Technical Guidance Series (TGS) for WHO Prequalification Diagnostic Assessment

Transcription

1 Technical Guidance Series (TGS) for WHO Prequalification Diagnostic Assessment Designing Instructions for use for in vitro diagnostic medical devices Draft for comment, 19 May 2017

2 World Health Organization 2017 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 non-commercial 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

3 WHO Prequalification Diagnostic Assessment: Technical Guidance Series WHO Prequalification Diagnostic Assessment The World Health Organization (WHO) Prequalification team is coordinated through the Department of Essential Medicines and Health Products. The aim of WHO prequalification of in vitro diagnostic medical devices (IVDs) is to promote and facilitate access to safe, appropriate and affordable IVDs of good quality in an equitable manner. Focus is placed on IVDs for priority diseases and their suitability for use in resource-limited settings. The WHO Prequalification Programme undertakes a comprehensive assessment of individual IVDs through a standardized procedure aligned with international best regulatory practice. In addition, the WHO Prequalification Programme undertakes post-qualification activities for IVDs to ensure the ongoing compliance with prequalification requirements. Procurement of prequalified IVDs Prequalification requirements About the Technical Guidance Series Audience and scope Products that are prequalified by WHO are eligible for procurement by United Nations (UN) agencies. The products are then commonly purchased for use in lowand middle-income countries. IVDs prequalified by WHO are expected to be accurate, reliable and be able to perform as intended for the lifetime of the IVD under conditions likely to be experienced by a typical user in resource-limited settings. The countries where WHO-prequalified IVDs are procured often have minimal regulatory requirements. In addition, the use of IVDs in these countries presents specific challenges. For instance, IVDs are often used by health care workers without extensive training in laboratory techniques, in harsh environmental conditions, without extensive preand post-test quality assurance capacity, and for patients with a disease profile different to those encountered in high income countries. Therefore, the requirements of the WHO Prequalification may be different to the requirements of high-income countries, and/or of the regulatory authority in the country of manufacture. The Technical Guidance Series concept was developed following a consultation, held on March 2015 in Geneva, Switzerland which was attended by experts from national regulatory authorities, national reference laboratories and WHO prequalification dossier reviewers and inspectors. The guidance series is a result of the efforts of this and other international working groups. This guidance is intended for manufacturers interested in WHO prequalification of their IVD. It applies in principle to all IVDs that are eligible for WHO prequalification for use in WHO Member States. It should be read in conjunction with relevant international and national standards and guidance. The TGS guidance documents are freely available on the WHO web site.

4 Contents Contents 1 Acknowledgements 3 1 Definitions Preferred terms and harmonization of labelling for malaria in vitro diagnostic medical devices (IVDs) 6 2 Purpose of this document About the instructions for use (IFU) Limitations of this guidance 7 3 Basic principles Suitability of IFU for the end user Readability Formats to use in an IFU Pictorial representations, graphics and job aids IFU version numbers and changes control Pre-testing the IFU by the manufacturer Accessing the IFU 11 4 Content of the IFU Table of contents Definition of terms and abbreviations (if required) Product identification Intended Use Statement Statement that the product is for in vitro diagnostic use The intended user Test principle summary and explanation Warnings and Precautions Materials provided (test device, reagents, calibrators, controls and accessories) Materials required but not provided Instrumentation (if applicable) Troubleshooting Collecting and preparing specimens IVD storage, operating conditions and stability Test procedure Reading test results Interpretation of test results Limitations of the procedure 21 Page 1

5 4.19 Performance characteristics List of references Contact information Document control Symbol key 23 5 References 24 Annex 1: Example tabulated performance characteristics for IFU 26 A1 1 Example table: Analytical performance study - Precision (Repeatability and Reproducibility) 26 A1 2 Example table: Analytical performance study - Interfering (endogenous) substances 26 A1 3 Example table: Analytical performance study - Cross-reacting infections, diseases and/or medical conditions 27 A1 4 Example table: Clinical performance study - Diagnostic Sensitivity 27 A1 5 Example table: Clinical performance study - Diagnostic Specificity 27 Annex 2: International symbols and warning pictograms 28 Page 2

6 Acknowledgements The document Technical Guidance Series for WHO Prequalification Diagnostic Assessment: Designing Instructions for use for in vitro diagnostic medical devices was developed with support from the Bill & Melinda Gates Foundation and UNITAID. This draft was prepared in collaboration with Dr E Cowan, MD, USA; D Healy; R Meurant, WHO and with input and expertise from Ms B Barbé, Institute of Tropical Medicine Antwerp, Belgium; Dr S Hojvat, MD, USA; Dr J Jacobs, Institute of Tropical Medicine Antwerp, Belgium; H Ardura and A Sands, WHO, Geneva, Switzerland. This document was produced under the coordination and supervision of D Healy, R Meurant and I Prat, Prequalification team Diagnostic Assessment, WHO, Geneva, Switzerland. The draft guidance has been posted on the WHO website for public consultation on 19 May Page 3

7 Definitions Accessories: Article intended explicitly by its manufacturer to be used together with an IVD medical device to enable the IVD medical device to achieve its intended purpose or to augment or extend the capabilities of the IVD medical device in the fulfilment of its intended purpose (1). WHO comment: the accessories should be validated by the manufacturer for use with the IVD Component: Part of a finished, packaged and labelled IVD medical device NOTE 1: Typical kit components include antibody solutions, buffer solutions, calibrators and/or control materials (1). WHO comment: the component should be dedicated, specific to and necessary for using the IVD. WHO considers the instructions for use as a component. Configuration: A combination of items of equipment, as specified by the manufacturer, that operate together to provide an intended use or purpose as a medical device. The combination of items may be modified, adjusted or customized to meet a customer need (2). Instructions for Use (IFU): Information supplied by the manufacturer to enable the safe and proper use of an IVD. NOTE 1: Includes the directions supplied by the manufacturer for the use, maintenance, troubleshooting and disposal of an IVD, as well as warnings and precautions (1). WHO comment: The IFU should provide information on the intended purpose. Please note to avoid confusion that in the USA the acronym IFU occasionally stands for Indications for Use, and the acronym IU stands for Intended Use or Indications For Use. Intended Use/purpose: The objective intent of the manufacturer regarding the use of a product, process or service as reflected in the specifications, instructions and information provided by the manufacturer (3) In vitro diagnostic (IVD) medical device: A medical device, whether used alone or in combination, intended by the manufacturer for the in vitro examination of specimens derived from the human body solely or principally to provide information for diagnostic, monitoring or compatibility purposes. NOTE 1: IVDs include reagents, calibrators, control materials, specimen receptacles, software, and related instruments or apparatus or other articles and are used, for example, for the following test purposes: diagnosis, aid to diagnosis, screening, monitoring, predisposition, prognosis, prediction, determination of physiological status (4). Page 4

8 Kit: Set of components that are packaged together and intended to be used to perform a specific IVD examination NOTE 1 Kit components can include reagents (such as antibodies, enzymes, buffer and diluents), calibrators, controls and other articles and materials (1) WHO comment: For rapid diagnostic tests this may include the IVD buffer bottle, specimen transfer device, lancet, alcohol swab and IFU (5) Job aid: Information excerpted from an approved procedure that is presented in a more readily viewable format; job aids are subject to document control (6) Labelling written, printed or graphic information provided upon the medical device itself or on the packaging of each unit, or on the packaging of multiple devices. (3) Limitations of the procedure: Specific situation in which an IVD examination procedure might not perform as intended (1) Lot /Batch: Defined amount of material that is uniform in its properties and has been produced in one process or series of processes (1) Batch code/lot number: Distinctive set of numbers and/or letters that specifically identifies a batch and permits its manufacturing, packaging, labelling and distribution history to be traced (1) 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 name; whether or not such a medical device is designed and/or manufactured by that person himself or on his behalf by another person(s) (7) Product code: The value given by the Regulated Entity (manufacturer) to identify the specific medical device as it relates to its form/fit, function and process (i.e., manufacturing processes requiring differentiation for distribution control (for example, sterilization, component material, reprocessing, etc.)) (8) Precaution: A statement that alerts users to special care or activities necessary for safe and effective use of an IVD medical device or to avoid damage to the IVD medical device that could occur as a result of use, including misuse (1) Self-testing Examination performed by a layperson to evaluate an individual's health status NOTE 1 Typically performed in a home or other environment outside a healthcare institution without supervision by a healthcare professional (1) 84 Page 5

9 Shelf life: User: Warning: The period of time until the expiry date during which an IVD reagent in its original packaging maintains its stability under the storage conditions specified by the manufacturer (1) NOTE 1: Stability and expiry date are related concepts. the person, either professional or lay, who uses a medical device. The patient may be the user. (3) A statement that alerts users about a situation that, if not avoided, could result in hazards or other serious adverse consequences from the use of an IVD medical device. NOTE 1 The designation of a hazard alert as a warning is reserved for the most significant consequences. NOTE 2 The distinction between a warning and a precaution is a matter of degree, considering the likelihood and seriousness of the hazard. NOTE 3 Use includes use errors and reasonably foreseeable misuse (1) Preferred terms and harmonization of labelling for malaria in vitro diagnostic medical devices (IVDs) The WHO Global Malaria Programme in collaboration with the Roll Back Malaria Secretariat, the Roll Back Malaria Procurement and Supply Management and Case Management working groups and partners and the Institute of Tropical Medicine, Antwerp developed a harmonization task force recommending harmonization of the labelling of IVD, boxes and accessories, language and format of the IFU. The task force has published the recommendations which can be accessed in the WHO/GMP publication Meeting report Harmonization of rapid diagnostic tests for malaria and implications for procurement (9). WHO encourages manufacturers where possible to adopt the preferred terminology recommended in this publication in relation to IVD applications for WHO Prequalification. Page 6

10 Purpose of this document 2.1 About the instructions for use (IFU) The IFU is a critical part of an IVD and is expected to effectively communicate the product information to the intended user and ensure the safe use of the IVD. It communicates for which purpose the test should be used, who should use it, how the test works, what types of specimens should be used with it, which materials and reagents are needed to perform the test, how to perform the test, how to interpret the test result, the limitations of the test, warnings and precautions that need to be considered when using the test, and evidence to support test performance claims. It therefore communicates all that the user needs to make good clinical use of the IVD. Any information that the manufacturer includes in the IFU should be supported by documentation such as the results of well-controlled studies to substantiate performance claims and manufacturing specifications for the stated composition of test kit components. Manufacturers have a regulatory responsibility to ensure the safe use of their product. WHO reviews the IFU as part of their WHO prequalification assessment 1. The IFU is reviewed for clarity, correctness, consistency with the information submitted in the product dossier and with international guidance (10), requirements, and suitability for the target user group in WHO Member States. This document provides guidance on the approaches to be taken by manufacturers in designing IFU for their products. This document draws on documents developed as part of the Roll Back Malaria mrdt Harmonization Taskforce (HarT) initiative to harmonize aspects of testing using malaria rapid diagnostic tests and suggests improvements to user-friendliness (11) Limitations of this guidance Labelling other than the IFU (e.g. primary and secondary package labels, and instrumentation manual requirements) are outside the scope of this document. There is an increasing interest in the availability of IFUs electronically on the internet. Considerations for electronic IFU accessible online are referred to in the document, however, the information below relates to IFUs supplied in paper format with the product. Specific requirements for instrument manuals can be found in International Organisation for Standardisation document ISO In vitro diagnostic medical devices - Information supplied by the manufacturer 1 See WHO document PQDx_018 Instructions for Compilation of a Product Dossier, Prequalification of In Vitro Diagnostics, v , Section 8.2. Instructions for use. Page 7

11 Basic principles (labelling) - Part 3: In vitro diagnostic instruments for professional use and WHO expects that this standard is used to demonstrate conformity. 3.1 Suitability of IFU for the end user The IFU provides the manufacturer the opportunity to directly interact with the end user and inform them about their product. The manufacturer needs to carefully consider the intended audience of the IFU to ensure that the information is clear and unambiguous to all users. This audience includes professional or lay providers who require the IFU to conduct the assay procedure correctly (as well as for self-testing) and procurers who will use the IFU to aid in the choice and procurement of the assay Readability The IFU are expected to be easily readable. Often it is necessary to use technical language in the IFU but this does not have to negatively impact on the readability as long as the writer uses short sentences and explains difficult words (e.g. desiccant, in vitro). Readability tests and calculators can be employed to indicate how difficult the IFU is to understand (e.g. if using the Flesch-Kincaid grade, the information should have a readability level no higher than 6 (12)). There are a number of readability calculators and resources available online to verify the readability of the IFU. These readability calculators look at the average sentence length and syllables per word and rates text for ease of reading (13,14). They are also available as a tool in Microsoft Word and in other word processing packages. Some specific recommendations to improve readability given below are taken from Clinical and Laboratory Standards Institute (CLSI) (6), the U.S. Food and Drug Administration (FDA) (12, 15 ), Medicines & Healthcare products Regulatory Agency, U.K. (MHRA) (16) and the European Commission guidance documents (17). Use type size of a minimum of 9 points and if elderly or visually impaired users are considered potential users, type size of at least 14 points should be used The font should not be narrowed. Spacing between lines should be at least 3 mm (17). Use simple words with few syllables (3 syllables or fewer) (12). Use sentences and terms that are short (9 10 sentences per 100 words) and easy to understand. Vary the length of sentences and explain difficult words in lay terms. Use consistent terms and words throughout the IFU (see section 1 Definitions for examples). Avoid synonyms or alternate phrases. Page 8

12 Avoid abbreviations or acronyms. If necessary to use them, spell them out in full when first used in the text. Use them consistently throughout the text (12). Use active verbs (imperative) rather than passive voice ( should ) to reduce the risk of ambiguity or confusion. Example: Open the cassette packaging (rather than: The cassette packaging should be opened ) Use positive not negative statements when possible. Important information can be highlighted by using boldface, capitals, italics, boxing of text, contrasting colour or underlining. When listing information points, use one line per action and utilize bullets (for non-specific order such as listing of materials) and numbering (for chronological order of steps) (12). Indicate warnings clearly and write them early in the text before the action step in the procedure. It should be clear to the user when an action should be taken. Example: If the colour indicator is pink, discard the test. Avoid glossy paper. Use paper that is thick enough so print and graphics do not show through (12). Use waterproof pages if required (e.g. for job aids) If the IFU is five or more pages long, it is recommended that a table of contents be included. For IVDs intended for self-testing, use personal pronouns (e.g. you rather than the user ). Explain difficult words in lay terms (e.g. desiccant, in vitro). Use of a flowchart or diagram can be useful to guide the user through an order of operations or multiple decisions (e.g. interpretation of results). Stepaction tables and If-then tables can be used to guide instructions and actions (12) Formats to use in an IFU Different formats can be used to provide the information and instructions in a clear way. Proposed formats are texts, flowcharts and lists. Regardless of the format used by a manufacturer, they must ensure that all regulatory requirements are met and the critical details supplied Pictorial representations, graphics and job aids It is recommended to provide pictorial representations and illustrations when appropriate next to the corresponding text. Some considerations for these are given below: Ensure that graphics (e.g. drawings, symbols) are large enough to be easily visible. Often drawings may be more informative than photographs. Ensure Page 9

13 that the figures used are consistent and accurate. The sample generic job aids for malaria rapid diagnostic tests published by WHO and the Foundation for Innovative New Diagnostics (FIND) (18) provide clear drawings. Place pictorial representations/figures to the left of the text, and refer to the pictorial representations in the text. The pictorial representations should match the real-life situation (e.g. cassette, specimen transfer device, colour of test lines, gloves, right-handed operator). Depict timing instructions by simple pictures of clocks showing start and end times. The pictures should match the instructions. Example: if the kit content is labelled alcohol swab, the image should be called the same. If one drop of reagent is to be used, one drop should be shown in image. Be consistent with illustrations in terms of format and placement of headings. Include image or schematic diagram of the IVD in the IFU. It is recommended to include a clear and simple job aid, either as a separate leaflet, or printed on the IVD packaging or on the box. It should contain the required samples and materials, the essential steps of the procedure and the interpretation of results. The information provided by the job aid needs to agree with that of the IFU. Clear graphics with few text and/or flowcharts and/or decision tables are recommended. Any job aid should have a version number and date of issue (see below) IFU version numbers and changes control Provide the IFU version number, including an indication of language and date of issue, with each updated IFU submitted for assessment. Any changes made with regard to the previous version should be highlighted in grey and the version number of the product and the IFU changed to reflect the update. In case of substantial changes to the IFU, it is recommended to draw the attention to the new IFU by an indication on the test kit box via a sticker label. For changes as part of an upgrade and/or field safety corrective action to an instrument, the manufacturer should consider: 1. including any changed page of the IFU provided in a paper copy with clear instructions on how to include them into the initially provided IFU and which old pages to be removed; or 2. include a full new paper copy; or 3. include a new copy of the IFU on a CD-Rom (or other suitable format other than paper) with clear instructions to destroy the previous version of the CD- Rom (20). Page 10

14 Pre-testing the IFU by the manufacturer Before issuing an IFU, it is important to find out if the information in the IFU is correctly understood and that any user can safely and effectively operate the IVD following the IFU instructions. A first step by the manufacturer is validating if the information in the IFU is correct. The author should re-read the IFU and check it for accuracy. Then another person that is familiar with the IVD should validate the information (12). As a second step, pre-testing of the IFU should be done. Pre-testing is the systematic and formal gathering of target audience reactions to the content and format of the IFU before issuing the IFU its final form (appendix F of reference (15)). Pre-testing can take many forms such as individual in-depth interviews, focus group interviews, questionnaires, etc. A very useful form of pre-testing is the operator performance study where potential users are asked to operate the IVD while following a draft of the IFU. Observers and users can then look for problems with the instructions (12) Accessing the IFU The adoption of electronic labelling, video guides, and detailed information resources via an internet web site where possible, can help simplify product labelling and increase access. IFUs should be provided in paper format and manufacturers are recommended to supplement the paper versions of the IFU with electronic labelling. Manufacturers should consider situations when the IVD may be separated from the labelling and what the user need to do to access the labelling, (e.g. clear instructions on the packaging on where to readily locate the IFU on a dedicated area of the website or advice by telephone (19)). Where multiple devices are available in a kit and the manufacturer provides a single copy of the instructions for use, the manufacturer should provide further copies upon request (3). Consideration should be given to the security requirement in terms of physical security (hardware and software and intrusion protection) and server certification, file format, and access (20) and undertake a risk assessment taking into account unavailability of the internet and back-up mechanisms. Page 11

15 Content of the IFU NOTE: WHO proposes that the format described in this guidance is adopted when creating an IFU. A harmonized format provides several benefits: it facilitates the review during the prequalification process and it facilitates ease of use of IFUs between products by users. WHO therefore recommends that manufacturers if no existing regulatory requirements exist (e.g. FDA), to organize the IFU for their product according to the sections shown below (4.1 to 4.23), which would correspond to sections of the product s IFU. The Malaria HarT consortium commissioned by the Roll Back Malaria Partnership have published a generic IFU template for malarial rapid diagnostic tests which is available online (21) and a checklist for completeness of Malaria rapid diagnostic tests labelling which will be available from the WHO GMP website later in Table of contents 4.2 Definition of terms and abbreviations (if required) It is recommended to keep the number of abbreviations to a minimum and avoid using any that may be confusing Product identification Product name State the name that identifies the IVD. The name could be a brand, trade/proprietary or common name Product code and configuration State the manufacturer s product code. State the configuration(s) and kit size(s) i.e. number of tests per kit. If the IFU covers a number of product codes, the configurations/contents should be equally described for each product code. This includes the number of tests, the contents of each kit, etc Intended Use Statement The intended use statement needs to provide a clear understanding of the purpose of the assay to the user. It is generally understood that the intended use is a formal statement of the claims made by the manufacturer for the capabilities of its product. The main elements of intended use should include the following (3): Page 12

16 What is detected Specify what the assay is designed to detect. Examples include: antibodies, antigens and nucleic acid. Identify the specific microorganisms variants/types/subtypes that the assay can detect, as appropriate, only if the claim is based on data from studies conducted to support it The function of the assay Identify the role that the assay plays in clinical use. Examples include: Screening (typically referring to use in blood donor screening). Diagnosis (the results of the test would be the sole basis for determining a clinical state). An aid in diagnosis (the results of the test would be used with other clinical parameters (additional test results, clinical presentation, etc.) to determine a clinical state). Monitoring (to evaluate the effectiveness of treatment for individuals known to have a clinical state). Prognosis Staging or aid to staging of a disease The clinical indication for the assay Identify the specific disorder, condition, or risk factor that the assay is intended to detect, define, or differentiate. For example, for a disease state caused by an infectious agent this would be the name of the infectious agent and/or the clinical condition caused by that infectious agent Whether the assay is qualitative or quantitative A simple statement to this effect is sufficient Whether the assay is automated or not If the IVD is intended to be performed without any automated steps, identify it as a manually performed assay. If the IVD is automated, identify the specific automated system(s) on which the assay must be run. If only a part of the testing process is automated, it would be considered to be semi-automated. Identify the steps that are automated and the instrument(s) to be used. Page 13

17 The type of specimen required Identify the validated specimen types in the intended use statement. More detailed information may be provided later in the IFU as described in section 4.13 Collecting and preparing specimens The intended testing population Identify the characteristics of individuals that would be tested. This may include individuals with signs and symptoms of a clinical state (symptomatic), individuals who are at elevated risk for a clinical state but who are not showing signs and symptoms (asymptomatic), or individuals being treated for a clinical condition. There may also be identification or restrictions regarding age groups (e.g. for assays to be used in paediatric populations) or other limiting characteristics (e.g. pregnancy). Provide this information in sufficient detail to make clear in whom the assay should be used Statement that the product is for in vitro diagnostic use Include a simple statement in the IFU, such as For In Vitro Diagnostic Use and/or international symbol (see page 28) The intended user State what type of user and setting is intended to operate the assay, such as The assay is intended to be performed by laboratory professional in a clinical laboratory. Other examples may be a laboratory professional at the point of care; or trained lay provider or an untrained user for self-testing. Also identify the level of training needed to operate the assay, for example: training by the manufacturer, knowledge of basic good clinical laboratory practices, or a statement that no specific training is needed, other than following the IFU Test principle summary and explanation Briefly describe the general biological, chemical, microbiological, immunochemical, etc. principles on which the assay is based. Proprietary information need not be disclosed, but provide enough detail to allow the user to understand how the assay is able to carry out its function. This would include, for example, identifying antibody, antigen, or nucleic acid primer and probe targets, and information on the chemical principles used to detect the analyte. If an instrument is required to perform the assay, then include a brief description of the instrument s principles of operation. Page 14

18 Warnings and Precautions The risk/benefit information that the user needs to know before using the assay is expected to be addressed in the Warnings and Precautions, as well as how to avoid these hazards. A warning is associated with increased likelihood and/or seriousness of a hazard. The designation as warning is reserved for the most serious problems. The term precaution is used for hazards that are less significant and if not avoided may result in minor or moderate injury to the user, patient or equipment. For the sake of clarity, it is best to list warnings and precautions separately. The use of international symbols and signal words such as WARNINGS and CAUTION are effective in alerting the user to a hazard (22). When listing warnings and precautions, it is recommended to: Use a signal word (WARNINGS, CAUTION) Use bullet points and concise, frank language Clearly state the action to avoid, and the nature of the hazard that informs the user of the severity and likelihood Specific consequences of the action to provide a clear idea of the risk (15) Location of warning and precautions in the IFU General warning and precautions need to be placed at the beginning of the IFU. In addition, procedure related warnings and precautions should be integrated in to the procedure instructions where users are more likely to read the information at the relevant time (e.g. the warnings made regarding the specimens are better placed before the associated instructional step relating to specimen manipulation occurs) List of warnings and precautions The list of Warnings and Precautions should be presented in a logical order and address issues related to the use of the assay and should include, but not be limited to, the following: IVD use Intended use or conditions that have not been validated (e.g. use as a donor screening assay). Populations that have not been validated (e.g. pregnancy, paediatrics). Reading and interpreting the results (e.g. minimum/maximum reading time, overlooking or over-reading faint test lines). Addition of specimen or reagent in the incorrect order. Page 15

19 Safety precautions Information on correct user handling and disposal of specimens and other potentially infectious materials, according to universal precautions Handling precautions Specimen handling (e.g. incorrect storage or incorrect specimen type, the effect of heat inactivation). Incorrect incubation time (e.g. too short or too long). The disposal of the device and/or its accessories (e.g. lancets), any consumables used with it (e.g. reagents) or any potentially infectious substances of human or animal origin. When addressing disposal issues, specific internationally recognized standards should be referenced or compliance with national and local requirements recommended Storage instructions Exposure of the product to environmental or site conditions (e.g. excessive temperature or humidity, requirement of flat surface to store device or conduct test procedure) Contamination and inhibition (when applicable) Precautions regarding contamination of reagents, inadequate washing of microwells Any other warning and/or precaution that is relevant for the assay Indication of instability or deterioration (e.g. when control value is outside the expected range). The need for proper maintenance of any instruments and the potential consequences if it is not done. Warning that testing another person using a self-test IVD without their consent is illegal Residual risks Identify any risks associated with the use of the IVD, including risks associated with calibrating or servicing an IVD (e.g. from contaminated equipment)(23) Biological Hazards If the product contains material from human or animal origin, it should have a statement warning the user to handle with care. Provide a statement that the biological material has (or has not) been treated to inactivate infectious agents, and state the possibility of residual risk. Page 16

20 Materials provided (test device, reagents, calibrators, controls and accessories) Description of the reagents, calibrators, controls and accessories List all components of the IVD and the quantity supplied for the kit size and configuration (e.g. volume per box, number of boxes, and number of specimen transfer devices) For easy reference, assign colours, numbers or letters to illustrations of the test kit components and their descriptions so that they correspond to each other. Include instructions that the user is advised to familiarise themselves with the components before they begin testing. Provide detail on the concentration and composition of each component (e.g. antibodies, preservatives). Identify any accessory intended to be used in combination with the product in as much detail as necessary to assure that they will be used appropriately. Identify any test kit accessory that is sterile and provide instructions on what actions the user should take in the event of damage to the sterile packaging. Identify any test kit device or accessory that is specified to be for single-use only. Identify when and how often to run controls and calibrators Materials required but not provided If applicable, identify specific materials that are required for testing but not provided in the kit (e.g. gloves, specimen collection materials, timer, additional reagents, equipment, software, pipettes, sharps disposal container, non-sharps disposal container, biohazard container, centrifuge, etc.). Give as much detail as necessary to assure that the appropriate materials will be used Instrumentation (if applicable) Instrumentation is provided with a dedicated instrumentation manual (sometimes also called user guides). Provide a copy with the initial delivery of the instrument (paper copy or electronic). Include instructions in the IFU that the user is advised to familiarise themselves with the instrument manual before they begin testing Software Identify any software (name and product code) to be used with the product. Some software version updates may require a revision of the IFU. List the software version that the IFU applies to and where to find the latest version of the instrumentation manual for the instrument. Page 17

21 IVDs not requiring dedicated instrumentation For automated and semi-automated IVDs that can be used on different instrument systems (e.g. open systems), describe the combination of reagents, consumables and equipment that have been validated: Instrumentation for assays: Describe the types of instruments or specific instruments needed in as much detail as necessary to assure that the appropriate instruments will be used Cleaning and maintenance (if applicable) Identify any requirements for routine maintenance and cleaning. Include details of frequency of cleaning (e.g. at prescribed intervals, as a result of an alert from the instrument or as required by the troubleshooting section), materials required and instructions for cleaning. The same instructions should be provided for maintenance requirements and information on who should perform this maintenance (e.g. the user, a representative of the manufacturer, or a third party). Include in the IFU Warnings and precautions section a statement regarding the need for proper maintenance and the potential consequences if it is not done Troubleshooting Identify issues that would prompt the user to take specific actions such as noting a change in performance or the product malfunctions. Provide detailed instructions on what actions to take. This would apply to a product that is not performing as expected (e.g. no background clearing due to excessive amount of specimen or buffer addition, no control line appears) or to a product that identifies a deficiency (e.g. error messages). Actions to take may involve a user intervention or contacting the manufacturer using the detailed contact information provided in the IFU. If applicable, describe the correct usage of any equipment or software required for the performance of the assay Collecting and preparing specimens Types of specimen(s) to be used and specimen preparation Identify the specimen types that may be used with the test (e.g. serum, plasma, venous whole blood, capillary (finger-prick/heel-prick) whole blood, dried blood spot specimens, sputum, oral mucosal transudate, urine etc.). Indicate the specimen volume required, collection method to be used and specimen storage and transport requirements including the validated anticoagulants/preservatives. Illustrations should be included where applicable and useful. Only specimen types and anticoagulants that have been validated in performance studies may be listed. Page 18

22 Steps to minimize the risk to the user when handling specimens should be clearly identified and be appropriate to the expected level of experience of the intended user (for example, for dried blood spot specimens, the filter paper should be stored in a bag with desiccant labelled with a biohazard symbol to alert users that the contents may be infectious) Specimen exclusion criteria Identify any restrictions on specimens that can be used with the assay, which may be based on the results of performance studies (e.g. specimens with visual evidence of hyperlipidaemia or haemolysis, excessive specimen age, excessive number of freeze/thaw cycles) or by risk assessment. A statement is sufficient Specimen storage and transport conditions Identify under what conditions the specimens can be stored and transported, and the recommended storage and handling instructions. Define the storage temperature and the maximum delay between specimen collection, processing and analysis. Provide as much detail as possible for any specimen collection and transport material that must be provided by the user, to assure that specimen integrity is not compromised. Provide clear instructions on how to label stored specimens with patient identification information to avoid loss of specimen/patient traceability IVD storage, operating conditions and stability Identify specific storage conditions (storage temperature, light, humidity and other relevant factors) and shelf life for kit components for the unopened kit, the opened kit and working solutions, such as reconstituted reagents. Include information on the recommended operating temperatures if they differ from the storage conditions. Kits that consist of more than one component should state the earliest expiration date assigned to a component as the kit expiration date (labelled life). WHO require units of measurement to be International System of Units (SI). Storage temperatures should be indicated in degrees Celsius ( C) Test procedure Instructions on test procedure The instructions or directions for using the IVD need to clearly describe how to use the IVD properly to get the correct result in terms that the intended user can understand. It should address all the areas of risk for incorrect use identified in the manufacturer s risk assessment, to minimise the user error. The user should be advised to read the information in the IFU before using the test (including self- Page 19

23 test users). This information should be displayed prominently on the IFU (boldface type, capital letters) and indicated on the box with an internationally recognized symbol (24, 25). In addition, include a statement (warning) to the effect that not following the test procedure exactly as described in the IFU could cause improper functioning of the assay and inaccurate test results including as applicable, known foreseeable misuse and potential outcomes. Describe all steps, including the use of assay calibrators and controls and calculations. Indicate the time needed to carry out each of the various steps. Number the instructions for each step of the procedure. Follow the basic principles described in Section 0 to maximize readability. Use clear and simple language, with numbered lists to identify each step. Provide drawings of steps and flow diagrams when possible to simplify and clarify the test procedure for the user. Highlight critical steps or parameters using visual cues such as bolded words, boxed messages and/or standardized symbols Quality control procedures Each type of assay should have a quality control procedure. This may involve running quality control specimens with the IVD to determine if it is functioning properly. In laboratory-based automated systems, quality control material is part of every test run (internal quality control). In single-use rapid diagnostic tests, external quality control material is run only under certain circumstances (e.g. when a new lot is received, when environmental conditions change, or when a user has not previously conducted the IVD test). Identify quality control procedures, including the required materials for quality control and the frequency, conditions under which quality control should be performed, expected test results, and actions to be taken if there is a failure. Explain what function of the procedure the quality control material will assess. If quality control material is not provided with the kit for the user, the user should be alerted that they are available separately and if known where they can be obtained Reading test results. Indicate the amount of time that the final reaction/result remains stable. Include a statement directing the user to read the control line prior to interpreting the test results Interpretation of test results An interpretation of all possible result outcomes should be provided. For quantitative assays this should also include the range over which measurements can be made and instructions if the result falls outside this range. Page 20

24 Where possible, include pictorial representations of all possible test results for visually read IVDs. If the results are indicated by a colour change, the colour should be shown on the pictorial representations (high quality photograph or a reproduction of results). The colour shown should be realistic and should match the real-life condition. Explain the meaning of each possible test outcome (including faint test lines and invalid results). Provide information on what should be done in the event of an invalid test result. Information on the interpretation and understanding of the result for a selftesting IVD needs to be provided in an easily understandable way (e.g. a reactive result indicates possible HIV infection). Provide clear and concise information on where to seek advice and follow up in the event of a reactive or invalid result (e.g. consult with a health facility for additional testing or repeat testing). Explain the meaning of a false-reactive or false-nonreactive test result. If applicable define appropriate formulae or algorithms if required to obtain final result. (E.g. a correction factor is required to obtain the final result depending on the specimen type used). In addition, include an example of a calculation using the formulae or algorithm to get the final result Limitations of the procedure Identify, in a list, issues or conditions that would affect assay performance (i.e. false-reactive results, false-nonreactive results, invalid results), based on the results of the analytical performance studies and clinical performance studies. Limitations may be related to the IVD itself, the end-user and/or the conditions during transport and storage. Issues may occur despite correct storage and procedure, and could be related to: the general design of the IVD (e.g. limit of detection, limit of quantification, high dose hook effect, assigning the cut-off). the impact of a serological window period on detection of antibodies (e.g. false negative results in early HIV infection, and possible very late for HIV infection). the measurand (e.g. absence of a Histidine rich protein-2 (HRP2) gene in certain populations, or persistence of HRP2 following resolved infection or ability to detect HIV-1 subtype O. the species not detected (e.g. sensitivity for Plasmodium falciparum > Plasmodium vivax > Plasmodium ovale/malariae. Further information on the limitations of malaria rapid diagnostic tests is available in the WHO Universal access to malaria diagnostic testing: an operational manual (26), or HIV-1 subtype O). potential interfering substances as identified in analytical specificity studies (e.g. for malaria rapid diagnostic tests, specimens with positive rheumatoid factor may produce false reactive results. For HIV oral fluid rapid diagnostic Page 21

25 tests, patients taking antiretroviral therapy may produce false nonreactive results) Performance characteristics Studies presented in the IFU should be relevant to the final and qualified version of the IFU. Provide a summary of analytical performance studies and clinical performance studies that support product performance claims, including at least the following specifications where applicable: 2 1. Analytical sensitivity (lower limit of detection). 2. Analytical specificity (e.g. rheumatoid factor, antinuclear antibody, influence of lipaemic/icteric/haemolysed specimens, cross-reacting organisms). 3. Diagnostic/clinical sensitivity Diagnostic/clinical specificity Repeatability (test-related, within-run variability in setting of intended use). 6. Reproducibility (operator-related, inter-day variability, inter-run variability, inter-site variability, inter-lot variability, inter-operator variability, interinstrument variability in setting of intended use). 7. Reference intervals. 8. Measurement range Identify one section of the performance characteristics as Analytical Performance Studies and another as Clinical Performance Studies, with subsections of each to describe individual studies. For each study, include a brief description of the purpose and design of the study, the manner and location in which the study was conducted, the number and type of samples studied, the reference methods used, the results, and the conclusions. Results from each different subset represented (e.g. population, specimen type), should be presented separately. In addition to the narrative of the results, include appropriately numbered and titled figures and/or tables that summarize the study results (see Annex 1: Example of tabulated performance characteristics for IFU). For IVDs for self-testing, manufacturers may modify the amount of detail provided on the clinical and analytical performance characteristics when designing the IFU. 2 See Instructions for Compilation of a Product Dossier, Prequalification of Diagnostics, PQDx_018, Section 7, for studies that are expected for a given product. 3 For any self-test device, the results of diagnostic/clinical specificity and sensitivity studies should be reported for both professional and self-use. Page 22

26 However, key performance characteristics (accuracy, sensitivity) should be included in clear and readily understood language. Where IVDs are intended for use by lay providers and professional users, any conflict of the needs of these different users need to be resolved (e.g. additional information for professional users provided in a separate section) (16) List of references Include a numbered list of references used in the IFU. Select relevant and recent publications in a practical and product-oriented way Contact information Provide the name and contact details of the manufacturer, (or an authorized representative of the manufacturer where required), and distributor whom the user can contact to obtain assistance. It is preferable that a mailing address, telephone number, address, and a website address are provided on the IFU. For IVDs for self-testing, a toll-free (free-phone) telephone number is a preferable means to provide direct health related support to the user Document control Include a document version number and date of issue for the IFU Symbol key The use of internationally recognized symbols simplifies communication. Using symbols can save space, spare costs with translation and improve clarity. They may be used instead of statements to convey information. There are a number of internationally recognized symbols for certain IVD characteristics (e.g. storage temperature limits, identification of in vitro diagnostic use, manufacturer information)(24). These symbols are especially useful when printed materials are generated in multiple languages or users are not familiar with the language in which the IFU is written. Symbols quickly communicate a concept to the user in a way that, if used properly, can transcend language differences. The symbols should be explained in a symbol key in the IFU and should appear on the last page of the IFU. See Annex 2: for an example of symbol key and warning pictograms for IVD labelling. Page 23

27 709 5 References 1 ISO :2009. In vitro diagnostic medical IVDs - Information supplied by the manufacturer (labelling) - Part 1: Terms, definitions and general requirements. Geneva. International Organization for Standardization; IMDRF/UDI WG/N7 FINAL:2013. UDI Guidance Unique Device Identification (UDI) of Medical Devices. International Medical Device Regulators Forum; GHTF/SG1/N70:2011: Label and Instructions for Use for Medical Devices. Global Harmonization Task Force (GHTF) Steering Committee; GHTF/SC/N4:2012 (Edition 2). Glossary and Definitions of Terms Used in GHTF Documents. Global Harmonization Task Force (GHTF) Steering Committee; Additional file 1. Suggested terms and abbreviations related to malaria RDTs. In: Jacobs J, Barbé B, Gillet P, Aidoo M, Serra-Casas E, Van Erps J et al. Harmonization of malaria rapid diagnostic tests: best practices in labelling including instructions for use. Malar J. 2014;13(1): CLSI: Quality Management System: Development and Management of Laboratory Documents; Approved Guidelines- Sixth Edition. CLSI document QMS02-A6. Wayne, PA: Clinical and Laboratory Standards Institute; GHTF/SG1/N055:2009: Definitions of the Terms Manufacturer, Authorised Representative, Distributor and Importer. Global Harmonization Task Force (GHTF) Steering Committee; IMDRF. RPS WG (PD1)/N19R1. PROPOSED DOCUMENT: Common Data Elements for Medical Device Identification. International Medical Device Regulators Forum; 2015 (unpublished) 9 Meeting report on Harmonization of rapid diagnostic tests for malaria and implications for procurement February 2015 Geneva, Switzerland. World Health Organization. ISBN ISO :2009. In vitro diagnostic medical IVDs - Information supplied by the manufacturer (labelling) - Part 2: In vitro diagnostic reagents for professional use. Geneva. International Organization for Standardization; Jacobs J, Barbé B, Gillet P, Aidoo M, Serra-Casas E, Van Erps J et al. Harmonization of malaria rapid diagnostic tests: best practices in labelling including instructions for use. Malar J. 2014;13(1): U.S. Food and Drug Administration. Write It Right. Rockville, MD: HHS Publication FDA ; Backinger CL and Kingsley PA. (Internet). Accessed 16 May Available from: 13 Readability Calculator. Mladen Adamovic, Accessed 22 July Flesch R. How to Write Plain English. University of Canterbury. Christchurch, New Zealand; 1981 (web page). Accessed 10 August Available from : Page 24

28 15 U.S. Food and Drug Administration. Guidance on medical device patient labelling; Final guidance for industry and FDA reviewer; MD, USA; 19 April 2001 (Internet). Accessed 16 May Available from: m pdf 16 MHRA. Guidance for notified bodies on the regulation of IVDs for self-testing. Competent Authority (UK) Medicines and Healthcare products Regulatory Agency. London, U.K European Commission. Guideline on the readability of the labelling and package leaflet of medicinal products for human use, also known as ENTR/F/2/SF/jr(2009)D/869. Brussels; 2009 Jan 12 (Internet). Accessed 16 September Available from: 2/c/2009_01_12_readability_guideline_final_en.pdf 18 WHO / FIND / TDR / Roll Back Malaria. Purchasing and Using RDTs RDT instructions and training (web page). World Health Organization Regional Office for the Western Pacific; Accessed 22 July FDA: Guidance for Industry and Food and Drug Administration Staff. Design Considerations for Devices Intended for Home Use. MD, USA. Center for Devices and Radiological Health (CDRH) and Center for Biologics Evaluation and Research (CBER), (Internet). MD, USA; MEDDEV. 2.14/3 rev.1 Guidelines on Medical Devices: IVD guidances: Supply of Instructions For Use (IFU) and other information for In-vitro Diagnostic (IVD) medical devices. A guide for manufacturers and notified bodies. Brussels, Belgium. European Commission Enterprise and Industry Directorate- General; Additional file 3. Generic template for Instructions for Use (IFU). In: Jacobs J, Barbé B, Gillet P, Aidoo M, Serra-Casas E, Van Erps J et al. Harmonization of malaria rapid diagnostic tests: best practices in labelling including instructions for use. Malar J. 2014;13(1): Guidance document: Labelling of In Vitro Diagnostic Devices. Ottawa. Health Canada; 2016 (Internet). (Accessed 16 May 2016) Available from 23 ISO 14971:2007 Medical devices - Application of risk management to medical devices. Geneva. International Organization for Standardization; ISO :2016. Medical Devices - Symbols to be used with medical device labels, labelling and information to be supplied - Part 1: General requirements. Geneva. International Organization for Standardization; Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006, OJCE (L353): , 31 December 2008 (the "CLP Regulation"). 26 WHO. Universal access to malaria diagnostic testing An operational manual. November 2011 (rev. February 2013). Geneva, Switzerland. World Health Organization; Page 25

29 Instructions for use for in vitro diagnostics Annex 1: Example tabulated performance characteristics for IFU The tables below are examples only and not an exhaustive list. A1 1 Example table: Analytical performance study - Precision (Repeatability and Reproducibility) Table A2-1 Summary of Assay Precision (Repeatability) Quality control panel Number of member replicate tests Mean S/Co Standard deviation (SD) Negative Control (Value) (Value) (Value) (Value) QC-1 (low titre positive) (Value) The table is for (Value) illustrative purposes. (Value) WHO expects (Value) QC-2 (mid-range (Value) manufacturers to (Value) provide all (Value) results for the studies (Value) in positive) an easy to read format. QC-3 (high-titre positive) (Value) (Value) (Value) (Value) Within-condition % Coefficient of variation (CV) Table A2-2 Summary of Assay Precision (Reproducibility) for Quality control panel member QC-1 (low titre positive) Results for Quality Number of S/Co Between-condition control panel member replicate tests %CV QC-1 (low titre positive) Mean SD Between-day (Value) (Value) (Value) (Value) The table is for illustrative purposes. WHO expects Between-operator (Value) (Value) (Value) (Value) manufacturers to provide all results for the studies in Between-lot (Value) (Value) (Value) (Value) an easy to read format. Between-instrument (Value) (Value) (Value) (Value) A1 2 Example table: Analytical performance study - Interfering (endogenous) substances Table A2-3 Summary of test results for determination of analytical specificity: potentially interfering endogenous substances Interfering Substance Specimen Test Results identification (ID) Unspiked specimen Specimen spiked with substance-1 Substance-1 (xx g/ml) ID-1 (Value) (Value) (Value) ID-2 The table (Value) is for illustrative purposes. (Value) WHO expects (Value) ID-3 manufacturers (Value) to provide all results (Value) for the studies (Value) in ID-4 (Value) an easy to read (Value) format. (Value) Substance-2 (x/ millimole) ID-1, etc (Value) (Value) (Value) Specimen spiked with substance-2 Page 26

30 Instructions for use for in vitro diagnostics A1 3 Example table: Analytical performance study - Cross-reacting infections, diseases and/or medical conditions Table A2-4 Summary of test results for determination of analytical specificity: potentially crossreacting unrelated infections, diseases and/or medical conditions Infection/disease/medical Number of Test Results condition specimens tested IVD being evaluated Reference Test Organism 1 (Value) (Value) (Value) Medical condition 1, The table is for illustrative purposes. WHO expects (Value) (Value) (Value) manufacturers to provide all results for the studies in Etc. (Value) an easy to read format. (Value) (Value) A1 4 Example table: Clinical performance study - Diagnostic Sensitivity Table A2-5 Summary of results of a clinical study to determine diagnostic sensitivity Finger-prick whole blood. Study site Number of specimens tested Number of specimens reactive by reference method Number of valid tests Number of specimens reactive in the IVD Number of specimens falselynonreactive % Sensitivity 95% Confidence interval 1 (Value) (Value) (Value) (Value) (Value) (Value) (Value) A1 5 Example table: Clinical performance study - Diagnostic Specificity Table A2-6 Summary of results of a clinical study to determine diagnostic specificity serum Study site Number of specimens tested Number of specimens reactive by reference method Number of valid tests Number of specimens nonreactive in the IVD Number of specimens falselyreactive % Specificity 95% Confidence interval 1 (Value) (Value) (Value) (Value) (Value) (Value) (Value) Page 27

31 Instructions for use for in vitro diagnostics 736 Annex 2: International symbols and warning pictograms 737 Table A3.1 Symbols to be used in medical device labelling (24). Symbol Explanation Symbol Explanation In vitro diagnostic medical device Product code/catalogue number Content sufficient for < n > tests (Indicates the total number of IVD tests that can be performed with the IVD.) Batch code Date of manufacture YYYY-MM-(DD) Consult Instructions for Use Use-by date YYYY-MM-(DD) Indicates the device manufacturer Do not re-use Do not use if package is damaged Temperature limit Lower limit of temperature Sterile Upper limit of temperature Irritant Biological risk Keep away from sunlight Keep dry 738 Page 28