WHO Prequalification: Sample Product Dossier for an IVD intended for HIV self-testing

Transcription

1 WHO Sample product dossier for SIMU self-test for HIV 12O WHO Prequalification: Sample Product Dossier for an IVD intended for HIV self-testing SIMU self-test for HIV 12O PQDx THE Manufacturing Company DRAFT DOSSIER FOR PUBLIC COMMENT Disclaimer This Product Dossier is entirely fictitious and has been produced for illustrative purposes only. Each manufacturer must determine what should be submitted to fulfil WHO requirements. Working document 21 December 2015

2 WHO Sample product dossier for SIMU self-test for HIV 12O World Health Organization 2015 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: ; fax: ; Requests for permission to reproduce or translate WHO publications whether for sale or for noncommercial distribution should be addressed to WHO Press, at the above address (fax: ; The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Contact: Irena Prat, EMP Prequalification Team Diagnostics WHO - 20 Avenue Appia Geneva 27 Switzerland Working document 21 December 2015

3 Table of contents Abbreviations Introduction Purpose of the sample product dossier Content of the sample product dossier Completeness of the sample product dossier Format of the sample product dossier Feedback on the sample product dossier Intended audience The product dossier WHO product dossier elements When to submit a product dossier WHO Product Dossier checklist The product Regulatory versions of this product Product description including variants (configurations) and accessories Product description Intended use Intended users Photographs of kit A general description of the principle of the assay method or instrument principles of operation A description of the components of the assay A description of the specimen collection and transport materials provided with the product or descriptions of specifications recommended for use For instruments of automated assays: a description of the appropriate assay characteristics or dedicated assays For automated assays: a description of the appropriate instrumentation characteristics or dedicated instrumentation If applicable, a description of any software to be used with the product If applicable, a description or complete list of the various configurations or variants of product that will be made available If applicable, a description of the accessories and other products that are intended to be used in combination with the diagnostic Essential principles (EP) check list Risk analysis and control summary Risk analysis policy Risk Categories Erroneous test results Interfering substances Testing process Stability Working document 21 December 2015 Page 3 of 165

4 Specimen type Risk/Benefit Design and manufacturing information Design control Product design Design overview Formulation and composition Biological safety Documentation of design changes Manufacturing process Overview of manufacture Batch release criteria/final lot release Sites of manufacture Key suppliers Product performance specifications and associated validation and verification studies QC panel for SIMU self-test for HIV 12O Product Codes: Y1234-B and Y1234-O Validation of the QC calibrator scale for use in stability studies and at release-to-sale Introduction Study objective Study design and planning QC panel members, criteria, rationale QC panel for SIMU self-test for HIV 12O Product Codes: Y1234-B and Y1234-O Analytical studies Specimen types Specimen type equivalence Specimen stability Analytical performance characteristics Accuracy of measurement Analytical sensitivity Analytical specificity - Effect of interfering substances and unrelated medical conditions Traceability of calibrators and control material values Measuring range of the assay Validation of assay cut-off Validation of assay procedure reading time Stability (excluding specimen stability) Claimed shelf life In-use stability and stability of result Shipping stability Robustness studies Robustness to volume variation Robustness to environment: temperature, humidity, time out of pouch Establishing clinical performance of SIMU self-test for HIV 12O device for professional use and self-testing Working document 21 December 2015 Page 4 of 165

5 7.4.1 Part 1: Clinical performance evaluation - professional use Part 2: Qualification of Usability (Validation of labelling and device interpretation for self-testing; Observed self-testing in trained and untrained users) Part 2-a: Validation of label comprehension for finger stick and OMT job aid and IFU Part 2-b: Validation of result interpretation of results from premade Y1234-B/O cassettes Part 2-c Validation of device usability by observed self-testing in trained users Part 3: Clinical performance evaluation self testing Labelling Packaging Shipping packaging Outer packaging for single test kit Pouch Labelling Outer packaging for single test kit labelling Pouch Instructions for Use Instrument manual Any other instructional materials provided to the user Job aid Other material pre- and post-testing information and instructional video Commercial history Countries of supply List of countries where product is currently supplied Minimum and maximum price in Training and support network Adverse events and field safety corrective actions Regulatory history Quality Management System Quality manual Quality manual system documents Quality manual system procedures Quality manual system certification Annex I: Essential Principles checklist Annex II: Risk management policy Annex III: Residual risk statement Annex IV: Design inputs FMEA Working document 21 December 2015 Page 5 of 165

6 Annex V: User and patient FMEA Annex VI: Input requirements self-testing device Annex VII: THE Manufacturing Company Quality Manual Working document 21 December 2015 Page 6 of 165

7 Abbreviations ACD-A CE CLSI CV DF EDTA EIA FMEA GHTF HBsAg HBV HCV HIV IgA, IgG, IgM IFU IMDRF ISO IVD NAT OMT OD OQ POCT POS QA QC QMS R&D RDT ROW SOP WRT anticoagulant citrate dextrose solution Conformité Européenne (European Conformity) Clinical and Laboratory Standards Institute coefficient of variation degrees of freedom ethylenediaminetetraacetic acid enzyme-linked immunoassay failure mode and effects analysis Global Harmonization Task Force hepatitis B surface antigen hepatitis B virus hepatitis C virus human immunodeficiency virus Immunoglobulins A, G and M instructions for use International Medical Devices Regulators Forum International Organization for Standardization in vitro diagnostic medical device nucleic acid test oral mucosal transudate optical density operational quality point of care test positive quality assurance quality control quality management system research and development rapid diagnostic test rest of world standard operating procedure with reference to Working document 21 December 2015 Page 7 of 165

8 Authors and Acknowledgements The document WHO Prequalification: Sample Product Dossier for an IVD intended for HIV selftesting was prepared by Julian Duncan (consultant, London, UK), Mark Lanigan (consultant, Australia), Mary-Kay Romero (consultant, USA), Deirdre Healy (WHO/HIS/EMP) and Robyn Meurant (WHO/HIS/EMP). This document was developed as part of the Bill & Melinda Gates Foundation Umbrella Grant and the UNITAID grant for Increased access to appropriate, quality-assured diagnostics, medical devices and medicines for prevention, initiation and treatment of HIV/AIDS, TB and malaria. This document was produced under the coordination and supervision of Deirdre Healy, Robyn Meurant and Irena Prat (WHO/HIS/EMP), Geneva, Switzerland. This document is now available for public consultation from 18 December Working document 21 December 2015 Page 8 of 165

9 1 Introduction 1.1 Purpose of the sample product dossier The purpose of this sample product dossier is to provide manufacturers with an example of a product dossier required for WHO Prequalification of an in vitro diagnostic. The product dossier should contain evidence submitted by the manufacturer to demonstrate to WHO that the diagnostic is of acceptable quality, is safe and performs optimally when used (as intended by the manufacturer). Evidence will take the form, for example, of results of testing, certifications, SOPs, systems and any other documentation necessary to support quality, safety and performance. As such, this sample product dossier contains the results of testing, extracts of SOPs and other information that may be of relevance in support of an application for prequalification of a self-test antibody diagnostic. 1.2 Content of the sample product dossier This dossier is based on a fictitious diagnostic, the Simu self-test for HIV 1.2(O) and its fictitious manufacturer, THE Manufacturing Company. As the product and its manufacturer do not exist, any related aspects that have been described within the sample product dossier are purely for the purposes of demonstrating the type of information that may be included in a product dossier submitted to WHO Prequalification. 1.3 Completeness of the sample product dossier Because of its invented nature, the information provided is considered exemplary and not necessarily the full level of detail that may be required to fulfil WHO Prequalification requirements. At times the information is presented in summary format. Additionally, the abbreviation XXX is used extensively to describe materials that do not exist, but again is incorporated to provide an example of the type of information that may be required. Further instructions are also provided in red coloured boxes to indicate where additional information may be expected. This sample product dossier is still in development and not all prequalification requirements have been addressed. WHO will continue to incorporate relevant sections. However, it is important to repeat that the purpose of this document to provide examples. This sample product dossier can never be considered to represent all the evidence that may be needed to meet WHO Prequalification requirements. Each manufacturer is responsible for identifying the type and volume of evidence that will be sufficient. WHO Prequalification staff are available to assist manufacturers at any point in the prequalification process. Staff may be contacted by at diagnostics@who.int. 1.4 Format of the sample product dossier The format of this sample product dossier, including the section numbering system, follows that contained in WHO Publication PQDx_018 Instructions for Compilation of a Product Dossier. This document can be found on the WHO website ( at the following link: pdf 1.5 Feedback on the sample product dossier Comments on this sample product dossier and its utility are welcomed by WHO at diagnostics@who.int. The document has been published for public comment from 21 December Working document 21 December 2015 Page 9 of 165

10 2 Intended audience This document has been created to assist manufacturers who wish to submit a product dossier for a self-test antibody diagnostic. This document provides an example of how a WHO Product Dossier should be compiled in accordance with the instructions and format described in the PQDx_018 Instructions for Compilation of a Product Dossier. This document is available at: pdf Working document 21 December 2015 Page 10 of 165

11 3 The product dossier 3.1 WHO product dossier elements For the purposes of WHO Prequalification Diagnostics, the product dossier is a selection of records and documents compiled by a manufacturer from their existing records and documents to provide evidence that the IVD submitted for WHO prequalification conforms to the Essential Principles of Safety and Performance of Medical Devices 1 and meets other WHO requirements. During the WHO review of a product dossier, WHO will take into account the information that was previously submitted in the WHO Publication PQDx_015 Prequalification of Diagnostics Presubmission form. Therefore, manufacturers should ensure that the content of the product dossier is consistent with the information submitted with the pre-submission form and that any changes in the information submitted with the respective pre-submission form are promptly notified to WHO. Furthermore, inadequacies identified at the pre-submission form stage and communicated by WHO to the manufacturer are expected to be addressed as part of the product dossier submission. 3.2 When to submit a product dossier Manufacturers should only submit a product dossier to WHO Prequalification when formally requested to do so by WHO. Dossiers that are submitted without a request from WHO will be returned to the manufacturer without review. Manufacturers should ensure that the dossier contains all the information as is prescribed in PQDx_018 Instructions for Compilation of a Product Dossier. The prequalification procedure may be terminated if the dossier does not contain the prescribed information, or where the information supplied is inadequate to complete the prequalification assessment effectively or where the requested information is not provided by the manufacturer within a specified time period. 1 GHTF/SG1/N41R9:2005 Essential Principles of Safety and Performance of Medical Devices Working document 21 December 2015 Page 11 of 165

12 4 WHO Product Dossier checklist The attached Product Dossier contains information in support of the previously submitted Prequalification of Diagnostics Pre-submission form (Document PQDx_015) for the following product: PQDx Number: Product Name: Manufacturer Name: PQDx Simu self-test for HIV 12O THE Manufacturing Company PRODUCT DOSSIER CHECKLIST Dossier Content Requirement Provided Location: NOTE: The below matches that of PQDx_018, Instructions for compilation of a Product Dossier. Letter of Agreement The Letter of Agreement is attached to the front page of the dossier and supports attestation of payment The information concerning the product is the same on the Letter of Agreement and the Prequalification Dossier 4. Dossier Format Yes Yes/No Yes Yes Volume/Section Page number Page number Annex XXX Page XX Annex XXX Page XX 4.1. Product Dossier Submission Format Yes Entire dossier One printed copy and one electronic copy of product dossier submitted Yes Not applicable A signed document attesting that the content of the electronic version is an exact duplicate of the printed copy was submitted Dossier is clearly presented (bound or in a clearly marked set of ringbinders) 4.2. Layout and Order Yes Yes Yes Annex XXX Page XX Entire dossier Proper formatting of 1 of 2, 2 of 2, etc., used Yes Entire dossier The submission is clearly divided into sections as described and all pages are numbered Table of contents included This checklist is attached to the front of the submission and used as a cross-reference Yes Yes Yes Page 6 Entire dossier The physical pages of the dossier and the pages numbers correspond Yes Entire dossier There are appropriately named tab identifiers Yes Entire dossier Standard A4 paper is used for all submissions Yes Entire dossier Font sizes are easily legible Yes Entire dossier Electronic Copy Requirements Yes The electronic copy is in PDF form with no password required The electronic copy is organized in the same format as the printed copy The name of the file is descriptive and doesn t contain any of the noted special characters Yes Yes Yes Working document 21 December 2015 Page 12 of 165

13 Dossier Content Requirement Provided Location: The electronic copy is in PDF form with no password required Language and Units of Measurement Yes Entire dossier English language and units of measure used Yes Entire dossier Any translations must be carried out by a certified translator Yes Entire dossier 5. Product Yes Page Regulatory versions of this product Yes Page 20 All regulatory versions of the product are identified and the version being submitted for assessment is indicated For all submissions, the regulatory version to which it relates is identified 5.2. Product description including variants (configurations) and accessories The intended use of the diagnostic, testing population, user, and setting of use for the diagnostic is included Photographs of all kit components, both packaged and individual, are included A description of the principle of the assay method/instrument principles of operation are provided Yes Yes Page 20 Yes Entire dossier Yes Page Yes Page 22 Yes Page 22 Yes Page A description of the components and reactive ingredients are included Yes Page 24 A description of the specimen collection and transport materials are provided A description of the appropriate assay and instrumentation characteristics are included If applicable, there are descriptions of software to be used with the product, a list of variants/configurations of the product, and a description of accessories are included. Yes Page 24 Yes Page 24 Yes Page Essential principles (EP) checklist Yes Page 25 Annex I A checklist in the form of a table that lists all relevant material is included Yes Annex I 5.4. Risk analysis and control summary Yes Page Annex II, III, IV, V There is a summary report of the risks identified during the risk analysis process Yes Page Annex II, III A description of how risks have been controlled to an acceptable level Yes Page A signed conclusion with evidence that the remaining risks are acceptable is presented There is evidence that the risk analysis is part of the manufacturer s risk management plan When applicable, specific standards/guidelines recommended by the WHO are identified Yes Annex III Yes Page 25 Annex II Yes Annex II 6. Design and manufacturing information Yes Page Product design Yes Page Working document 21 December 2015 Page 13 of 165

14 Dossier Content Requirement Provided Location: Design Overview Yes Page 30 Annex VI Information to provide a general understanding on design is provided Yes Page 20-24, There is a flowchart of the design process Yes Page A general description of the critical assay ingredients for use with the product is provided Yes Page If applicable, a controlling site is identified Yes Page Formulation and composition Yes Page For each of the ingredients, formulation/composition information is provided Yes Page Sources of IVD component materials are identified Yes Page Biological safety Yes Page Annex X There is a table, including all needed information, listing all biological components included in the product If applicable, a determination of the residual risk of transmission/infection to the user is provided There is information on how users of the device are informed of any residual risk Yes Page Yes Page Yes Page Documentation of design changes Yes Page Records of each design change for the product submitted, with all pertinent information, is included Yes Page Manufacturing process Yes Page Overview of manufacture Yes Page A flow chart of the entire manufacturing process is included Yes Page A site master file, with a diagram of the floor plan, is provided Yes Page If applicable, certified copies of Quality Management System certificates are annexed to the dossier There are details of each major step in the manufacturing process with all needed information included in the proper form There is an overview of verification, validation, and quality-control activities for all stages of design and manufacture Yes Annex XX Yes Page Yes Page Batch release criteria for the product are included Yes Page 36 Annex XX Sites of manufacture Yes Page 37 All critical manufacturing sites for all necessary stages of manufacture are listed with all necessary information Yes Page Key suppliers Yes Page 38 All key suppliers are listed with all needed information Yes Page 38 If applicable, certified copies of the key suppliers certificates are annexed to the dossier 7. Product performance specifications and associated validation and verification studies Yes Annex XX Yes Page Working document 21 December 2015 Page 14 of 165

15 Dossier Content Requirement Provided Location: 7.1. Analytical studies Yes Page Specimen types Yes Page Annex XX The different specimen types that can be used with the product are identified The studies needed information for support of the specimen type are included The studies and needed information for support of claims made for specimen types are included Yes Page 48 Yes Page Yes Page Analytical performance characteristics Yes Page Annex XX Accuracy of measurement Yes Page Trueness of measurement Yes Page 51 The studies and information needed to establish trueness of measurement are provided Yes Page Precision of measurement Yes Page Repeatability Yes Page The studies and information needed to establish within-run variability are included If applicable, provide studies to establish repeatability undertaken by non-laboratory personnel Yes Page Yes Page Reproducibility Yes Page Studies and information to establish the appropriate types variability are included The use of specimens that represent the full range of expected analyte concentration are included If applicable, provide studies to establish repeatability undertaken by non-laboratory personnel Yes Page Yes Page Yes Page Analytical sensitivity Yes Page The studies needed to establish analytical sensitivity are included with all needed information If applicable, the needed parameters are provided and there are details on their derivation Yes Page Yes Page Analytical specificity Yes Page There are studies and information included that evaluate the effects of potentially interfering and cross-reacting substances/agents on the assay Metrological traceability of calibrators and control material values There is detailed information about the traceability of values assigned to calibrators and trueness control materials Yes Page Yes Page 63 Yes Page Measuring range of the assay Yes Page 63 Studies and information that define the measuring range of the assay are included Yes Page 63 Working document 21 December 2015 Page 15 of 165

16 Dossier Content Requirement Provided Location: Validation of assay cut-off Yes Page 63 Studies and information on how the assay cut-off time was determined are included Yes Page Validation of assay procedure-reading time Yes Page Studies and information on how the reading time was determined are included Yes Page Stability (excluding specimen stability) Yes Page The studies and information on stability are included Yes Page When applicable, the manufacturer has looked to internationally accepted methods for determining stability of diagnostics and followed WHO recommendations for stability Yes Page Claimed shelf-life Yes Page Ensure that testing is done on at least three different lots manufactured under conditions equivalent to routine production conditions Yes Page The study protocol specifies acceptance criteria and testing intervals Yes Page Accelerated studies/extrapolated data are acceptable for initial shelf life claim, but have been/will be followed up with real time stability studies Yes Not applicable If applicable, the method used for accelerated studies is identified Yes Not applicable The shelf life is derived from the lot with the shortest real time stability data Yes Page The conclusions clearly identify claimed shelf life stability Yes Page In use stability Yes Page There are studies and information for each assay component s in-use stability provided Yes Page For each component, there is testing on at least one lot Yes Page The studies reflect routine use of the device Yes Page The study protocol specifies acceptance criteria and testing intervals Yes Page If applicable, supporting data for calibration stability claims is provided Yes Page Conclusions clearly identify the claimed in-use stability Yes Page Shipping stability Yes Page Information needed on shipping stability studies is included. These Yes Page studies are of one lot to evaluate the tolerance of products to the anticipated shipping conditions Studies are done under real/simulated conditions that include variable Yes Page conditions The studies reflect the environmental conditions of the countries of Yes Page supply, along with justification The study protocol specifies acceptance criteria and testing intervals Yes Page If applicable, the methods of simulated conditions must be identified Yes Page The results and conclusions must clearly demonstrate that the product will be effective at the end of its claimed shelf life after being subjected to the stressed conditions Yes Page Working document 21 December 2015 Page 16 of 165

17 Dossier Content Requirement Provided Location: 7.3. Robustness studies Yes Page There is a summary of all evidence for the robustness study(ies) Yes Page The test environment and its relation to the intended environment are stated There is a discussion of what tests were considered for the device and why they were/were not performed There is a discussion to support why the evidence presented is sufficient to support the application If applicable, there is reference to the studies and endpoints for performance studies that include human factors/usability end points Yes Page Yes Page Yes Page Yes Page Clinical evidence (clinical or diagnostic sensitivity and specificity) Yes Page Clinical evaluation - Part 1 Clinical performance evaluation - professional use All performance claims are supported by well-designed performance evaluations that have been carried out/coordinated by the manufacturer and these studies are included with all needed information Clinical evaluation - Part 2: Qualification of Usability (Validation of labelling and device interpretation for self-testing) Yes Page Yes Page Yes Page If applicable, publication details of the independent study(ies) is included Yes Annex XX Testimonials are not included as evidence of performance Clinical evaluation - Part 3: Establishing clinical performance for self-testing If applicable, publication details of the independent study(ies) is included Testimonials are not included as evidence of performance Not applicable Yes Page Yes Annex XX Not applicable 8. Labelling Yes Page The product dossier contains a complete set of labelling associated with the product with all four needed inclusions Yes Annex XX 8.1. Labels Yes Page Copies of all packaging labels for the assay are included and contain all needed information Yes Page Instructions for use Yes Page 100 Annex XX A copy of the current instructions for use are included and these instructions include all needed information Yes Annex XX 8.3. Instrument manual Yes Not applicable If applicable, there is a copy of the instrument manual/associated operator manuals included Yes Not applicable 8.4. Any other instructional materials provided to the user Yes Page 101 Annex XX If applicable, any other instructional material copies are provided Yes Annex XX 9. Commercial History Yes Page 102 Working document 21 December 2015 Page 17 of 165

18 Dossier Content Requirement Provided Location: 9.1. Countries of supply Yes Page 102 There is a list of all countries in which the product under assessment is currently supplied and the year when supply started For each country, detailed information about the training and support network are provided with all needed information The minimum and maximum global price of supply for the product for the last financial year or included (quote in USD) Yes Page 102 Yes Page 102 Yes Page Adverse events and field safety corrective actions Yes Page 102 A list of all adverse events within the last five years, with details of the corrective and preventive action taken, is provided There is a list of all events within the last five years that required field safety corrective action Yes Page 102 Yes Page Regulatory History Yes Page 103 If applicable, include a list of National Regulatory Authorities that have Yes Page 103 provided current regulatory approval for the supply of the in vitro IVD under assessment, as well as the type of regulatory approval obtained, in the countries/regions of the product authority Current evidence of the regulatory approval, such as certified copies, Yes Page 103 must be included If applicable, there are details regarding any situations in which the Yes Page 103 product was rejected by a National Regulatory Authority, an application was withdrawn, or approval was withdrawn Information relating the export-only regulatory approvals are clearly identified Yes Page Quality Management System Yes Page 104 Annex VII Quality manual system documents and procedures Yes Page 104 Annex XX There is a copy of the current version of the manufacturer s quality manual and all needed points are addressed Yes Annex VII An organizational chart for the manufacturer is provided Yes Annex XX A complete list of all valid quality management systems documents, with needed information, is included Documented procedure/s for the control of design and development changes are included Documented procedure/s relevant to risk management planning and implementation are included Documented procedure/s relevant to control of non-conforming goods are included Documented procedure/s relevant to the control of the key suppliers are included Yes Yes Yes Yes Yes Annex XX Annex XX Annex XX Annex XX Annex XX Quality management system documents Yes Annex XX If applicable, there is evidence of certification for the manufacturer of the product Yes Annex XX Working document 21 December 2015 Page 18 of 165

19 Dossier Content Requirement Provided Location: The two previous inspection reports issued by the certification body are included Yes Annex XX 14. Essential principles (EP) checklist Yes Annex I This checklist is filled in as per the description and examples provided in the instructions Yes Entire dossier Manufacturer Declaration: The undersigned authorized contact person for the Manufacturer makes the following declarations on behalf of the Manufacturer and, in signing this product dossier checklist form, declares that he/she has the authority to bind the Manufacturer. I declare that: I am authorized to represent the manufacturer specified in this prequalification product dossier (the "Manufacturer") for the purposes of WHO Prequalification of Diagnostics Programme of the product specified in this product dossier (the "Product"). All the information provided in this product dossier is current and correct. This product dossier contains all the information as is prescribed in WHO Publication PQDx 018 Instructions for compilation of a Product Dossier. The Manufacturer will notify WHO of all changes and variations to the Product prior to implementation of the changes. The Manufacturer will notify WHO of any changes to the regulatory approval status for the Product, such as suspension or withdrawal of regulatory approval, in all countries of manufacture and supply. Name of the Authorized Contact Person for the Manufacturer: Alan Bloggs Signature of the Authorized Contact Person for the Manufacturer: Alan Bloggs Date: 14/December/2015 Please Note: The Checklist submitted to WHO must be signed and dated. Working document 21 December 2015 Page 19 of 165

20 1 2 5 The product Insert intended use statement Regulatory versions of this product There are two regulatory versions of the SIMU self-test for HIV-12O. The ROW version, which will be submitted for approval by WHO, has two product codes: Y1234-B SIMU self-test for HIV-12O for use with whole blood, Y1234-O SIMU self-test for HIV-12O for use with oral mucosal transudate (OMT). There is a version for Jordan (product code Y1222-B and Y1222-O) approved by the local agency Jordan Food and Drug Administration. The test device is presented in a single, waterproof primary package that contains all materials necessary for testing: Y1234-B SIMU self-test for HIV-12O for use with whole blood is supplied with a retractable safety lancet, an alcohol swab and an adhesive bandage and an opaque, zip lock disposal bag for discrete disposal. Y1234-O SIMU self-test for HIV-12O for use with oral mucosal transudate is supplied with an oral fluid collection device for oral mucosal transudate collection OMT (also known as gingival crevicular fluid), and an opaque, zip lock disposal bag for discrete disposal. Spare lancets are available at the point of distribution as an accessory pack (of 20 items) with alcohol swab and adhesive bandage (product code A1234), if required for use in a supervised selftesting service. The device is shipped to distributors in secondary packaging of 100 units, as described in Section 8 of this dossier. Unless stated otherwise, all data submitted in this application were generated using only the ROW version of the product, with the finalised version of the method written and depicted in the Instructions for Use (IFU) using reagents made to final validated scale on manufacturing equipment that will be used for routine production. There are no differences in design, specifications, materials or manufacturing processes between the regulatory versions of the product. In-process controls use the same materials between the two product versions. However, the version for sale in Jordan undergoes extra lot release testing using specific specimens, and has particular labelling that is required by the local regulations. Aside from extra regulatory testing and labelling there are no differences between the ROW and Jordan versions of the product. 5.2 Product description including variants (configurations) and accessories Product description The product is comprised of a small moulded hand-held auto-transfer cassette and either a lancet for fingerstick capillary blood release (Y1234-B) or a device for collecting oral mucosal transudate (Y1234-O). See Figure for an overview of the construction and components of the cassette. Working document 21 December 2015 Page 20 of 165

21 39 Figure 5.2 1: Components of the SIMU self-test for HIV-12O The device is completely self-contained. It is prefilled with all required reagents and includes an EDTA-coated chamber of defined volume. This design eliminates the need for a user to pipette a specific volume of test fluid, whether whole blood or OMT. Fingerstick blood is added by applying a hanging drop to the specimen port. OMT is collected from gingival tissue using the oral fluid collection device provided. The collection device is then inserted directly into the specimen port and squeezed to release fluid. Adding specimen to the port will fill the specimen chamber. Addition of insufficient specimen volume can be readily observed through the specimen chamber view (a dye included in the Y1234- O cassette, which is also visible to visually impaired individuals, allows OMT to be observed). More specimen can be added if required. However, only a small volume is needed and validation shows that it is extremely unusual that the chamber does not fill on the first attempt (insufficient specimen volume is most likely to occur as a result of intentional manipulation by the user). Once the chamber has been filled the test is started by the user squeezing the end of the device until a loud click is heard and the device changes shape (becomes shorter). Clicking the device prevents not only the addition of more fluid but also the user coming into contact with any fluid in or around the port. Once the test is started, excess specimen remains safely contained in the device. See Figure Working document 21 December 2015 Page 21 of 165

22 57 Figure 5.2 2: Operating the SIMU self-test for HIV-12O once loaded with specimen Intended use The SIMU self-test for HIV 12O is a qualitative in vitro diagnostic test for the detection of antibodies to HIV-1 (Groups M and O) and HIV-2. Two different formats exist Y1234-B SIMU self-test for HIV-12O for use with whole blood (fingerstick or venepuncture), and Y1234-O SIMU self-test for HIV-12O for use with oral mucosal transudate The test is for use in adults and adolescents. It is a single use test and is suitable for self-use. This test does not need to be used in a medical setting. NOTE: This test should not be used for blood donor screening Intended users The SIMU self-test for HIV 12O is intended for use by the adult and adolescent population (aged 11 years and above) as a triage test for antibodies to HIV-1 (Groups M and O) and HIV-2. When used as a self-test, it should not be considered as a step in the testing algorithm Photographs of kit Insert photographs of all kit configurations with all components and accessories collectively and individual components and accessories, in and out of any packaging Working document 21 December 2015 Page 22 of 165

23 A general description of the principle of the assay method or instrument principles of operation. The mechanism of antibody detection is a third generation (antigen sandwich) lateral flow (immunochromatographic) assay using both colour-augmented, nanoparticle-labelled recombinant HIV antigens and a synthetic peptide in the flow path. The fixed capture reagents at the test line are antigens of the same amino-acid sequences but cloned into a different host organism to prevent anti-species false reactivity (see European patent Eur. Pat priority 1988). In addition, the test line contains anti-human Ig (G, M, A) to act as a second capture system. This double capture system overcomes the problems of a potential prozone effect with blood and of very low antibody content in oral mucosal transudate (Parry, J.V., Ann. N.Y. Acad. Sci. 694 (1993) ). The control line, which contains the same mixture of capture reagents as the test line, acts as a stability and functionality monitor. A third reagent line, between the test and control lines, contains a monoclonal humanised antibody directed against the primary HIV-1 epitope. When labelled antigens (regardless of whether the specimen is positive or negative) pass across this line they react exactly as with a positive specimen, bind to the monoclonal antibody and are then captured at the control line. This ensures that reagents in the system are active (stable) at the time of use, and that the flow of liquid is sufficient to ensure a valid test. Specimen (OMT or whole blood) is added to the device through the sample port. Whole blood is entered by touching a drop of blood from fingerstick to the absorbent material at the base of the port, OMT is entered by squeezing the oral fluid collection device provided into the port, where both the corrugations on the moulding and the absorbent material draw liquid into the device. Clicking the device opens the running fluid reservoir, forces the wicking system into the fluid and moves a shutter across the specimen port, sealing the device and allowing it to be safely handled and discarded (see Figure 5.2 2). After the reservoir is opened the fluid travels by capillary action along the device membrane, allowing both HIV antibodies (if present) and labelled antigens to migrate across the test capture line, the monoclonal humanised anti-hiv-1 antibody, the control line and finally into the waste reservoir. A valid test, where the control is visible, gives a high degree of assurance at the time a test is conducted that the antigens in both capture line and conjugate are stable and functional. In-built timing: Dye in the specimen chamber flows rather more slowly than the bulk liquid. This occurs because of a combination of an intrinsic property of the dye and the manner in which it interacts with the membrane. When the result window is completely clear of dye, the entire specimen will have passed at an appropriate speed across the test and control lines and a result is able to be read. With this design there is no need for a timing device, just observation of clearance of the dye from the result window. In-built volume control: The design of the specimen chamber provides assurance that a sufficient volume of specimen has been provided for testing. Continuity of flow across the test and control lines is demonstrated by complete clearance of the band of dye from the results window. Timing is not critical once dye flow indicates that a test has been completed. The colour at the test and control lines does not develop in the same way as for an enzymatic test once the colouraugmented nanoparticles are bound to a line it is coloured, with the intensity of colouration dependent on the amount of specific antibody present. Once all the specimen has passed across the test line and the test is valid (a visible control line indicating appropriate flow rate of functional Working document 21 December 2015 Page 23 of 165

24 reagents) and complete (dye has cleared the results window) the capture is maximal and both test and control lines become colour-stable A description of the components of the assay All reactive components of the assay are contained within the device. The antigens in both the conjugate and the test line were engineered as fusion proteins from the immunodominant regions of the envelope of HIV-1 and HIV-2 by THE Manufacturing Company. Antigens used in the test and control lines are cloned and cultured in different species of microorganism. The antibody used alongside the antigen as a capture reagent is from a commercial source. The HIV-1 (O) peptide is synthesised by THE Manufacturing Company The monoclonal humanised antibody used as part of the system to monitor stability and functionality of the antigens (both capture and conjugate) at the time of use of the device was developed and validated by THE Manufacturing Company. It is directed against the immunodominant epitope of HIV-1 and cross-reacts to a large extent with that of HIV-2. Competition experiments showed that it reacts with the same epitope structures as antibodies from plasma at the time of HIV-1 seroconversion and so should be suitable for monitoring functionality of the antigens in the device A description of the specimen collection and transport materials provided with the product or descriptions of specifications recommended for use. Product code Y1234-B contains an auto-retractable lancet (1.5mm blade size) for obtaining fingerstick blood, two alcohol swabs and a bandage. Product code Y1234-O contains a device for collection of oral mucosal transudate. The oral fluid collection device was developed by a national health protection agency. As the device is intended for use in a private environment by relatively unskilled users, transport of specimens is not a primary consideration. Nevertheless, the device has been validated for use with venepuncture whole blood in EDTA anticoagulant and must be transported at 2 8 C and tested within 24 hours of collection For instruments of automated assays: a description of the appropriate assay characteristics or dedicated assays Not applicable - there are no instruments required For automated assays: a description of the appropriate instrumentation characteristics or dedicated instrumentation. Not applicable If applicable, a description of any software to be used with the product. Not applicable. Working document 21 December 2015 Page 24 of 165

25 If applicable, a description or complete list of the various configurations or variants of product that will be made available At present both configurations of the product are sold as a single pack only. THE Manufacturing Company is considering the configuration of a two test pack. WHO will be notified of the new configuration as per WHO PQDx_121 WHO Procedure of Changes to a WHO Prequalified in vitro diagnostic, in which case this section of the dossier will be updated to reflect the new configuration of a two test pack If applicable, a description of the accessories and other products that are intended to be used in combination with the diagnostic The kit comes fully equipped with all accessories listed above that are required to perform the test. For professional or home use (as required) disposable gloves should be worn when collecting specimen and using the test. 5.3 Essential principles (EP) check list An EP checklist has been produced for the device and is provided in Annex I: Essential Principles checklist The evidence supporting performance requirements is submitted as Section 7 of this dossier and other evidence of manufacturing and quality management is also provided throughout this dossier, in agreement with GHTF/SG1/n046 and with Annex II of the proposal for a regulation on in vitro diagnostic medical devices of the European Community ( the proposed IVD regulation ). 5.4 Risk analysis and control summary Risk analysis policy The risk management policy of THE Manufacturing Company is attached as Annex II: Risk management policy. The SOPs lead to the FMEA output documents attached ( Working document 21 December 2015 Page 25 of 165

26 Annex IV: Design inputs FMEA and Annex V: User and patient FMEA), and to the risk statement (Annex III: Residual risk statement) which describes any residual risks and their control by warning statements. The process and supplier management FMEA for this product, which are of the same format as the submitted FMEAs for 'risk to users and patients', are kept on file but have not been submitted with this dossier. The design input FMEA is prepared before any R&D and is updated as work progresses and the requirements are satisfied as is the risk FMEA for user and patient (usually the same individual with a home self-test device but not always, since this device is also intended to be used in remote clinics by health care workers). A series of control measures arises from the risk assessment these are listed in the spreadsheets of the risk analyses and also shown on the flow diagram of the manufacturing process. The effectiveness of the controls and changes in eliminating the identified risk is shown in the FMEA. Some of the risks such as instability arising from different factors, common- (but not specific-) interfering agents are regarded as routine and evaluated as a matter of course. The data are presented in Section 7 of this dossier. Instability and allowable life-times are evaluated for OMT and fingerstick whole blood, for the shelf life of the device itself using several independent manufactured lots, for the life of the materials once taken out of the pouch, the length of time between adding the specimen to device and reading, and for the length of time after adding specimen to device for which the result is valid Risk Categories Erroneous test results Various types of instability that could lead to erroneous test results have been evaluated, including OMT and fingerstick whole blood, shipping conditions, shelf life of the device, life of the materials once opened, and length of time after adding specimen to cartridge for which the result is valid. Evaluations were performed with several independently manufactured lots of reagents and device kits. The main risks to intended users stem from the potential for false reactive and false nonreactive results. With self-test, untrained users are responsible for specimen collection, performing the test, and interpreting the test result. False reactive results can cause emotional distress while false non-reactive outcomes can result in delayed treatment or no treatment and risk of HIV transmission to others. Stability conditions are clearly described on labels and temperature indicators in the packaging alert the user not to use the test if excursions outside of specified shipping or storage conditions occurred, as this could cause inaccurate test results. Temperature indicators can, for example, provide monitoring of shipping and storage conditions by changing colour to indicate an event outside specified conditions has occurred and are available commercially for pharmaceutical and medical product applications. In addition the device does not require any special storage conditions, such as refrigeration. Product labelling is also important for addressing the risks associated with use of the test and includes language or illustrations and symbols describing the accuracy of the test, how to collect specimen and apply it to the device, how to perform the test properly, how to interpret the test correctly, what to do if the result is positive, what a positive and negative result mean and do not mean, how often to test, and that a negative result does not validate risky behaviour. Product labelling and language is easily readable (Flesch-Kincaid grade <6). In addition, the inherent rate of incorrect results is very low when the test is performed by trained users and the test is Working document 21 December 2015 Page 26 of 165