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Technical Guidance Series (TGS)
for WHO Prequalification – Diagnostic Assessment
Designing Instructions
for use for in vitro
diagnostic medical
devices
TGS–5
Draft for comment, 19 May 2017
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Designing Instructions for use for IVDs TGS–5
© 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.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). 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: +41 22 791 4806; e-mail: permissions@who.int). 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 - 1211 Geneva 27 Switzerland
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Designing Instructions for use for IVDs TGS–5
WHO Prequalification – Diagnostic Assessment: Technical Guidance Series
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.
Products that are prequalified by WHO are eligible for procurement by United
Nations (UN) agencies. The products are then commonly purchased for use in low-
and 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 pre-
and 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 10-13 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.
WHO
Prequalification –
Diagnostic
Assessment
Procurement of
prequalified IVDs
Prequalification
requirements
About the
Technical Guidance
Series
Audience and
scope
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Designing Instructions for use for IVDs TGS–5
Page | 1
Contents
Contents 1
Acknowledgements 3
1 Definitions 4
1.1 Preferred terms and harmonization of labelling for malaria in vitro diagnostic medical devices (IVDs) 6
2 Purpose of this document 7
2.1 About the instructions for use (IFU) 7
2.2 Limitations of this guidance 7
3 Basic principles 8
3.1 Suitability of IFU for the end user 8
3.2 Readability 8
3.3 Formats to use in an IFU 9
3.4 Pictorial representations, graphics and job aids 9
3.5 IFU version numbers and changes control 10
3.6 Pre-testing the IFU by the manufacturer 11
3.7 Accessing the IFU 11
4 Content of the IFU 12
4.1 Table of contents 12
4.2 Definition of terms and abbreviations (if required) 12
4.3 Product identification 12
4.4 Intended Use Statement 12
4.5 Statement that the product is for in vitro diagnostic use 14
4.6 The intended user 14
4.7 Test principle summary and explanation 14
4.8 Warnings and Precautions 15
4.9 Materials provided (test device, reagents, calibrators, controls and accessories) 17
4.10 Materials required but not provided 17
4.11 Instrumentation (if applicable) 17
4.12 Troubleshooting 18
4.13 Collecting and preparing specimens 18
4.14 IVD storage, operating conditions and stability 19
4.15 Test procedure 19
4.16 Reading test results. 20
4.17 Interpretation of test results 20
4.18 Limitations of the procedure 21
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Designing Instructions for use for IVDs TGS–5
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4.19 Performance characteristics 22
4.20 List of references 23
4.21 Contact information 23
4.22 Document control 23
4.23 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
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Designing Instructions for use for IVDs TGS–5
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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 2017.
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1 Definitions 1
Accessories: Article intended explicitly by its manufacturer to be used together with an IVD 2
medical device to enable the IVD medical device to achieve its intended purpose 3
or to augment or extend the capabilities of the IVD medical device in the 4
fulfilment of its intended purpose (1). 5
WHO comment: the accessories should be validated by the manufacturer for use 6
with the IVD 7
8
Component: Part of a finished, packaged and labelled IVD medical device 9
NOTE 1: Typical kit components include antibody solutions, buffer solutions, 10
calibrators and/or control materials (1). 11
WHO comment: the component should be dedicated, specific to and necessary 12
for using the IVD. WHO considers the instructions for use as a component. 13
14
Configuration: A combination of items of equipment, as specified by the manufacturer, that 15
operate together to provide an intended use or purpose as a medical device. The 16
combination of items may be modified, adjusted or customized to meet a 17
customer need (2). 18
19
Instructions for Use (IFU): Information supplied by the manufacturer to enable the safe and proper 20
use of an IVD. 21
NOTE 1: Includes the directions supplied by the manufacturer for the use, 22
maintenance, troubleshooting and disposal of an IVD, as well as warnings and 23
precautions (1). 24
WHO comment: The IFU should provide information on the intended purpose. 25
Please note to avoid confusion that in the USA the acronym IFU occasionally 26
stands for Indications for Use, and the acronym IU stands for Intended Use or 27
Indications For Use. 28
29
Intended Use/purpose: The objective intent of the manufacturer regarding the use of a product, 30
process or service as reflected in the specifications, instructions and information 31
provided by the manufacturer (3) 32
33
In vitro diagnostic (IVD) medical device: A medical device, whether used alone or in combination, 34
intended by the manufacturer for the in vitro examination of specimens derived 35
from the human body solely or principally to provide information for diagnostic, 36
monitoring or compatibility purposes. 37
NOTE 1: IVDs include reagents, calibrators, control materials, specimen 38
receptacles, software, and related instruments or apparatus or other articles and 39
are used, for example, for the following test purposes: diagnosis, aid to diagnosis, 40
screening, monitoring, predisposition, prognosis, prediction, determination of 41
physiological status (4). 42
43
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Kit: Set of components that are packaged together and intended to be used to 44
perform a specific IVD examination 45
NOTE 1 Kit components can include reagents (such as antibodies, enzymes, buffer 46
and diluents), calibrators, controls and other articles and materials (1) 47
WHO comment: For rapid diagnostic tests this may include the IVD buffer bottle, 48
specimen transfer device, lancet, alcohol swab and IFU (5) 49
50
Job aid: Information excerpted from an approved procedure that is presented in a more 51
readily viewable format; job aids are subject to document control (6) 52
53
Labelling written, printed or graphic information provided upon the medical device itself or 54
on the packaging of each unit, or on the packaging of multiple devices. (3) 55
56
Limitations of the procedure: Specific situation in which an IVD examination procedure might not 57
perform as intended (1) 58
59
Lot /Batch: Defined amount of material that is uniform in its properties and has been 60
produced in one process or series of processes (1) 61
62
Batch code/Lot number: Distinctive set of numbers and/or letters that specifically identifies a batch 63
and permits its manufacturing, packaging, labelling and distribution history to be 64
traced (1) 65
66
Manufacturer: Any natural or legal person with responsibility for design and/or manufacture of a 67
medical device with the intention of making the medical device available for use, 68
under his name; whether or not such a medical device is designed and/or 69
manufactured by that person himself or on his behalf by another person(s) (7) 70
71
Product code: The value given by the Regulated Entity (manufacturer) to identify the specific 72
medical device as it relates to its form/fit, function and process (i.e., 73
manufacturing processes requiring differentiation for distribution control (for 74
example, sterilization, component material, reprocessing, etc.)) (8) 75
76
Precaution: A statement that alerts users to special care or activities necessary for safe and 77
effective use of an IVD medical device or to avoid damage to the IVD medical 78
device that could occur as a result of use, including misuse (1) 79
80
Self-testing Examination performed by a layperson to evaluate an individual's health status 81
NOTE 1 Typically performed in a home or other environment outside a healthcare 82
institution without supervision by a healthcare professional (1) 83
84
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Shelf life: The period of time until the expiry date during which an IVD reagent in its original 85
packaging maintains its stability under the storage conditions specified by the 86
manufacturer (1) 87
NOTE 1: Stability and expiry date are related concepts. 88
89
User: the person, either professional or lay, who uses a medical device. The patient 90
may be the user. (3) 91
92
Warning: A statement that alerts users about a situation that, if not avoided, could result in 93
hazards or other serious adverse consequences from the use of an IVD medical 94
device. 95
NOTE 1 The designation of a hazard alert as a warning is reserved for the most 96
significant consequences. 97
NOTE 2 The distinction between a warning and a precaution is a matter of degree, 98
considering the likelihood and seriousness of the hazard. 99
NOTE 3 Use includes use errors and reasonably foreseeable misuse (1) 100
101
1.1 Preferred terms and harmonization of labelling for malaria in vitro 102
diagnostic medical devices (IVDs) 103
The WHO Global Malaria Programme in collaboration with the Roll Back Malaria 104
Secretariat, the Roll Back Malaria Procurement and Supply Management and Case 105
Management working groups and partners and the Institute of Tropical Medicine, 106
Antwerp developed a harmonization task force recommending harmonization of 107
the labelling of IVD, boxes and accessories, language and format of the IFU. The 108
task force has published the recommendations which can be accessed in the 109
WHO/GMP publication “Meeting report Harmonization of rapid diagnostic tests 110
for malaria and implications for procurement” (9). 111
WHO encourages manufacturers where possible to adopt the preferred 112
terminology recommended in this publication in relation to IVD applications for 113
WHO Prequalification. 114
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2 Purpose of this document 115
2.1 About the instructions for use (IFU) 116
The IFU is a critical part of an IVD and is expected to effectively communicate the 117
product information to the intended user and ensure the safe use of the IVD. It 118
communicates for which purpose the test should be used, who should use it, how 119
the test works, what types of specimens should be used with it, which materials 120
and reagents are needed to perform the test, how to perform the test, how to 121
interpret the test result, the limitations of the test, warnings and precautions that 122
need to be considered when using the test, and evidence to support test 123
performance claims. It therefore communicates all that the user needs to make 124
good clinical use of the IVD. 125
Any information that the manufacturer includes in the IFU should be supported by 126
documentation such as the results of well-controlled studies to substantiate 127
performance claims and manufacturing specifications for the stated composition 128
of test kit components. Manufacturers have a regulatory responsibility to ensure 129
the safe use of their product. 130
WHO reviews the IFU as part of their WHO prequalification assessment1. The IFU 131
is reviewed for clarity, correctness, consistency with the information submitted in 132
the product dossier and with international guidance (10), requirements, and 133
suitability for the target user group in WHO Member States. This document 134
provides guidance on the approaches to be taken by manufacturers in designing 135
IFU for their products. This document draws on documents developed as part of 136
the Roll Back Malaria “mRDT Harmonization Taskforce” (HarT) initiative to 137
harmonize aspects of testing using malaria rapid diagnostic tests and suggests 138
improvements to user-friendliness (11). 139
2.2 Limitations of this guidance 140
Labelling other than the IFU (e.g. primary and secondary package labels, and 141
instrumentation manual requirements) are outside the scope of this document. 142
There is an increasing interest in the availability of IFUs electronically on the 143
internet. Considerations for electronic IFU accessible online are referred to in the 144
document, however, the information below relates to IFUs supplied in paper 145
format with the product. Specific requirements for instrument manuals can be 146
found in International Organisation for Standardisation document ISO 18113-3 “In 147
vitro diagnostic medical devices - Information supplied by the manufacturer 148
1 See WHO document PQDx_018 Instructions for Compilation of a Product Dossier, Prequalification of In Vitro
Diagnostics, v3 27.08.2014, Section 8.2. Instructions for use.
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(labelling) - Part 3: In vitro diagnostic instruments for professional use” and WHO 149
expects that this standard is used to demonstrate conformity. 150
3 Basic principles 151
3.1 Suitability of IFU for the end user 152
The IFU provides the manufacturer the opportunity to directly interact with the 153
end user and inform them about their product. The manufacturer needs to 154
carefully consider the intended audience of the IFU to ensure that the information 155
is clear and unambiguous to all users. This audience includes professional or lay 156
providers who require the IFU to conduct the assay procedure correctly (as well as 157
for self-testing) and procurers who will use the IFU to aid in the choice and 158
procurement of the assay. 159
3.2 Readability 160
The IFU are expected to be easily readable. Often it is necessary to use technical 161
language in the IFU but this does not have to negatively impact on the readability 162
as long as the writer uses short sentences and explains difficult words (e.g. 163
desiccant, in vitro). Readability tests and calculators can be employed to indicate 164
how difficult the IFU is to understand (e.g. if using the Flesch-Kincaid grade, the 165
information should have a readability level no higher than 6 (12)). There are a 166
number of readability calculators and resources available online to verify the 167
readability of the IFU. These readability calculators look at the average sentence 168
length and syllables per word and rates text for ease of reading (13,14). They are 169
also available as a tool in Microsoft Word and in other word processing packages. 170
Some specific recommendations to improve readability given below are taken 171
from Clinical and Laboratory Standards Institute (CLSI) (6), the U.S. Food and Drug 172
Administration (FDA) (12, 15 ), Medicines & Healthcare products Regulatory 173
Agency, U.K. (MHRA) (16) and the European Commission guidance documents 174
(17). 175
Use type size of a minimum of 9 points and if elderly or visually impaired users 176
are considered potential users, type size of at least 14 points should be used 177
The font should not be narrowed. Spacing between lines should be at least 178
3 mm (17). 179
Use simple words with few syllables (3 syllables or fewer) (12). 180
Use sentences and terms that are short (9 – 10 sentences per 100 words) and 181
easy to understand. Vary the length of sentences and explain difficult words in 182
lay terms. 183
Use consistent terms and words throughout the IFU (see section 1 Definitions 184
for examples). Avoid synonyms or alternate phrases. 185
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Avoid abbreviations or acronyms. If necessary to use them, spell them out in 186
full when first used in the text. Use them consistently throughout the text 187
(12). 188
Use active verbs (imperative) rather than passive voice (“should”) to reduce 189
the risk of ambiguity or confusion. 190
Example: “Open the cassette packaging…” (rather than: “The cassette 191
packaging should be opened…”) 192
Use positive not negative statements when possible. 193
Important information can be highlighted by using boldface, capitals, italics, 194
boxing of text, contrasting colour or underlining. 195
When listing information points, use one line per action and utilize bullets (for 196
non-specific order such as listing of materials) and numbering (for 197
chronological order of steps) (12). 198
Indicate warnings clearly and write them early in the text before the action 199
step in the procedure. It should be clear to the user when an action should be 200
taken. 201
Example: “If the colour indicator is pink, discard the test.” 202
Avoid glossy paper. Use paper that is thick enough so print and graphics do 203
not show through (12). 204
Use waterproof pages if required (e.g. for job aids) 205
If the IFU is five or more pages long, it is recommended that a table of 206
contents be included. 207
For IVDs intended for self-testing, use personal pronouns (e.g. “you” rather 208
than “the user”). Explain difficult words in lay terms (e.g. desiccant, in vitro). 209
Use of a flowchart or diagram can be useful to guide the user through an 210
order of operations or multiple decisions (e.g. interpretation of results). Step-211
action tables and If-then tables can be used to guide instructions and actions 212
(12). 213
3.3 Formats to use in an IFU 214
Different formats can be used to provide the information and instructions in a 215
clear way. Proposed formats are texts, flowcharts and lists. Regardless of the 216
format used by a manufacturer, they must ensure that all regulatory 217
requirements are met and the critical details supplied. 218
3.4 Pictorial representations, graphics and job aids 219
It is recommended to provide pictorial representations and illustrations when 220
appropriate next to the corresponding text. Some considerations for these are 221
given below: 222
Ensure that graphics (e.g. drawings, symbols) are large enough to be easily 223
visible. Often drawings may be more informative than photographs. Ensure 224
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that the figures used are consistent and accurate. The sample generic job aids 225
for malaria rapid diagnostic tests published by WHO and the Foundation for 226
Innovative New Diagnostics (FIND) (18) provide clear drawings. 227
Place pictorial representations/figures to the left of the text, and refer to the 228
pictorial representations in the text. The pictorial representations should 229
match the real-life situation (e.g. cassette, specimen transfer device, colour of 230
test lines, gloves, right-handed operator). 231
Depict timing instructions by simple pictures of clocks showing start and end 232
times. 233
The pictures should match the instructions. 234
Example: if the kit content is labelled “alcohol swab”, the image should 235
be called the same. If one drop of reagent is to be used, one drop should 236
be shown in image. 237
Be consistent with illustrations in terms of format and placement of headings. 238
Include image or schematic diagram of the IVD in the IFU. 239
It is recommended to include a clear and simple job aid, either as a separate 240
leaflet, or printed on the IVD packaging or on the box. It should contain the 241
required samples and materials, the essential steps of the procedure and the 242
interpretation of results. The information provided by the job aid needs to 243
agree with that of the IFU. Clear graphics with few text and/or flowcharts 244
and/or decision tables are recommended. Any job aid should have a version 245
number and date of issue (see below). 246
3.5 IFU version numbers and changes control 247
Provide the IFU version number, including an indication of language and date of 248
issue, with each updated IFU submitted for assessment. Any changes made with 249
regard to the previous version should be highlighted in grey and the version 250
number of the product and the IFU changed to reflect the update. In case of 251
substantial changes to the IFU, it is recommended to draw the attention to the 252
new IFU by an indication on the test kit box via a sticker label. 253
For changes as part of an upgrade and/or field safety corrective action to an 254
instrument, the manufacturer should consider: 255
1. including any changed page of the IFU provided in a paper copy with clear 256 instructions on how to include them into the initially provided IFU and which 257 old pages to be removed; or 258
2. include a full new paper copy; or 259 3. include a new copy of the IFU on a CD-Rom (or other suitable format other 260
than paper) with clear instructions to destroy the previous version of the CD-261 Rom (20). 262
263
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3.6 Pre-testing the IFU by the manufacturer 264
Before issuing an IFU, it is important to find out if the information in the IFU is 265
correctly understood and that any user can safely and effectively operate the IVD 266
following the IFU instructions. 267
A first step by the manufacturer is validating if the information in the IFU is 268
correct. The author should re-read the IFU and check it for accuracy. Then another 269
person that is familiar with the IVD should validate the information (12). 270
As a second step, pre-testing of the IFU should be done. Pre-testing is the 271
systematic and formal gathering of target audience reactions to the content and 272
format of the IFU before issuing the IFU its final form (appendix F of reference 273
(15)). Pre-testing can take many forms such as individual in-depth interviews, 274
focus group interviews, questionnaires, etc. A very useful form of pre-testing is 275
the operator performance study where potential users are asked to operate the 276
IVD while following a draft of the IFU. Observers and users can then look for 277
problems with the instructions (12). 278
3.7 Accessing the IFU 279
The adoption of electronic labelling, video guides, and detailed information 280
resources via an internet web site where possible, can help simplify product 281
labelling and increase access. IFUs should be provided in paper format and 282
manufacturers are recommended to supplement the paper versions of the IFU 283
with electronic labelling. 284
Manufacturers should consider situations when the IVD may be separated from 285
the labelling and what the user need to do to access the labelling, (e.g. clear 286
instructions on the packaging on where to readily locate the IFU on a dedicated 287
area of the website or advice by telephone (19)). Where multiple devices are 288
available in a kit and the manufacturer provides a single copy of the instructions 289
for use, the manufacturer should provide further copies upon request (3). 290
Consideration should be given to the security requirement in terms of physical 291
security (hardware and software and intrusion protection) and server certification, 292
file format, and access (20) and undertake a risk assessment taking into account 293
unavailability of the internet and back-up mechanisms. 294
295
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4 Content of the IFU 296
NOTE: WHO proposes that the format described in this guidance is adopted 297
when creating an IFU. A harmonized format provides several benefits: it 298
facilitates the review during the prequalification process and it facilitates ease 299
of use of IFUs between products by users. 300
WHO therefore recommends that manufacturers if no existing regulatory 301
requirements exist (e.g. FDA), to organize the IFU for their product according to 302
the sections shown below (4.1 to 4.23), which would correspond to sections of 303
the product’s IFU. 304
The Malaria HarT consortium commissioned by the Roll Back Malaria Partnership 305
have published a generic IFU template for malarial rapid diagnostic tests which is 306
available online (21) and a checklist for completeness of Malaria rapid diagnostic 307
tests labelling which will be available from the WHO GMP website later in 2017. 308
4.1 Table of contents 309
4.2 Definition of terms and abbreviations (if required) 310
It is recommended to keep the number of abbreviations to a minimum and avoid 311
using any that may be confusing. 312
4.3 Product identification 313
4.3.1 Product name 314
State the name that identifies the IVD. The name could be a brand, 315
trade/proprietary or common name. 316
4.3.2 Product code and configuration 317
State the manufacturer’s product code. State the configuration(s) and kit size(s) 318
i.e. number of tests per kit. 319
If the IFU covers a number of product codes, the configurations/contents should 320
be equally described for each product code. This includes the number of tests, the 321
contents of each kit, etc. 322
4.4 Intended Use Statement 323
The intended use statement needs to provide a clear understanding of the 324
purpose of the assay to the user. It is generally understood that the intended use 325
is a formal statement of the claims made by the manufacturer for the capabilities 326
of its product. The main elements of intended use should include the following (3): 327
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4.4.1 What is detected 328
Specify what the assay is designed to detect. Examples include: antibodies, 329
antigens and nucleic acid. Identify the specific microorganisms 330
variants/types/subtypes that the assay can detect, as appropriate, only if the 331
claim is based on data from studies conducted to support it. 332
4.4.2 The function of the assay 333
Identify the role that the assay plays in clinical use. Examples include: 334
Screening (typically referring to use in blood donor screening). 335
Diagnosis (the results of the test would be the sole basis for determining a 336
clinical state). 337
An aid in diagnosis (the results of the test would be used with other clinical 338
parameters (additional test results, clinical presentation, etc.) to determine a 339
clinical state). 340
Monitoring (to evaluate the effectiveness of treatment for individuals known 341
to have a clinical state). 342
Prognosis 343
Staging or aid to staging of a disease. 344
4.4.3 The clinical indication for the assay 345
Identify the specific disorder, condition, or risk factor that the assay is intended to 346
detect, define, or differentiate. For example, for a disease state caused by an 347
infectious agent this would be the name of the infectious agent and/or the clinical 348
condition caused by that infectious agent. 349
4.4.4 Whether the assay is qualitative or quantitative 350
A simple statement to this effect is sufficient. 351
4.4.5 Whether the assay is automated or not 352
If the IVD is intended to be performed without any automated steps, identify it as 353
a manually performed assay. If the IVD is automated, identify the specific 354
automated system(s) on which the assay must be run. 355
If only a part of the testing process is automated, it would be considered to be 356
semi-automated. Identify the steps that are automated and the instrument(s) to 357
be used. 358
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4.4.6 The type of specimen required 359
Identify the validated specimen types in the intended use statement. More 360
detailed information may be provided later in the IFU as described in section 4.13 361
Collecting and preparing specimens. 362
4.4.7 The intended testing population 363
Identify the characteristics of individuals that would be tested. This may include 364
individuals with signs and symptoms of a clinical state (symptomatic), individuals 365
who are at elevated risk for a clinical state but who are not showing signs and 366
symptoms (asymptomatic), or individuals being treated for a clinical condition. 367
There may also be identification or restrictions regarding age groups (e.g. for 368
assays to be used in paediatric populations) or other limiting characteristics (e.g. 369
pregnancy). Provide this information in sufficient detail to make clear in whom the 370
assay should be used. 371
4.5 Statement that the product is for in vitro diagnostic use 372
Include a simple statement in the IFU, such as “For In Vitro Diagnostic Use” and/or 373
international symbol (see page 28). 374
4.6 The intended user 375
State what type of user and setting is intended to operate the assay, such as “The 376
assay is intended to be performed by laboratory professional in a clinical 377
laboratory”. Other examples may be a laboratory professional at the point of care; 378
or trained lay provider or an untrained user for self-testing. 379
Also identify the level of training needed to operate the assay, for example: 380
training by the manufacturer, knowledge of basic good clinical laboratory 381
practices, or a statement that no specific training is needed, other than following 382
the IFU. 383
4.7 Test principle summary and explanation 384
Briefly describe the general biological, chemical, microbiological, immunochemical, 385
etc. principles on which the assay is based. Proprietary information need not be 386
disclosed, but provide enough detail to allow the user to understand how the 387
assay is able to carry out its function. This would include, for example, identifying 388
antibody, antigen, or nucleic acid primer and probe targets, and information on 389
the chemical principles used to detect the analyte. If an instrument is required to 390
perform the assay, then include a brief description of the instrument’s principles 391
of operation. 392
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4.8 Warnings and Precautions 393
The risk/benefit information that the user needs to know before using the assay is 394
expected to be addressed in the Warnings and Precautions, as well as how to 395
avoid these hazards. A warning is associated with increased likelihood and/or 396
seriousness of a hazard. The designation as warning is reserved for the most 397
serious problems. The term precaution is used for hazards that are less significant 398
and if not avoided may result in minor or moderate injury to the user, patient or 399
equipment. For the sake of clarity, it is best to list warnings and precautions 400
separately. 401
The use of international symbols and signal words such as WARNINGS and 402
CAUTION are effective in alerting the user to a hazard (22). When listing warnings 403
and precautions, it is recommended to: 404
Use a signal word (WARNINGS, CAUTION) 405
Use bullet points and concise, frank language 406
Clearly state the action to avoid, and the nature of the hazard that informs 407
the user of the severity and likelihood 408
Specific consequences of the action to provide a clear idea of the risk (15) 409
4.8.1 Location of warning and precautions in the IFU 410
General warning and precautions need to be placed at the beginning of the IFU. In 411
addition, procedure related warnings and precautions should be integrated in to 412
the procedure instructions where users are more likely to read the information at 413
the relevant time (e.g. the warnings made regarding the specimens are better 414
placed before the associated instructional step relating to specimen manipulation 415
occurs). 416
4.8.2 List of warnings and precautions 417
The list of Warnings and Precautions should be presented in a logical order and 418
address issues related to the use of the assay and should include, but not be 419
limited to, the following: 420
4.8.2.1 IVD use 421
Intended use or conditions that have not been validated (e.g. use as a donor 422
screening assay). 423
Populations that have not been validated (e.g. pregnancy, paediatrics). 424
Reading and interpreting the results (e.g. minimum/maximum reading time, 425
overlooking or over-reading faint test lines). 426
Addition of specimen or reagent in the incorrect order. 427
428
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4.8.2.2 Safety precautions 429
Information on correct user handling and disposal of specimens and other 430
potentially infectious materials, according to universal precautions. 431
4.8.2.3 Handling precautions 432
Specimen handling (e.g. incorrect storage or incorrect specimen type, the 433
effect of heat inactivation). 434
Incorrect incubation time (e.g. too short or too long). 435
The disposal of the device and/or its accessories (e.g. lancets), any 436
consumables used with it (e.g. reagents) or any potentially infectious 437
substances of human or animal origin. When addressing disposal issues, 438
specific internationally recognized standards should be referenced or 439
compliance with national and local requirements recommended. 440
4.8.2.4 Storage instructions 441
Exposure of the product to environmental or site conditions (e.g. excessive 442
temperature or humidity, requirement of flat surface to store device or 443
conduct test procedure). 444
4.8.2.5 Contamination and inhibition (when applicable). 445
Precautions regarding contamination of reagents, inadequate washing of 446
microwells. 447
4.8.2.6 Any other warning and/or precaution that is relevant for the assay 448
Indication of instability or deterioration (e.g. when control value is outside the 449
expected range). 450
The need for proper maintenance of any instruments and the potential 451
consequences if it is not done. 452
Warning that testing another person using a self-test IVD without their 453
consent is illegal. 454
4.8.3 Residual risks 455
Identify any risks associated with the use of the IVD, including risks associated 456
with calibrating or servicing an IVD (e.g. from contaminated equipment)(23). 457
4.8.4 Biological Hazards 458
If the product contains material from human or animal origin, it should have a 459
statement warning the user to handle with care. Provide a statement that the 460
biological material has (or has not) been treated to inactivate infectious agents, 461
and state the possibility of residual risk. 462
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4.9 Materials provided (test device, reagents, calibrators, controls and 463
accessories) 464
4.9.1 Description of the reagents, calibrators, controls and accessories 465
List all components of the IVD and the quantity supplied for the kit size and 466
configuration (e.g. volume per box, number of boxes, and number of specimen 467
transfer devices). 468
For easy reference, assign colours, numbers or letters to illustrations of the 469
test kit components and their descriptions so that they correspond to each 470
other. 471
Include instructions that the user is advised to familiarise themselves with the 472
components before they begin testing. 473
Provide detail on the concentration and composition of each component (e.g. 474
antibodies, preservatives). 475
Identify any accessory intended to be used in combination with the product in 476
as much detail as necessary to assure that they will be used appropriately. 477
Identify any test kit accessory that is sterile and provide instructions on what 478
actions the user should take in the event of damage to the sterile packaging. 479
Identify any test kit device or accessory that is specified to be for single-use 480
only. 481
Identify when and how often to run controls and calibrators 482
4.10 Materials required but not provided 483
If applicable, identify specific materials that are required for testing but not 484
provided in the kit (e.g. gloves, specimen collection materials, timer, additional 485
reagents, equipment, software, pipettes, sharps disposal container, non-sharps 486
disposal container, biohazard container, centrifuge, etc.). Give as much detail as 487
necessary to assure that the appropriate materials will be used. 488
4.11 Instrumentation (if applicable) 489
Instrumentation is provided with a dedicated instrumentation manual (sometimes 490
also called user guides). Provide a copy with the initial delivery of the instrument 491
(paper copy or electronic). Include instructions in the IFU that the user is advised 492
to familiarise themselves with the instrument manual before they begin testing. 493
4.11.1 Software 494
Identify any software (name and product code) to be used with the product. Some 495
software version updates may require a revision of the IFU. List the software 496
version that the IFU applies to and where to find the latest version of the 497
instrumentation manual for the instrument. 498
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4.11.2 IVDs not requiring dedicated instrumentation 499
For automated and semi-automated IVDs that can be used on different 500
instrument systems (e.g. open systems), describe the combination of reagents, 501
consumables and equipment that have been validated: 502
Instrumentation for assays: Describe the types of instruments or specific 503
instruments needed in as much detail as necessary to assure that the 504
appropriate instruments will be used. 505
4.11.3 Cleaning and maintenance (if applicable) 506
Identify any requirements for routine maintenance and cleaning. Include details 507
of frequency of cleaning (e.g. at prescribed intervals, as a result of an alert from 508
the instrument or as required by the troubleshooting section), materials required 509
and instructions for cleaning. The same instructions should be provided for 510
maintenance requirements and information on who should perform this 511
maintenance (e.g. the user, a representative of the manufacturer, or a third party). 512
Include in the IFU “Warnings and precautions” section a statement regarding the 513
need for proper maintenance and the potential consequences if it is not done. 514
4.12 Troubleshooting 515
Identify issues that would prompt the user to take specific actions such as noting a 516
change in performance or the product malfunctions. Provide detailed instructions 517
on what actions to take. This would apply to a product that is not performing as 518
expected (e.g. no background clearing due to excessive amount of specimen or 519
buffer addition, no control line appears) or to a product that identifies a 520
deficiency (e.g. error messages). Actions to take may involve a user intervention 521
or contacting the manufacturer using the detailed contact information provided in 522
the IFU. If applicable, describe the correct usage of any equipment or software 523
required for the performance of the assay. 524
4.13 Collecting and preparing specimens 525
4.13.1 Types of specimen(s) to be used and specimen preparation 526
Identify the specimen types that may be used with the test (e.g. serum, plasma, 527
venous whole blood, capillary (finger-prick/heel-prick) whole blood, dried blood 528
spot specimens, sputum, oral mucosal transudate, urine etc.). Indicate the 529
specimen volume required, collection method to be used and specimen storage 530
and transport requirements including the validated anticoagulants/preservatives. 531
Illustrations should be included where applicable and useful. 532
Only specimen types and anticoagulants that have been validated in 533
performance studies may be listed. 534
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Steps to minimize the risk to the user when handling specimens should be clearly 535
identified and be appropriate to the expected level of experience of the intended 536
user (for example, for dried blood spot specimens, the filter paper should be 537
stored in a bag with desiccant labelled with a biohazard symbol to alert users that 538
the contents may be infectious). 539
4.13.2 Specimen exclusion criteria 540
Identify any restrictions on specimens that can be used with the assay, which may 541
be based on the results of performance studies (e.g. specimens with visual 542
evidence of hyperlipidaemia or haemolysis, excessive specimen age, excessive 543
number of freeze/thaw cycles) or by risk assessment. A statement is sufficient. 544
4.13.3 Specimen storage and transport conditions 545
Identify under what conditions the specimens can be stored and transported, and 546
the recommended storage and handling instructions. Define the storage 547
temperature and the maximum delay between specimen collection, processing 548
and analysis. Provide as much detail as possible for any specimen collection and 549
transport material that must be provided by the user, to assure that specimen 550
integrity is not compromised. Provide clear instructions on how to label stored 551
specimens with patient identification information to avoid loss of 552
specimen/patient traceability. 553
4.14 IVD storage, operating conditions and stability 554
Identify specific storage conditions (storage temperature, light, humidity and 555
other relevant factors) and shelf life for kit components for the unopened kit, the 556
opened kit and working solutions, such as reconstituted reagents. 557
Include information on the recommended operating temperatures if they differ 558
from the storage conditions. 559
Kits that consist of more than one component should state the earliest expiration 560
date assigned to a component as the kit expiration date (labelled life). 561
WHO require units of measurement to be International System of Units (SI). 562
Storage temperatures should be indicated in degrees Celsius (°C). 563
4.15 Test procedure 564
4.15.1 Instructions on test procedure 565
The instructions or directions for using the IVD need to clearly describe how to 566
use the IVD properly to get the correct result in terms that the intended user can 567
understand. It should address all the areas of risk for incorrect use identified in 568
the manufacturer’s risk assessment, to minimise the user error. The user should 569
be advised to read the information in the IFU before using the test (including self-570
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test users). This information should be displayed prominently on the IFU (boldface 571
type, capital letters) and indicated on the box with an internationally recognized 572
symbol (24, 25). In addition, include a statement (warning) to the effect that not 573
following the test procedure exactly as described in the IFU could cause improper 574
functioning of the assay and inaccurate test results including as applicable, known 575
foreseeable misuse and potential outcomes. 576
Describe all steps, including the use of assay calibrators and controls and 577
calculations. Indicate the time needed to carry out each of the various steps. 578
Number the instructions for each step of the procedure. 579
Follow the basic principles described in Section 0 to maximize readability. Use 580
clear and simple language, with numbered lists to identify each step. Provide 581
drawings of steps and flow diagrams when possible to simplify and clarify the 582
test procedure for the user. Highlight critical steps or parameters using visual 583
cues such as bolded words, boxed messages and/or standardized symbols. 584
4.15.2 Quality control procedures 585
Each type of assay should have a quality control procedure. This may involve 586
running quality control specimens with the IVD to determine if it is functioning 587
properly. In laboratory-based automated systems, quality control material is part 588
of every test run (internal quality control). In single-use rapid diagnostic tests, 589
external quality control material is run only under certain circumstances (e.g. 590
when a new lot is received, when environmental conditions change, or when a 591
user has not previously conducted the IVD test). 592
Identify quality control procedures, including the required materials for quality 593
control and the frequency, conditions under which quality control should be 594
performed, expected test results, and actions to be taken if there is a failure. 595
Explain what function of the procedure the quality control material will assess. If 596
quality control material is not provided with the kit for the user, the user should 597
be alerted that they are available separately and if known where they can be 598
obtained. 599
4.16 Reading test results. 600
Indicate the amount of time that the final reaction/result remains stable. Include 601
a statement directing the user to read the control line prior to interpreting the 602
test results. 603
4.17 Interpretation of test results 604
An interpretation of all possible result outcomes should be provided. For 605
quantitative assays this should also include the range over which measurements 606
can be made and instructions if the result falls outside this range. 607
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Where possible, include pictorial representations of all possible test results for 608
visually read IVDs. If the results are indicated by a colour change, the colour 609
should be shown on the pictorial representations (high quality photograph or a 610
reproduction of results). The colour shown should be realistic and should match 611
the real-life condition. Explain the meaning of each possible test outcome 612
(including faint test lines and invalid results). Provide information on what should 613
be done in the event of an invalid test result. 614
Information on the interpretation and understanding of the result for a self-615
testing IVD needs to be provided in an easily understandable way (e.g. a reactive 616
result indicates possible HIV infection). Provide clear and concise information on 617
where to seek advice and follow up in the event of a reactive or invalid result (e.g. 618
consult with a health facility for additional testing or repeat testing). Explain the 619
meaning of a false-reactive or false-nonreactive test result. 620
If applicable define appropriate formulae or algorithms if required to obtain final 621
result. (E.g. a correction factor is required to obtain the final result depending on 622
the specimen type used). In addition, include an example of a calculation using 623
the formulae or algorithm to get the final result. 624
4.18 Limitations of the procedure 625
Identify, in a list, issues or conditions that would affect assay performance (i.e. 626
false-reactive results, false-nonreactive results, invalid results), based on the 627
results of the analytical performance studies and clinical performance studies. 628
Limitations may be related to the IVD itself, the end-user and/or the conditions 629
during transport and storage. Issues may occur despite correct storage and 630
procedure, and could be related to: 631
the general design of the IVD (e.g. limit of detection, limit of quantification, 632
high dose hook effect, assigning the cut-off). 633
the impact of a serological window period on detection of antibodies (e.g. 634
false negative results in early HIV infection, and possible very late for HIV 635
infection). 636
the measurand (e.g. absence of a Histidine rich protein-2 (HRP2) gene in 637
certain populations, or persistence of HRP2 following resolved infection or 638
ability to detect HIV-1 subtype O. 639
the species not detected (e.g. sensitivity for Plasmodium falciparum > 640
Plasmodium vivax > Plasmodium ovale/malariae. Further information on the 641
limitations of malaria rapid diagnostic tests is available in the WHO “Universal 642
access to malaria diagnostic testing: an operational manual”(26), or HIV-1 643
subtype O). 644
potential interfering substances as identified in analytical specificity studies 645
(e.g. for malaria rapid diagnostic tests, specimens with positive rheumatoid 646
factor may produce false reactive results. For HIV oral fluid rapid diagnostic 647
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tests, patients taking antiretroviral therapy may produce false nonreactive 648
results). 649
4.19 Performance characteristics 650
Studies presented in the IFU should be relevant to the final and qualified version 651
of the IFU. 652
Provide a summary of analytical performance studies and clinical performance 653
studies that support product performance claims, including at least the following 654
specifications where applicable:2 655
1. Analytical sensitivity (lower limit of detection). 656
2. Analytical specificity (e.g. rheumatoid factor, antinuclear antibody, influence 657
of lipaemic/icteric/haemolysed specimens, cross-reacting organisms). 658
3. Diagnostic/clinical sensitivity3. 659
4. Diagnostic/clinical specificity3. 660
5. Repeatability (test-related, within-run variability in setting of intended use). 661
6. Reproducibility (operator-related, inter-day variability, inter-run variability, 662
inter-site variability, inter-lot variability, inter-operator variability, inter-663
instrument variability in setting of intended use). 664
7. Reference intervals. 665
8. Measurement range 666
Identify one section of the performance characteristics as “Analytical Performance 667
Studies” and another as “Clinical Performance Studies”, with subsections of each 668
to describe individual studies. 669
For each study, include a brief description of the purpose and design of the study, 670
the manner and location in which the study was conducted, the number and type 671
of samples studied, the reference methods used, the results, and the conclusions. 672
Results from each different subset represented (e.g. population, specimen type), 673
should be presented separately. In addition to the narrative of the results, include 674
appropriately numbered and titled figures and/or tables that summarize the study 675
results (see Annex 1: Example of tabulated performance characteristics for IFU). 676
For IVDs for self-testing, manufacturers may modify the amount of detail provided 677
on the clinical and analytical performance characteristics when designing the IFU. 678
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.
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However, key performance characteristics (accuracy, sensitivity) should be 679
included in clear and readily understood language. 680
Where IVDs are intended for use by lay providers and professional users, any 681
conflict of the needs of these different users need to be resolved (e.g. additional 682
information for professional users provided in a separate section) (16). 683
4.20 List of references 684
Include a numbered list of references used in the IFU. Select relevant and recent 685
publications in a practical and product-oriented way. 686
4.21 Contact information 687
Provide the name and contact details of the manufacturer, (or an authorized 688
representative of the manufacturer where required), and distributor whom the 689
user can contact to obtain assistance. It is preferable that a mailing address, 690
telephone number, email address, and a website address are provided on the IFU. 691
For IVDs for self-testing, a toll-free (free-phone) telephone number is a preferable 692
means to provide direct health related support to the user. 693
4.22 Document control 694
Include a document version number and date of issue for the IFU. 695
4.23 Symbol key 696
The use of internationally recognized symbols simplifies communication. Using 697
symbols can save space, spare costs with translation and improve clarity. They 698
may be used instead of statements to convey information. There are a number of 699
internationally recognized symbols for certain IVD characteristics (e.g. storage 700
temperature limits, identification of in vitro diagnostic use, manufacturer 701
information)(24). These symbols are especially useful when printed materials are 702
generated in multiple languages or users are not familiar with the language in 703
which the IFU is written. Symbols quickly communicate a concept to the user in a 704
way that, if used properly, can transcend language differences. The symbols 705
should be explained in a symbol key in the IFU and should appear on the last page 706
of the IFU. See Annex 2: for an example of symbol key and warning pictograms for 707
IVD labelling. 708
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Designing Instructions for use for IVDs TGS–5
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5 References 709
1 ISO 18113-1:2009. In vitro diagnostic medical IVDs - Information supplied by the manufacturer
(labelling) - Part 1: Terms, definitions and general requirements. Geneva. International Organization
for Standardization; 2009.
2 IMDRF/UDI WG/N7 FINAL:2013. UDI Guidance Unique Device Identification (UDI) of Medical Devices.
International Medical Device Regulators Forum; 2013.
3 GHTF/SG1/N70:2011: Label and Instructions for Use for Medical Devices. Global Harmonization Task
Force (GHTF) Steering Committee; 2011.
4 GHTF/SC/N4:2012 (Edition 2). Glossary and Definitions of Terms Used in GHTF Documents. Global
Harmonization Task Force (GHTF) Steering Committee; 2012.
5 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):505.
6 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; 2013.
7 GHTF/SG1/N055:2009: Definitions of the Terms Manufacturer, Authorised Representative, Distributor
and Importer. Global Harmonization Task Force (GHTF) Steering Committee; 2009.
8 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 26–27 February 2015 Geneva, Switzerland. World Health Organization. ISBN 978 92 4
150997 8
10 ISO 18113-2:2009. 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; 2009.
11 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):505.
12 U.S. Food and Drug Administration. Write It Right. Rockville, MD: HHS Publication FDA 93-4258; 1993.
Backinger CL and Kingsley PA. (Internet). Accessed 16 May 2016. Available from:
http://www.fda.gov/downloads/MedicalDevices/.../ucm070771.pdf
13 Readability Calculator. http://www.online-utility.org/english/readability_test_and_improve.jsp.
Mladen Adamovic, 2009. Accessed 22 July 2015.
14 Flesch R. How to Write Plain English. University of Canterbury. Christchurch, New Zealand; 1981 (web
page). Accessed 10 August 2015. Available from :
http://www.mang.canterbury.ac.nz/writing_guide/writing/flesch.shtml.
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Designing Instructions for use for IVDs TGS–5
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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 2016. Available from:
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/uc
m070801.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. 2012.
17 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 2016. Available from: http://ec.europa.eu/health/files/eudralex/vol-
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; 2009. Accessed 22 July 2015
19 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; 2014
20 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; 2007
21 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):505.
22 Guidance document: Labelling of In Vitro Diagnostic Devices. Ottawa. Health Canada; 2016 (Internet).
(Accessed 16 May 2016) Available from http://www.hc-sc.gc.ca/dhp-mps/md-im/applic-
demande/guide-ld/labl_etiq_ivdd_dic-eng.php
23 ISO 14971:2007 Medical devices - Application of risk management to medical devices. Geneva.
International Organization for Standardization; 2007
24 ISO 15223-1:2016. 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; 2016.
25 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): 1–1355, 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; 2011.
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Annex 1: Example tabulated performance characteristics for IFU 710
The tables below are examples only and not an exhaustive list. 711
A1 – 1 Example table: Analytical performance study - Precision (Repeatability 712
and Reproducibility) 713
Table A2-1 Summary of Assay Precision (Repeatability) 714
Quality control panel member
Number of replicate tests
S/Co Within-condition % Coefficient of variation (CV) Mean Standard deviation
(SD)
Negative Control (Value) (Value) (Value) (Value)
QC-1 (low titre positive) (Value) (Value) (Value) (Value)
QC-2 (mid-range positive)
(Value) (Value) (Value) (Value)
QC-3 (high-titre positive) (Value) (Value) (Value) (Value)
715
Table A2-2 Summary of Assay Precision (Reproducibility) for Quality control panel member QC-1 (low 716 titre positive) 717
Results for Quality control panel member QC-1 (low titre positive)
Number of replicate tests
S/Co Between-condition %CV
Mean SD
Between-day (Value) (Value) (Value) (Value)
Between-operator (Value) (Value) (Value) (Value)
Between-lot (Value) (Value) (Value) (Value)
Between-instrument (Value) (Value) (Value) (Value)
718
A1 – 2 Example table: Analytical performance study - Interfering (endogenous) 719
substances 720
Table A2-3 Summary of test results for determination of analytical specificity: potentially interfering 721 endogenous substances 722
Interfering Substance Specimen identification (ID)
Test Results
Unspiked specimen
Specimen spiked with substance-1
Specimen spiked with substance-2
Substance-1 (xx g/mL) ID-1 (Value) (Value) (Value)
ID-2 (Value) (Value) (Value)
ID-3 (Value) (Value) (Value)
ID-4 (Value) (Value) (Value)
Substance-2 (x/ millimole) ID-1, etc… (Value) (Value) (Value)
723
The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in
an easy to read format.
The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in
an easy to read format.
The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in
an easy to read format.
Instructions for use for in vitro diagnostics TGS–5
Page | 27
A1 – 3 Example table: Analytical performance study - Cross-reacting infections, 724
diseases and/or medical conditions 725
Table A2-4 Summary of test results for determination of analytical specificity: potentially cross-726 reacting unrelated infections, diseases and/or medical conditions 727
Infection/disease/medical condition
Number of specimens tested
Test Results
IVD being evaluated Reference Test
Organism 1
(Value) (Value) (Value)
Medical condition 1,
(Value) (Value) (Value)
Etc.…
(Value) (Value) (Value)
728
A1 – 4 Example table: Clinical performance study - Diagnostic Sensitivity 729
Table A2-5 Summary of results of a clinical study to determine diagnostic sensitivity – Finger-prick 730 whole blood. 731
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 falsely-nonreactive
% Sensitivity 95% Confidence interval
1 (Value) (Value) (Value) (Value) (Value) (Value) (Value)
732
A1 – 5 Example table: Clinical performance study - Diagnostic Specificity 733
Table A2-6 Summary of results of a clinical study to determine diagnostic specificity – serum 734
Study site
Number of specimens tested
Number of specimens reactive by reference method
Number of valid tests
Number of specimens non-reactive in the IVD
Number of specimens falsely-reactive
% Specificity 95% Confidence interval
1 (Value) (Value) (Value) (Value) (Value) (Value) (Value)
735
The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in
an easy to read format.
Instructions for use for in vitro diagnostics TGS–5
Page | 28
Annex 2: International symbols and warning pictograms 736
Table A3.1 Symbols to be used in medical device labelling (24). 737
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.)
Consult Instructions for Use
Batch code
Use-by date YYYY-MM-(DD)
Date of manufacture 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
Instructions for use for in vitro diagnostics TGS–5
Page | 29
Table A3.2: Globally harmonized system of classification and labelling of chemicals 739
(hazard pictograms) (25). 740
New CLP symbols Explanation New CLP symbols Explanation
(very) Toxic
Dangerous for the environment
Oxidizing
Highly or extremely flammable
Corrosive
Explosive
Replaces the harmful symbol:
Refers to less serious health hazards such as skin irritancy / sensitisation
Reflects serious longer term health hazards such as carcinogenicity and respiratory sensitisation
741
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