Malaria rapid diagnostic test products

Transcription

1 Global Malaria Programme Malaria rapid diagnostic test products Suggested use of terms, requirements and preferences for labelling and instructions for use

2 World Health Organization 2017 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization ( rules). Suggested citation. Malaria rapid diagnostic test products: Suggested use of terms, requirements and preferences for labelling and instructions for use. Geneva: World Health Organization; Licence: CC BY- NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at Sales, rights and licensing. To purchase WHO publications, see To submit requests for commercial use and queries on rights and licensing, see Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any thirdparty-owned component in the work rests solely with the user. General disclaimers. 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 WHO 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 and dashed 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 WHO 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 WHO 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 WHO be liable for damages arising from its use. WHO/HTM/GMP/

3 Table of contents Introduction 1 Suggested use of terms 2 WHO requirements and preferences for the labelling of malaria RDT kit components: box, cassette packaging, cassette, buffer bottle and accessories 8 Labelling of the RDT box 9 Labelling of kit contents 12 Labelling of the cassette 14 Labelling of the buffer bottle 16 Labelling of accessories 17 WHO suggested generic template for Instructions for Use (IFU) 19 Annexes 32

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5 Introduction Rapid diagnostic tests (RDTs) largely account for the scale-up of malaria diagnosis in endemic settings. However, diversity in terminology, labelling and the instructions for use (IFU) limits their interchangeability and userfriendliness. Uniform, easy to follow and consistent terminology and labelling, aligned with international standards and appropriate for the level of the end user s education and training, is crucial. This document is intended as a reference for malaria RDT manufacturers and follows on from the consensus building efforts of a 2014 Roll Back Malaria Partnership stakeholder consultation and special taskforce to harmonize terms and abbreviations as well as specifications for labelling of box, device packaging, cassettes, buffer bottle and accessories. 1 Specifically, this reference indicates if WHO considers these specifications are requirements based on international standards or preferences based on the outcome of consultations with country programme implementers, experts in RDT implementation, IVD regulatory experts and manufacturers. These requirements and preferences are aligned with those of the WHO Prequalification (PQ) of IVDs programme and compliance will be monitored through the dossier and laboratory evaluation components of the WHO PQ process. 2 1 Jacobs et al. Malaria Journal 2014, 13: Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 1

6 2 Suggested use of terms

7 term Abbrev. Description Accessories Articles intended and validated by the RDT manufacturer to be used with the RDT in order to achieve its intended purpose (i.e. specimen transfer device, lancet, alcohol swab) Alcohol swab A pad saturated with alcohol that is used to clean and/or disinfect skin Buffer A buffered solution to enable specimen flow and conditioning of specimens, to optimize sensitivity and minimize non-specific reactions. Buffer bottle Plastic bottle, often with cap and nozzle, containing the buffer, intended to be used in multiple tests Buffer vial Small vial containing a sufficient volume of buffer to perform a single RDT test. See primary packaging Buffer well Physical place in the test device in which the buffer is applied. Cassette This is the test format in which the nitrocellulose strip is encased in a plastic housing, presenting openings for the result window, for the specimen and buffer well(s) and in some cases for evaporation. Combination rapid diagnostic test Test for detecting multiple malaria species and which distinguishes P. falciparum from other malaria species Component Dedicated parts of a finished, packaged, labelled RDT kit that are specific to and necessary for performing the RDT. These include the test device, buffer bottle/vial and instructions for use. Control line Visible line on the nitrocellulose strip that generally only, indicates satisfactory migration of buffer a Desiccant Drying agent used to protect the test device from humidity. These may change colour (self-indicating) to indicate humidity saturation. The beads are contained in a transparent, partially transparent or non-transparent fiber pouch. Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use Synonym (not suggested term) Comments Category Ancillary items The accessories provided might be replaced by other items without compromising safe, accurate performance of the test, e.g. different lancets This possibility of substitution differentiates accessories from components (see Component ). Alcohol pad, alcohol wipe, alcohol pre-pad There was consensus that alcohol swab is the term in broadest use, both in spoken language and in labelling. Many synonyms are in use, e.g. blood lysis buffer, clearing buffer, assay diluent, sample diluent, reagent Buffer ampulla Some RDTs have a single well for both buffer and specimen. Commonly referred to as the device Commonly referred to as a combo test Note: There can be no substitution for a kit component, whereas accessories such as a lancet or alcohol swab may be replaced by items that perform the same function or are purchased separately. Silica gel is the most commonly used desiccant for RDT products. 3

8 term Abbrev. Description In vitro diagnostic medical device A device, used alone or in combination, intended by the manufacturer for in vitro examination of specimens derived from the human body, solely or principally to provide information for diagnosis, monitoring or compatibility. They include reagents, calibrators, control materials, specimen receptacles, software, related instruments or apparatus or other articles (International Medical Devices Regulators forum) Instructions for use IFU Information provided by the manufacturer to the user about the intended purpose and proper use of in vitro diagnostics and any precautions to be taken (GHTF/SG1/ n70:2011) Job aid(s) Document describing the essential materials to perform an RDT (i.e. procedure or interpretation) provided apart from the IFU, either as a separate leaflet and/or printed on the device packaging or in/on the RDT box Kit Set of components and accessories packed together and intended for using a specific RDT (test device, buffer bottle, specimen transfer device, lancet, alcohol swab, instructions for use) (definition adapted from ISO :2009) Lancet Sharp, needle-like, sterile medical device used to puncture skin to obtain blood (CLSI H04-A6) They include: plain metal lancets (packed in a single packages for sterility) safety-seal lancets (in plastic housing with a plastic cap) auto-lancing lancets (mounted in plastic housing that is ejected automatically when the plunger is pressed) auto-retractable lancets (mounted in plastic housing that is retracted automatically after puncture) Lot Defined amount of material with uniform properties that has been produced in one process or series of processes so that it can be expected to be homogeneous (ISO :2009) Synonym (not suggested term) Comments Category docs/ghtf/archived/ sg1/technical-docs/ ghtf-sg1-n045r12- in-vitro-diagnosticclassification pdf Package insert, instructions leaflet Quick guide, pictogram testing procedure Refer to the WHO generic job aids for an example. Batch 4

9 Synonym term Abbrev. Description Comments Category (not suggested term) Lot number Distinctive set of numbers and/or letters for a kit or component that specifically identifies a lot and permits tracing of its manufacture, packaging, labelling and distribution history (ISO :2009) Batch number, batch code Malaria rapid diagnostic test RDT A collection of reagents and other associated materials for in vitro diagnostics, intended to be used for the qualitative and/or quantitative detection of antigens from one or more species of Plasmodium in a clinical specimen within a short period, relative to standard laboratory testing procedures, typically by an immunochromatographic test method This test is commonly used in the laboratory or in pointof-care analyses. Manufacturer Any natural or legal person with responsibility for design and/or manufacture of a medical device with the intention of making the medical device available for use, under his or her name, whether the medical device is designed and/or manufactured by that person him- or herself or on his or her behalf by another person(s) (GHTF/SG1/N055: 2009 Definitions of the terms manufacturer, authorized representative, distributor and importer ) Plasmodium antigen Antigen b produced by malaria parasites and detected with RDTs Target, marker, analyte Plasmodium P P is to be used only as the abbreviation of the genus and in combination with the species name (e.g. P. ovale) or as part of the abbreviations Pm, Po, Pv, Pf and Pvom ; it should not be used alone. pan- A group of human Plasmodium species: Pf, Pv, Po and Pm Plasmodium falciparum Pf Plasmodium falciparum Plasmodium (or parasite) lactate dehydrogenase pldh Plasmodium (or parasite) lactate dehydrogenase In papers and documents, both parasite and Plasmodium lactate dehydrogenase are used. In the present context and documents (such as IFU). it would be better to maintain Plasmodium Plasmodium malariae Pm Plasmodium malariae Plasmodium ovale Po Plasmodium ovale Plasmodium vivax Pv Plasmodium vivax Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 5

10 term Abbrev. Description Synonym (not suggested term) Plasmodium vivax, ovale, malariae Pvom Plasmodium vivax, ovale, malariae Point-of-care testing POCT Testing used at or near the site of patient care, leading to a possible change in the care of the patient (ISO ) Primary packaging of alcohol swabs, lancets, desiccant and cassettes Layer of packaging in immediate contact with the item Alcohol swab, lancet, desiccant or cassette packaging Packaging of alcohol swab, lancet, desiccant or cassette Pouch, sachet Product RDT as currently marketed and identified, with assigned name, product code and regulatory version Product code Unique code identifying one product (or product variant) with an assigned name and a regulatory version Catalogue number, product number, reference number RDT box or Box Physical box, usually made of cardboard, in which the kit contents (components and accessories) are packed Secondary packaging, kit box Reading legend Acronyms or characters in the result window, referring to the control and test lines. The characters may be embossed in the plastic housing or printed on it. The reading legend can be on either side of the result window. Reading scale (Minimum and maximum) reading time Interval during which valid results can be obtained Result window Opening in the test cassette showing the area of the strip containing the control and test line(s) Reading window Revision history A table in which amendments are recorded each time a new version of the IFU is issued Single pack Kit individually packed with all the content required for the performance of one test Single test pack, single test, individually packaged test Species spp. Species Comments Category Use primary packaging in technical comments for manufacturers (for instance when describing requirements for labelling), and use packaging of the alcohol swab or alcohol swab packaging when addressing users during training and in IFU (for instance: open the cassette packaging ). 6

11 Synonym term Abbrev. Description Comments Category (not suggested term) Specimen well Physical place in the test cassette or dipstick to which the specimen is applied Some malaria RDTs have a single well for both specimen and buffer. Specimen transfer device Device used to transfer blood (or plasma or serum) to the test device. This includes: inverted cup, loop, (glass) capillary tube, (plastic) straw, pipette. Sampling device The term specimen transfer device may be shortened to transfer device. Symbol key List of symbols with written explanation ( legend ) Key to symbols Test line Line on the nitrocellulose strip that is intended to display the reaction with a specific target antigen (HRP2, pldh, aldolase) The term band can be used depending on the RDT design (two-, three- and four-band RDT products) Test strip The physical medium, e.g. nitrocellulose, in which the migration and reaction take place Test membrane Two-, three- and four-band RDTs RDTs with two, three or four lines, including the migration control line, and one, two or three test lines User A trained or skilled person, who is competent and who uses the RDT Operator, end-user Version number Number given to any labelling, including labels, instructions for use (or job aids) or any other materials distributed with the product, to allow tracking of changes. a. In the case of malaria RDTs, the control line becomes visible if sufficient dye-labelled antibody (carried in the buffer) accumulates on the test strip line containing sufficient, intact bound capture antibody. b. Antigens are not recombinant. Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 7

12 WHO requirements and preferences for the labelling of malaria RDT kit components box, cassette packaging, cassette, buffer bottle and accessories General note on labelling legibility There are no international guidelines on font sizes for labels of in-vitro diagnostics. According to the Guideline on the readability of the labelling and package leaflet of medicinal products for human use, revision 1, 12 January 2009, characters of at least 7 points (or of a size in which the lower case x is at least 1.4 mm in height) with a space between the lines of at least 3 mm are recommended.* The US Food and Drug Administration document Guidance on medical device patient labelling; final guidance for industry and FDA reviewers (2001), for patients and lay caregivers, recommends use of at least 12-point type whenever possible and a serif font for text. * en.pdf 8

13 Labelling of the RDT box Orientation Figure 1. Convention of terms for the front view of a malaria RDT box Back Top Left (lateral) Right (lateral) Front Bottom Labelling of the RDT box Left (lateral) Top Back Front Right (lateral) Bottom General requirements and preferred options for labelling malaria RDT boxes 1. Labels should be printed on the cardboard as permanent printing or applied as water-resistant labels (applied with water-resistant glue). Printing should be indelible and should last the life span of the RDT product. 2. Use only internationally recognized symbols (ISO or, if applicable, the Globally harmonized system of classification and labelling of chemicals Labelling must be legible, for instance in open letter type and font size equivalent to Miriad bold The official language(s) in which the intended use is displayed should be relevant to the region in which the RDT product will be used. In Figure 2, English, French, Spanish and Portuguese are displayed. 5. Display the essential information on the top (see Figure 2), front and at least one lateral side of the RDT box (left or right) (see Figure 3). The label contains all the relevant information required for stock management (e.g. product identity, storage conditions and material provided). An exception can be made for custom or variable prints, such as lot number and expiration date, and, in case of use, also production date. These can be printed on only one side of the box Category Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 9

14 What should be displayed: 1. Product name with sufficient detail for the user to uniquely identify the device and its intended use, e.g. commercial name of the RDT product malaria targeted species and antigen(s) antigen or Ag Category 2. Product code (and symbol) 3. Intended use (to be included if the product name does not include sufficiently specific information). If there is insufficient space on the label, this statement can be included on the IFU: diagnosis of malaria, in vitro diagnostic, professional use. 4. Number of tests provided in the kit box 5. In vitro diagnostic (symbol) 6. Name and physical address of the legal manufacturer Telephone and/or fax number and/or website 7. Lot number (and symbol) 8. Expiration date (and symbol) format: YYYY-MM 9. 9a. 9b. Materials (content) and quantities Materials provided, and quantities of each Items required but not provided, i.e. those items required for safe, accurate use of the test, such as a lancet (with symbol) 10. Storage conditions (symbols) 11. Warnings or precautions (symbols) For instance: - do not use if package is damaged (symbol) read instructions before use (symbol) biohazard (symbol), if applicable i.e. desiccant containing cobalt chloride; buffer with sodium azide concentration ( 0.1%) 12. Additional easily visible warning in case the procedure or IFU has changed substantially Information about the change and effective date should be included as a separate note in the box or in the IFU 10

15 Figure 2. Example label on the top of the RDT box. Blue indicates specific RDT product items 30 C 4 C Commercial name, Malaria Antigen Pf/Pan (HRP2/ pldh) RDT xxxxxxxxxx Σ xx Rapid test for the antigen detection of malaria (Plasmodium x) Test rapide de détection d antigène du paludisme (Plasmodium x) Prueba rápida para detección de antígeno de malaria (Plasmodium x) Teste rápido para detecção de antígeno da malária (Plasmodium x) Professional use only xxxxxxx YYYY-MM Name, physical address of legal manufacturer, website, telephone and/or fax number Figure 3. Example labelling of one lateral side and the front of an RDT box. Blue indicates specific RDT product items Content: but not provided Commercial name, Malaria Antigen Pf/Pan (HRP2/pLDH) RDT xxxxxxxxxxx XX indicates quantities. Could state number of pouches and what each pouch contains Cassettes (XX) Specimen Transfer devices (XX) Alcohol swabs (XX) Lancets (XX) Buffer bottle (XX) Instructions for use (X) Gloves Biosafety sharps container Biohazard waste container Timer Pencil/pen Σ xx xxxxxxx Indicate symbol for method of sterilization YYYY-MM 4 C 30 C Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 11

16 Labelling of kit contents General note According to ISO :2009, in the case of a kit, each component shall be identified by name, letter, number, symbol, colour or graphics in the same manner on all labels and in the instructions for use. Labelling of cassette primary packaging What should be displayed: 1. Product name with sufficient detail for the user to uniquely identify the product and its intended use, e.g. commercial name of the RDT product malaria targeted species and antigen(s) antigen or Ag Example: Commercial name, Malaria Pf/Pv (HRP2/pLDH) Antigen (RDT) Category 2. For product code (or symbol) 3. Intended use (to be included if the product name does not include sufficiently specific information): If there is insufficient space on the label, this statement can be included on the IFU: diagnosis of malaria, in vitro diagnostic, professional use only, point-of-care. 4. In vitro diagnostic (symbol) 5. Name (or logo) of the legal manufacturer 6a. 6b. Lot number (and symbol) The lot number is preferably identical to the one on the RDT box. 7a. 7b. Expiration date (and symbol) format: YYYY-MM The expiration date is preferably identical to that on the RDT box. The expiration date must not be earlier than the expiration date on the RDT box. 8. Quantity of tests per packaging (if more than one test) 9. Unless there is no space, list contents of packaging and quantities, including desiccant 10. Storage conditions (symbols) 11. Warnings or precautions (symbols) For instance: do not use if package is damaged (symbol) read instructions before use (symbol) single use (symbol) 12

17 Where labels should be put: Display all standard generic information on one side of the packaging and the custom or variable information (expiration date, lot number) on the opposite side. Figure 4. Example labelling of cassette primary packaging. Blue indicates specific RDT product items 30 C 4 C Commercial name, Malaria Antigen Pf/Pan (HRP2/ pldh) RDT For product code: XXXXXXX Σ xx Content: 1 cassette 1 desiccant 1 specimen transfer device Manufacturer name or logo xxxxxxx YYYY-MM Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 13

18 Labelling of the cassette Convention of terms used to describe the orientation of the cassette Figure 5 shows the most common RDT, a three-band RDT targeting two antigens (P. falciparum and pan-plasmodium antigens) in a two-step procedure (add specimen, next add buffer), with a cassette containing individual specimen and buffer wells. The following convention of terms is used: proximal (closest to the specimen and buffer wells) and distal (at the end of the migration [absorption] pad). A vertical view of the cassette (with the direction of the specimen and buffer flow upwards ) shows a right- and a left-hand side. Figure 5. Conventions for terms to describe the cassette Distal Long axis Left Right Proximal Short axis 14

19 Labelling: 1. Printing in indelible ink is recommended instead of characters embossed in the cassette housing. The test and control line legends and the actual test lines should be well aligned. Category 2. All printing should be along the short axis. 3. A single, unequivocal reading legend should be present on the right-hand side of the results window. 4. All abbreviations comply with those listed in document Abbreviations. In addition, 1 for the sample well, 2 for the buffer well (chronological order) 5. Labelling must be legible: for instance, open letter type, clear print Note: The cassette surface should be of a material (and profile) on which it is possible to write (with a standard ink pen or pencil). Space should be left for writing patient identification. What should be displayed: 1. Product name (with indication of Malaria, antigen-based Ag, the Plasmodium species and the antigens detected) or logical abbreviation (referenced in the IFU) 2. Labelled specimen and buffer wells (see above) e.g. 1 for the sample well, 2 for the buffer well (chronological order) Category 3. Reading legend with Plasmodium species detected (see abbreviations: Pf, pan, Pv) Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 15

20 Labelling of the buffer bottle General requirements and outlines for labelling RDT buffer bottles: 1. Labels: Well-fixed water-resistant label (applied with water-resistant glue) or permanent printing, indelible ink lasting the life span of the RDT product. Category 2. Use only internationally recognized symbols (ISO ). 3. The official language(s) displayed should be relevant to the region in which the RDT product will be used. What should be displayed: 1. Product name, with sufficient detail for the user to uniquely identify the product and its intended use, e.g. commercial name of the RDT product malaria targeted species and antigen(s) antigen or Ag Example: Commercial name, Malaria Pf/Pv (HRP2/pLDH) Antigen(RDT) (preferred option) or with sufficient detail for the user to identify the type of product with which to use the buffer, e.g. Malaria RDT (acceptable option) Category 2. Contents: Buffer 3a. 3b. For product code (symbol) (preferred option) or a reference code that is also written on the RDT packaging and/or in the instructions for use (acceptable option) 4. In vitro diagnostic (symbol) 5. Name (or logo) of the legal manufacturer 6. Lot number (and symbol) 7. Volume of contents or number of examinations that can be performed 8. Expiration date (and symbol) format: YYYY-MM The expiration date must not be earlier than the expiration date on the RDT box and test packaging. 9. Storage conditions (symbols) 10. Warnings or precautions (symbols) At least :do not use if package is damaged (symbol); hazard symbol, if sodium azide concentration is 0.1% (symbol); read instructions before use (symbol) 16

21 Figure 6. Proposal for printing relevant information on the buffer bottle 30 C 4 C Commercial name, Malaria Antigen Pf/Pan (HRP2/ pldh) RDT For product code: XXXXXX Contents : Buffer xxxxxxx YYYY-MM Manufacturer name (or logo) xx ml or number of examinations Labelling of accessories Definitions Accessories of in vitro diagnostics are articles specifically and explicitly intended by the manufacturer to be used with a device to enable that device to be used in accordance with the intended purpose (ISO , CE Directive 98/79). Specimen transfer devices, lancets, alcohol swabs and desiccant are included. General requirements and outlines: 1. Labels should be printed on the device or packaging as permanent printing or applied as water-resistant labels (with water-resistant glue). The ink should be indelible and should last the life span of the product. If it is not practicable to display the information on the device itself (e.g. lancets, specimen transfer devices), some or all of the information may appear on the packaging of multiple items (if used) (GHTF/SG1/N70/2011:5.0 and Annex of EU Directive 98/79). 2. Use of symbols, when adequate, is encouraged instead of text. Only Internationally recognized symbols (ISO ) should be used. 3. The language(s) used should be relevant to the region in which the RDT product will be used. 4. The table below lists the information to be displayed on different accessories or on their packaging. Category Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 17

22 Label information Transfer device Lancet Alcohol swab Desiccant Category Name of accessory X X X X Intended use if name of accessory does not indicate it (sufficient to identify the device and its intended use: e.g. transfer device, antiseptic, desiccant) Name of the legal manufacturer of the accessory (preferred to RDT manufacturer) X X X X X X X X For alcohol swab: antiseptic, product and concentration (e.g. isopropyl alcohol70%) X Product code of the accessory X X For a transfer device other than inverted cup and loop: permanent volume mark X Lot number X X X X Indicate in vitro diagnostic use X Expiration date (preferred format: YYYY-MM) X X X Quantity of items, indicated on the outer packaging (if applicable) (symbol) X X X Specimen volume transferred X Single use (symbol) X X X Sterile (and by what method), if applicable X X Do not use if package is damaged (symbol) X X Warning: Do not swallow or eat and harmful (text or symbols) in relevant language(s) X X Interpretation of colour change, if applicable X, if applicable 18

23 WHO suggested generic template for Instructions for Use (IFU) The present document is a template for generic IFU of malaria rapid diagnostic tests. It must be adapted to the specific product. Words or terms that are definitely product-related and variable are in blue. This template can be adapted according to present or future characteristics of the concrete product. Instructions for the designer are printed in italics and put into text boxes. The present document uses the safety-seal lancet and inverted cup as an example. Other combinations are possible. General suggestions Provide IFU version number including indication of language and date. Highlight changes (shaded in grey) with regard to the previous version. Text: ensure that the IFU is easily readable (e.g. Flesch-Kincaid grade < 6) use type size of at least 9 points, as measured in font Times New Roman, not narrowed, with a space between lines of at least 3 mm and an open letter type; use short sentences and terms that are easy to understand; use consistent terms and words throughout the IFU (see the section on Suggested use of terms); use active verb (imperative) rather than passive voice/ should ; stress important information (capitals, italics, underline); turn any list into a bulleted or numbered list; put when and if before what ( If the color indicator is red, discard the test ); put the warning before the action step in the procedure; make sure warnings are clearly indicated; use one line per action. References on readability and a readability calculator are included in Annex 1. Figures: use figures that are large enough so that they are easily visible; drawings may be more informative than photographs; Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 19

24 Generic job aids for malaria RDTs published by WHO-FIND provide clear drawings (see put figures on the left side, text on the right side; refer to each figure in the text; check that the figures match the real-life situation (device, transfer device, gloves, right-handed operator). 20

25 Table of contents Product Product name Product code Number of tests provided in the kit Intended use Test principle Intended user specimen Warnings and precautions Materials Materials provided Materials required but not provided Storage and stability Procedure Before testing Sample preparation Test procedure Capillary whole blood from finger prick Venous whole blood from venipuncture Interpretation of the test result Limitations of the test, causes of false-negative and false-positive results Limitations of Malaria RDTs False negative results False positive results Invalid tests and problems of background clearing Performance specifications Bibliography Manufacturer contact information IFU version number and date of issue of the instructions for use Symbol key Product specific and other variables printed in blue Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 21

26 Product Commercial name, Malaria Antigen Pf/Pan (HRP2/ pldh) Rapid Diagnostic Test (RDT) Product code xxxxxx and presentation (number of tests per kit) Intended use This XXX test kit is an in-vitro diagnostic immunochromatographic assay for the qualitative detection of infection with Plasmodium parasites causing malaria in human whole blood specimens. It does not assess parasite densities. It assists trained competent users and is not intended for lay users: in detecting Plasmodium infections to differentiate infection by Plasmodium falciparum from the non-p. falciparum species (Plasmodium vivax, Plasmodium malariae, Plasmodium ovale). Note: Malaria RDTs can give positive results after successful anti-malarial treatment. Therefore, the XXX test kit is not recommended for monitoring response to anti-malarial treatment. Test principle The following Plasmodium antigens are detected in this test: Histidine rich protein 2 specific for P. falciparum (Pf-HRP2) Plasmodium lactate dehydrogenase specific for P. falciparum (Pf-pLDH) Plasmodium lactate dehydrogenase specific for P. vivax (Pv-pLDH) Plasmodium lactate dehydrogenase common to all human Plasmodium species (pan-pldh) Aldolase common to all human Plasmodium species The cassette contains a test strip pre-coated with capture antibodies. The sequence of events is as follows: 1. Whole blood is applied to the specimen well (labelled well 1). 2. Next, buffer is applied to the buffer well (labelled well 2). 22

27 3. Migration of the specimen/buffer mixture starts, towards the other end of the cassette. 4. The specimen-buffer mixture passes the conjugate pad, which contains detection antibodies targeting Pf-HRP2, Pf-pLDH, Pv-pLDH, pan-pldh and/or aldolase antigens. These detection antibodies are conjugated to colloidal gold. If present in the specimen, Plasmodium target antigens bind to this detection antibody-conjugate. 5. The antigen-antibody-conjugate complex migrates further and binds to the capture Plasmodium-specific antibodies present on the test line. These capture antibodies bind to another site (epitope) of the Plasmodium target antigens. 6. The capture antibodies are applied on a narrow section of the test strip: as a result, the antibody-conjugate with the colloidal gold will be concentrated and become visible as a red colored line. 7. The excess of the detection antibody-conjugate that was not bound by the Plasmodium target antigens and the capture antibodies moves further until it binds to a goat anti-mouse control antibody. There, the colloidal gold will create a red colored control line. The visualization of the control line indicates that the migration was successful. It does not confirm the presence of specimen. The main components of the test are: Test strip: Detection antibodies conjugated to colloidal gold (in the conjugate pad): Mouse monoclonal antibodies (IgG) specific to Pf-HRP2-gold colloid Mouse monoclonal antibodies (IgG) specific to pan-pldh-gold colloid (any other combination) Capture antibodies (on the nitrocellulose membrane): Plasmodium falciparum line: Mouse monoclonal antibodies (IgG) specific to Pf-HRP2 Plasmodium species (pan) line: Mouse monoclonal antibodies (IgG) specific to pan-pldh Control line (on the nitrocellulose membrane) : Goat anti-mouse polyclonal antibodies (IgG) Buffer vial: Intended user Bovine serum albumin, Triton X-100, Sodium azide (0.095 %) The test is intended to be performed by a trained user. Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 23

28 Specimen required Capillary whole blood or venous whole blood with the following anticoagulant: EDTA, heparin, oxalate or citrate. Time between specimen collection and specimen testing: Capillary: immediately Venous: immediately. If immediate testing is not possible, store the whole blood specimen at X-X C for maximum XX hours. Do not use any other specimen than whole blood Warnings and precautions For in vitro diagnostic use only. Read the instructions carefully before performing the test. Apply standard biosafety precautions for handling and disposal of potentially infective material. Handle all specimens as potentially infectious. Wear gloves while handling specimens and performing the test. Avoid splashing and aerosol formation. Clean up spills thoroughly using an appropriate disinfectant. The buffer contains 0.095% sodium azide as a preservative which may be toxic if ingested. When disposed of through a sink, flush with large quantities of water. Do not use any other buffer than the buffer supplied within this kit. Do not use the kit beyond the expiration date. Do not use if the packaging is damaged. Do not use any other specimen than whole blood. Do not use if the product has been exposed to excessive heat or humidity. Perform the test immediately after opening of the cassette packaging. Do not re-use the test. Materials Materials provided XX cassette package, each containing: 1 test device 1 packet of desiccant X buffer bottle(s) XX ml 24

29 XX specimen transfer devices (inverted cup) x µl XX single-use safety-seal lancets XX alcohol swabs 1 instructions for use Materials required but not provided New pair of disposable gloves Pen/pencil Timer Extra lancets and alcohol swabs, if needed (lancet misfires, lancet does not produce sufficient blood volume, alcohol swab is dried out, etc.) Biosafety sharps container Biohazard waste container (for potentially infectious waste) If whole blood is collected by venipuncture, venipuncture blood collection materials and precision pipette, plus tips Test kit storage and stability Store the kit between X XX C. Do not store the kit in the freezer. Protect the kit from humidity. The kit has a shelf life of XX months from the date of manufacture. The kit is stable until the expiration date marked on the RDT box and/or the packaging of individual components when stored as specified. The buffer is stable for XX months (or until the expiry date) even after opening. Procedure Before testing 1. Prepare all necessary materials : When stored in the refrigerator, bring the kit to room temperature (XX-XX C) minimum xx minutes before use. Prepare the materials (refer to the section on Materials). 2. Check the expiration date of the kit (including buffer). If expired, do not use but take another unexpired kit. Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 25

30 3. Check that the cassette packaging is not damaged. If damaged, discard the test and use another test. 4. Open the cassette packaging and check the desiccant (if provided). If there is a humidity indicator and it shows saturation (color changed from orange to green), throw away the cassette and take another cassette packaging. If the color of the desiccant does not show a change, you can use the test. Throw away the desiccant in the nonsharps (non-infectious) disposal container. Perform the test immediately after opening of the cassette packaging. Do not re-use the test. 5. Take the cassette and place it on a flat surface, horizontally. You see: a result window (marked with C, pan, Pf ) a circle well marked 1 (for specimen) a square well 2 (for buffer) 6. Write the patient name or identifier on the cassette. 7. Put on gloves. Use new gloves for each patient. 8. Add if needed additional instructions on how to open the buffer bottle correctly for instance, how to pierce the nozzle. Test procedure (see reference Generic RDT training manual in Annex 2) Capillary whole blood from finger prick 1. Wear gloves. 2. Choose a finger for the finger prick: Do not choose a finger that is swollen, bruised or scarred. Preferably choose the 3rd or 4 th finger of the hand the patient does not use to write. Alternatively choose the heel or the earlobe for neonates. 3. Open the packaging of the alcohol swab. Take out the alcohol swab. Do not throw away the empty packaging (wrapper) but keep it aside. 4. Wipe the complete fingertip with the alcohol swab. Wait until the finger has completely dried (minimum 30 seconds). 5. Place the alcohol swab in the wrapper and set it aside (you will use it again to stop the bleeding after you collected the patient s blood). 6. Take the safety-seal lancet. 7. Detach the cap of the lancet. 26

31 Puncture the side of the pulp (ball) of the finger with the lancet, perpendicular to the lines of the fingerprint. Avoid the tip or center of the finger. Dispose the lancet immediately into the sharps box. 8. Make sure a well-formed drop of blood is present. 9. If there is no well-formed drop of blood, repeat the finger prick using a new lancet and choose a different puncture site. 10. Take the inverted cup and collect 5 µl of blood by dipping the circular end of the inverted cup into the whole blood drop. 11. Place the circular end of the inverted cup in the circle well (marked 1 ) so that it touches the strip (pad at the bottom of the well). Press down lightly to transfer all the blood to the strip. Put the used inverted cup into the non-sharps disposal container for potentially infectious waste. 12. Take the alcohol swab you put aside (step 5). Ask the patient to press it to the finger prick to stop the bleeding. After use, put the alcohol swab into the non-sharps disposal container for potentially infectious waste. 13. Take the buffer bottle. Hold the open buffer bottle vertically above the square well (marked 2 ). In a vertical position, squeeze the buffer bottle gently and apply exactly X drops into the square well (marked 2 ). 14. Remove your gloves and discard them into the non-sharps disposal container for potentially infectious waste. 15. Write the time on the cassette or set a countdown timer to the required reading time. 16. Read test results after a minimum of xx minutes but no later than xx minutes. Use a good light source when reading the test results. Venous whole blood from venipuncture 1. Wear gloves. 2. Collect blood by standard venipuncture procedure into a tube containing the correct anticoagulant (EDTA, heparin, oxalate or citrate). 3. Mix the tube gently. Do not use water or any other buffer than the buffer supplied within this kit. Hold the buffer bottle vertically this ensures that the drops contain the correct volume of buffer. Do not read results after xx minutes Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 27

32 4. Transfer 5 µl of whole blood in the circle well (marked 1 ) of the cassette using a precision pipette. 5. Perform steps of the previous section ( Capillary whole blood from finger prick ). Interpretation of the test result 1. After xx but no later than xx minutes: compare the test lines with the presentation in the table below. 2. Where possible, have the results confirmed by a second reader within this time frame. 3. Line intensities may vary from faint to strong intensity. Consider also a faint test line as a positive result. 4. Record the test results as noted in the table below. 5. Consult the national guidelines for malaria case management to complement the table below. Lines that you see Picture/Drawing Record the following result Take the following action NO line at C (= control) Put figures of all possible line combinations Invalid Take a new cassette packaging and repeat the test Line at C and NO other line Put figures of all possible line combinations Negative Line at C AND at Pf Put figures of all possible line combinations Positive for Plasmodium falciparum Line at C, at Pf AND at pan Put figures of all possible line combinations Positive for Plasmodium falciparum (or rarely, a mixed infection with P. vivax, P. ovale and/or P. malariae) Line at C AND at pan Put figures of all possible line combinations Positive for non-falciparum malaria: P. vivax, P. ovale or P. malariae (or, rarely, a mixed infection with these species) Other line combinations Put figures of all possible line combinations Write down the result Note: the XXX test kit does not differentiate between P. vivax, P. ovale and P. malariae 28

33 Limitations of the product, causes of false-negative and falsepositive results All malaria RDTs have limitations in common They may occur despite correct storage and test procedure and are related to: the general design of the RDT (detection limit, prozone, no quantification) the antigen (HRP-2 deletions, HRP-2 persistence after treatment) the operator (overlooking faint test lines) the species (in general: sensitivity for P. falciparum > P. vivax > P. ovale/ malariae). Other limitations related to the end-user and the conditions during transport and storage. Some limitations are listed below unless they do not apply for the RDT product under consideration, they should be mentioned. See also reference Universal access to malaria diagnostic testing: an operational manual. World Health Organization 2011 Malaria RDT have limitations They may be the cause of: false-negative results (no test lines but the patient has malaria) false-positive results (test lines visible but the patient does not have malaria) invalid test result (no control line and/or incomplete clearing of background) Sensitivity for detecting malaria is lower in the case of P. ovale and P. malariae. False-negative results can occur in the following conditions: very low antigen concentrations/parasite densities, for instance < 100 parasites/ µl. Note that most clinical cases have higher parasite densities. very high parasite densities (very exceptional, prozone or high-hook effect) for the HRP-2 antigen deletions in the HRP-2 gene resulting in no production of the HRP-2 antigen (of relevance only for mrdts that detect this antigen, and only significantly present in the Peruvian Amazon) high fraction of insterstitial fluid due to milking of fingertip False-positive results can occur amongst others in the following conditions: rheumatoid factors, antinuclear antibodies, human anti-mouse antibodies viral infection (such as hepatitis B or hepatitis C, dengue) parasitic infection (such as schistosomiasis and trypanosomiasis) Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 29

34 Invalid tests and problems of background clearing may occur: In lipaemic and icteric specimens Note: The presence of the control line only means that migration of added liquid occurred. It does not guarantee that: the correct specimen has been used the specimen has been applied correctly the specimen and test have been correctly stored the test procedure was followed correctly Performance specifications Recommendations for diagnostic performance specifications State at least the following specifications and information: 1. Analytical sensitivity (detection limit) 2. Analytical specificity (rheumatoid factor, antinuclear antibody, other infections and influence of lipemic/icteric/hemolyzed specimens) 3. Diagnostic sensitivity 4. Diagnostic specificity 5. Repeatability (test-related, laboratory conditions) 6. Reproducibility (operator-related, field conditions) Give enough detail and oversight: the numbers of specimens used (and if applicable, confidence intervals) the different specifications for P. falciparum, P. vivax, P. ovale and P. malariae type of study and setting, geographic place, study period and population (e.g. laboratory study on stored specimens, clinical study, field study) parasite densities and reference methods when appropriate present results in a clear way (e.g. table) refer to type of study (in-house study, external study, study report or published in scientific literature)/include a bibliography/reference list 30

35 Bibliogaphy Recommendations for bibliography Select relevant publications in a practical and product-oriented way. In Annex 3, some references for relevant topics are provided. Product-related publications Test kit evaluations (product related studies) General publications Biosafety and sampling WHO reference documents Description of problems on RDT implementation, end-user errors Contact of manufacturer Name of the legal manufacturer Full physical address of the manufacturing site (street, city, zip code, country) Contact for technical assistance ( telephone/fax number, address) Version number of IFU and date of issue XXXXX Language (En, Esp, Fr, etc.) YYYY/MM/DD Symbol key Recommendations for Symbol key Only use internationally recognized symbols. In Annex 4, an example of a symbol key is provided. Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 31

36 Annexes Annex 1: References for readability The following websites explain how to assess and calculate readability the tool is primarily developed for English texts. Readility can also be assessed in a Microscoft Word document: 1. Click the File tab, and then click Options 2. Click Proofing 3. Under When correcting spelling and grammar in Word, make sure the Check grammar with spelling check box is selected 4. Select Show readability statistics and click on OK After you enable this feature, open a file that you want to check, and check the spelling. When Outlook or Word finishes checking the spelling and grammar, it displays information about the reading level of the document. Annex 2: resources Generic and product specific job aids for Pf only and combination RDT Refer to the following websites: Generic: Product specific: Generic RDT training manual How to use a rapid diagnostic test (RDT): a guide for training at a village and clinic level Universal access to malaria diagnostic testing: an operational manual. World Health Organization

37 Annex 3: Example of bibliogaphy Product-related publications Test evaluations (product related study) General publications Biosafety and sampling 1. Clinical and Laboratory Standards Institute. Procedures and devices for the collection of diagnostic capillary blood specimens; approved standard, fifth edition. CLSI H04-A6, Vol. 28, No. 25, Clinical and Laboratory Standards Institute. Procedures for the collection of diagnostic blood specimens by venipuncture; approved standard, sixth edition. CLSI H03-A6, Vol. 27, No. 26, World Health Organization: Laboratory biosafety manual, third edition. Geneva: WHO; Biosafety7.pdf WHO reference documents 1. World Health Organization: Good practices for selecting and procuring rapid diagnostic tests for malaria. Geneva: WHO; publications/atoz/ /en/ 2. World Health Organization: Guidelines for the treatment of malaria. Third edition. Geneva: WHO; atoz/ /en/ 3. World Health Organization: Malaria Rapid Diagnostic Test Performance; Results of WHO product testing of malaria RDTs: Rounds 1 7 ( ). Geneva: WHO; eng.pdf 4. World Health Organization: Malaria RDT job-aids and training manuals World Health Organization: Management of severe malaria A practical handbook. Third edition. Geneva: WHO; publications/atoz/ /en/ 6. World Health Organization: Transporting, storing and handling malaria rapid diagnostic tests at central and peripheral storage facilities. Geneva: WHO; World Health Organization: Universal access to malaria diagnostic testing. An operational manual. Geneva: WHO; publications/atoz/ /en/ Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 33

38 Description of problems on RDT implementation, end-user errors (included prozone, buffer substitution, false positive, ) 1. Gamboa D, Ho M, Bendezu J, Torres K, Chiodini P, Barnwell J, Incardona S, Perkins M, Bell D, McCarthy J, Cheng Q: A large proportion of P. falciparum isolates in the Amazon region of Peru lack pfhrp2 and pfhrp3: implications for malaria rapid diagnostic tests. PLoS One 2010, 5:e org/article/info%3adoi%2f %2fjournal.pone Gillet P, Scheirlinck A, Stokx J, De Weggeleire A, Chauque H, Canhanga O, Tadeu B, Mosse C, Tiago A, Mabunda S, Bruggeman C, Bottieau E, Jacobs J: Prozone in malaria rapid diagnostics tests: how many cases are missed? Malar J 2011, 10: Gillet P, Mori M, Van Den Ende J, Jacobs J: Buffer substitution in malaria rapid diagnostic tests causes false-positive results. Malar J 2010, 9:215 malariajournal.com/content/9/1/ Maltha J, Gillet P, Cnops L, Van Den Ende J, Van Esbroeck M, Jacobs J: Malaria rapid diagnostic tests: Plasmodium falciparum infections with high parasite densities may generate false positive Plasmodium vivax pldh lines. Malar J 2010, 9: Maltha J., Gillet P., Jacobs J. Review: Malaria rapid diagnostic tests in endemic settings. Clin Microbiol Infect 2013; 19: doi/ / /pdf 6. Maltha J., Gillet P., Jacobs J. Review: Malaria rapid diagnostic tests in travel medicine. Clin Microbiol Infect 2013; 19: doi/ / /pdf 34

39 Annex 4: Example of symbol legend Symbol Explanation Symbol Explanation In vitro diagnostic medical device Product code Σ Content sufficient for < n > tests Consult instructions for use Lot number Use by YYYY-MM-(DD) Date of manufacture YYYY-MM-(DD) Manufacturer Do not reuse Do not use if packaging is damaged Temperature limitation Lower limit of temperature Sterile Upper limit of temperature Irritant Keep away from sunlight Biological risk Keep dry Malaria rapid diagnostic test products suggested use of terms, requirements and preferences for labelling and instructions for use 35