Designing Instructions for use for in vitro TGS 5 · Technical Guidance Series (TGS) for WHO Prequalification – Diagnostic Assessment Designing Instructions for use for in vitro

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: [email protected]). 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: [email protected]). 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

mailto:[email protected]


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


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


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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


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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.

http://www.who.int/diagnostics_laboratory/evaluations/100506_pqdx_018_dossier_instructns_v1.pdf



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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


Page | 15

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


Page | 16

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


Page | 17

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


Page | 18

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


Page | 19

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


Page | 20

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


Page | 21

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


Page | 22

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.



Page | 23

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


Page | 24

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.

http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-131209-udi-guidance-140901.pdf

http://www.imdrf.org/docs/ghtf/final/sg1/technical-docs/ghtf-sg1-n70-2011-label-instruction-use-medical-devices-110916.pdf

http://www.imdrf.org/docs/ghtf/final/steering-committee/procedural-docs/ghtf-sc-n4-2012-definitions-of-terms-121109.pdf

http://www.online-utility.org/english/readability_test_and_improve.jsp

http://www.mang.canterbury.ac.nz/writing_guide/writing/flesch.shtml


Page | 25

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.

http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf

http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf

http://www.wpro.who.int/malaria/sites/rdt/using_rdts/training/

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm331681.pdf

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm331681.pdf

http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_14_3_rev1_ifu_final_en.pdf

http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_14_3_rev1_ifu_final_en.pdf

http://www.hc-sc.gc.ca/dhp-mps/md-im/applic-demande/guide-ld/labl_etiq_ivdd_dic-eng.php

http://www.hc-sc.gc.ca/dhp-mps/md-im/applic-demande/guide-ld/labl_etiq_ivdd_dic-eng.php

https://www.iso.org/obp/ui/#iso:std:iso:14971:ed-2:v2:en

http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32008R1272



http://www.who.int/malaria/publications/atoz/9789241502092/en/

Instructions for use for in vitro diagnostics TGS–5

Page | 26

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)



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.






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,


Etc.…


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 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 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




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


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