that are time sensitive for Emergency Medicine Expand Disease-specific IVDs to non-communicable diseases Cancer (includes new Anatomical Pathology section under General IVDs) Sources of potential additions in EDL2: Submissions were advertised. EDL Secretariat reviewed EDL1 for gaps. 14/04/2019

Process for review of applications for inclusion in the EDL Application assessed by EDL Secretariat for completeness & circulated to WHO departments Successful candidates invited to make full submissions Submission posted on WHO website for review Submission assessed by experts selected by WHO Expert reviews published on WHO website Assessment reports presented at SAGE IVD meeting SAGE IVD recommend inclusions & exclusions to WHO SAGE IVD recommendations presented to WHO DG Screening application received

EDL 2.0 submissions to date Infectious diseases: Gonorrhoea/chlamydia Histoplasmosis Dengue Zika Procalcitonin for Sepsis Cancer tests: Screening, e.g. faecal occult blood, Pap test Diagnosis, e.g. bcr-abl PCR Choice of therapy, e.g. immunohistochemistry for ER, PR ^ Her-2 in breast cancer Immunodeficiency tests: Serum immunoglobulins and blood lymphocyte subsets 14/04/2019

Further Test Proposals for EDL 2.0 WHO commissioned a study to match: medicines in the EML (446) medical conditions (279) diagnostic tests (325) Many of the General IVDs in EDL1 were linked to very large numbers of medicines and conditions. E.g. CBC is relevant to: 270 medicines on the EML 187 medical conditions Schroeder, Guarner & Amukele (2018) Clin Chem 64:1148-1157 14/04/2019

“Higher Priority Tests” Tests were put on the higher priority list if all 3 authors in Schroeder et al agreed they should be higher priority on the basis of clinical priority, disease burden and test utility - Expert opinion The majority of these tests are already in EDL1. 30 higher priority tests are not in EDL1: 7 had been independently submitted to EDL2 11 Therapeutic Drug Monitoring are now undergoing independent assessment through the EML team 4 in discussion with WHO teams 8 other tests Schroeder, Guarner & Amukele (2018) Clin Chem 64:1148-1157 14/04/2019 | Title of the presentation

The 8 other tests… Anatomical Pathology section General IVDs Anatomical Pathology section Ketones etc in urinalysis TSH Further coagulation assays GGT Urine protein/creatinine ratio Further transfusion testing B-type natriuretic peptide (BNP) 14/04/2019

Draft Anatomical Pathology Section Supporting the new Disease Specific Tests Section for Cancer Diagnostic Tests: Macroscopic assessment Histopathology Cytology (cytopathology) Histopathology with special stains, e,g, Ziehl-Nielsen, silver Immunohistochemistry e.g. ER, PR, HER-2 in breast cancer The draft does not include: Fluorescence microscopy Cytogenetics In situ hybridization 14/04/2019

Conclusion: The need to implement the EDL The EDL is only part of provision of a quality diagnostics service Reliable diagnostics results also need to be supported by: Laboratory infrastructure Qualified personnel Supply chain/communication Quality assurance WHO welcomes your collaboration Emphasise the importance of adoption and implementation. Implementation is the focus of the workshop discussions at this Forum and WHO will be seeking input and opinions from member states on ways to support you in that task. Source: Image from iStock.com 14/04/2019

Gracias Thank you Merci Shokran Xie xie Spasiva WHO 20, Avenue Appia 1211 Geneva EDL Secretariat EDL website: http://www.who.int/medical_device s/diagnostics/Selection_in- vitro_diagnostics/en/ Email: edlsecretariat@who.int Switzerland