Guidance for post-market surveillance and market

Draft 1, 31 July 2020 Page 1 of 79

Guidance for post-market surveillance and market surveillance of medical devices, including

in-vitro-diagnostics

Post-market surveillance and market surveillance of medical devices, including in vitro diagnostics

Page 2 of 79


Table of contents

Acknowledgements...................................................................................................................... 4

Disclaimers .................................................................................................................................. 4

INTRODUCTION ........................................................................................................................... 5 1 Introduction to post-market surveillance and market surveillance of medical devices,

including in vitro diagnostics .................................................................................................... 5 2 Scope and intended audience of this guidance ....................................................................... 6 3 Definitions and acronyms......................................................................................................... 8 4 Basic principles of post market surveillance .......................................................................... 13 5 Stakeholders’ roles in post-market surveillance and market surveillance ............................ 16

Part I: PROVIDING FEEDBACK BY USERS AND PATIENTS/CLIENTS ................................................. 18 Overview of responsibilities ................................................................................................... 18 1 Detect/observe....................................................................................................................... 19 2 Document ............................................................................................................................... 21 3 Report ..................................................................................................................................... 22 4 Act .......................................................................................................................................... 22

PART II: POST-MARKET SURVEILLANCE BY MANUFACTURERS (and their economic operators: authorised representatives, agents, and distributors) ................................................................. 24 Basics for post-market surveillance ....................................................................................... 24 1 Receiving feedback ................................................................................................................. 27 2 Classify feedback and escalate where needed....................................................................... 30 3 Undertake root cause analysis ............................................................................................... 35 4 Decide if a correction is required ........................................................................................... 35 5 Take corrective action ............................................................................................................ 36

Part III: MARKET SURVEILLANCE BY NRAs ................................................................................... 42 Overview of responsibilities ................................................................................................... 42 1 Collect reports ........................................................................................................................ 45 2 Oversee testing ...................................................................................................................... 46 3 Collect other post-market information .................................................................................. 49 4 Decide if additional regulatory action is required .................................................................. 49 5 Share information .................................................................................................................. 50

PART IV: SPECIFIC REQUIREMENTS FOR PRODUCTS RECOMMENDED BY WHO ............................. 52 1 Role of WHO ........................................................................................................................... 52

Bibliography .............................................................................................................................. 55 Annex 1 – Device Feedback Reporting Form ........................................................................................ 57


Annex 2– Manufacturer Vigilance Reporting Form .............................................................................. 59 Annex 3 – Field Safety Corrective Action Report .................................................................................. 63 Annex 4 – Example Field Safety Notice ................................................................................................. 65 Annex 5 – Post-Market Information Exchange Reporting Form for NRAs ............................................ 66 Annex 6 – Recommendations for specific end-user groups ................................................................. 69 Annex 7 – Lot testing for IVDs ............................................................................................................... 70


Page 4 of 79

Acknowledgements

To be added.

Disclaimers

To be added.

Introduction


INTRODUCTION 1

1 Introduction to post-market surveillance and market surveillance of medical 2

devices, including in vitro diagnostics 3

Post-market surveillance is the process for manufacturers of medical devices to 4

collect and analyse experience gained from medical devices that have been placed 5

on the market. Post-market surveillance is a crucial tool to ensure that medical 6

devices that have been placed on the market remain safe and effective and to 7

consider necessary actions if the risk of continuing to use the device outweighs the 8

benefit. The outcome of the analysis of post-market surveillance data can also 9

highlight opportunities to improve the medical device. The WHO Global Model 10

Regulatory Framework for Medical Devices, including in vitro diagnostic medical 11

devices, like many other international regulatory frameworks, requires the 12

implementation of post-market surveillance systems [ref]. This document indicates 13

that receiving and evaluating feedback is the minimum for post-market surveillance, 14

and that this can be expanded to include other activities. This framework also 15

includes the activities of the national regulatory authorities (NRAs) to act upon 16

complaints and reports of adverse events received, so-called vigilance. The 17

definition of post-market surveillance in the WHO-framework focusses on the 18

activities of the NRAs. In the context of the current document on post-market 19

surveillance, such activities by NRAs are called market surveillance. The term post-20

market surveillance is reserved for the activities by the manufacturers. 21

Thus, the terms post-market surveillance, vigilance and market surveillance are 22

closely linked. Post-market surveillance, as explained above, is an activity of the 23

manufacturer to collect data from the actual use of medical devices, to analyse such 24

data, and to identify the need to take action. Part of these data can be adverse 25

events. Vigilance is the process whereby the manufacturer reports certain adverse 26

events to the NRA and keeps the NRA updated on the actions taken in relation to 27

the adverse event. The NRA will oversee the process of investigation of adverse 28

events and further actions taken by manufacturers. This is closely connected to their 29

market surveillance responsibilities. Market surveillance comprises the total package 30

of activities undertaken by NRAs to obtain an oversight of medical devices on the 31

market in their territory and to ensure that the safety, quality and performance of 32

the devices on the market is adequate. 33

Over the last years, several developments have impacted on post-market 34

surveillance. Around the same time that the WHO Global Model Regulatory 35

Framework was published, also new European regulations on medical devices and 36

in-vitro diagnostic medical devices (IVDs) were published in 2017 [ref]. These 37

regulations establish strong and relatively detailed requirements on post-market 38

surveillance and on how post-market surveillance data are to be used (e.g. updates 39

to the risk management file and to the clinical evaluation). Also, the United States’ 40

Food and Drug Administration (FDA) have been placing an increased emphasis on 41

Post-market surveillance and market surveillance of medical devices, including IVDs

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the possibilities for using data from experiences gained with the use of medical 42

devices.1 43

Recent horizontal ISO standards for medical devices place increased emphasis on 44

the importance of post-market surveillance. The ISO standard ISO 13485 on Quality 45

Management Systems for medical devices, used by most manufacturers, requires a 46

post-market surveillance system to be in place. Furthermore, in the recent revision 47

of the ISO standard on Risk Management, ISO 14971, requirements on post-market 48

surveillance were also strengthened. The specific ISO guidance document on post-49

market surveillance for manufacturers of medical devices (ISO TR 20416) was 50

recently published. Together, these documents provide a framework for conducting 51

post-market surveillance and using post-market surveillance data to ensure devices’ 52

continued safety and performance. 53

Post-market surveillance, as described in this guidance, is essential for all devices in 54

order to enable continuous improvement of the devices. 55

In Part IV of this guidance, specific requirements for manufacturers of WHO-56

recommended medical devices and IVDs are given, including reporting to WHO. 57

Although the user/patient/client does not have an official role in post-market 58

surveillance, most of the information on the actual use of medical devices comes 59

from their feedback. On the other hand, users/patients/clients will benefit 60

themselves if the medical devices on the market remain safe and effective and 61

therefore should be encouraged to provide feedback to the manufacturer. 62

Medical devices and IVDs will be indicated by medical devices or otherwise specified, 63

if appropriate. 64

2 Scope and intended audience of this guidance 65

This document pertains to the objectives and processes for post-market surveillance 66

for medical devices conducted by manufacturers and their economic operators, as 67

well as market surveillance conducted by regulators and the role of other 68

stakeholders in these processes. It describes the measures taken to ensure the 69

ongoing compliance of medical devices with the requirements for safety, quality and 70

performance after they are placed on the market. 71

All medical devices, including in IVDs, are covered by this guidance. 72

The intended audience of this guidance is: 73

• Manufacturers 74

• Other economic operators 75

• Health care providers and their clients 76

• Programme implementers including procurement agencies and central 77

medical stores 78

• NRAs. 79 1 https://www.fda.gov/media/99447/download

Scope

Audience

Introduction


This document provides an overview of pro-active and reactive procedures for post-80

market surveillance, with emphasis on reactive post-market surveillance through 81

providing and evaluating feedback, and any required actions to correct and prevent 82

recurrence. It also provides an overview of the market surveillance activities that are 83

the responsibility of NRAs. 84

The post-market surveillance procedures described in this document are intended to 85

supplement, and not substitute, the internal procedures for post-market activities 86

that are expected to be an integral part of the manufacturer's quality management 87

system. National regulations may require manufacturers and other stakeholders to 88

perform post-market activities and submit relevant post-market information to 89

NRAs. The market surveillance activities described in this document are also 90

intended to supplement existing activities as performed by the NRAs. Nascent NRAs 91

are encouraged to take a risk-based approach to expanding market surveillance 92

activities for medical devices. 93

The principles laid down in this document may be considered by NRAs when 94

developing or amending existing national post-market surveillance and market 95

surveillance obligations. It can also be used by procurement agencies and other 96

entities that procure medical devices and wish to be assured of their continued 97

quality, safety and performance. 98

99

This document intends to give an overview of the technical aspects of post-market 100

surveillance and market surveillance for medical devices. NRAs are invited to adopt 101

these guidelines in relation to the resources available, i.e. a phased implementation 102

may be most appropriate. 103

Comprehensive

guidance

Build on existing

systems

Guidance for

adaptation

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3 Definitions and acronyms 104

3.1 Definitions 105

Abnormal use: conscious, deliberate act or deliberate omission of an act that is 106

counter to or violates normal use and is also beyond any further reasonable means 107

of user interface-related risk control by the manufacturer 108

EXAMPLES Reckless use or sabotage or deliberate disregard of information for Safety 109

are such acts. 110

Note 1; deleted. 111

Note 2 to entry: An intended but erroneous action that is not ABNORMAL USE is 112

considered a type of USE ERROR. 113

Note 3 to entry: ABNORMAL USE does not relieve the MANUFACTURER from 114

considering non-USER INTERFACE-related means of RISK CONTROL. 115

Source: IEC 62366-1:2015 116

Accessory to a medical device: means an article intended specifically by its 117

manufacturer to be used together with a particular medical device to enable or 118

assist that device to be used in accordance with its intended use. 119

Accessory to an IVD: means an article intended specifically by its manufacturer to be 120

used together with a particular IVD medical device to enable or assist that device to 121

be used in accordance with its intended use. 122

Note: Some jurisdictions include ‘accessories to a medical device’ and ‘accessories to 123

an IVD medical device’ within their definitions of ‘medical device’ or ‘IVD medical 124

device’, respectively. Other jurisdictions do not adopt this approach but still subject 125

an accessory to the regulatory controls (e.g. classification, conformity assessment, 126

quality management system requirements etc.) that apply to medical devices or IVD 127

medical devices. 128

Source: GHTF/SG1/N071:2012 129

Adverse event: any unfavourable and unintended sign, symptom, disease, or other 130

medical occurrence, including abnormal laboratory findings, with a temporal 131

association with the use of a medical device, procedure, or other therapy, or in 132

conjunction with a research study, regardless of causal relationship 133

EXAMPLE: Death, back pain, headache, pulmonary embolism, heart attack. 134

Source: ISO 14199:2015, “including abnormal laboratory findings” added and 135

medical product changed to medical device. 136

Client/Patient: person undergoing testing with an IVD, person who a medical device 137

is used on 138

Conformity: fulfilment of a requirement 139

Source: ISO 35001:2019 140

Conformity assessment: determining whether the relevant requirements in 141

technical regulations or standards are fulfilled 142

Source: Essential principles IMDRF (2018), taken from definition of conformity 143

assessment body 144

Competent authority: see national regulatory authority, used in European Union. 145

Component: one of the different parts of which a device is composed 146


Note: An accessory is also considered a component 147

Source: ISO 10993-9:2019, note added. 148

Complaint: written, electronic or oral communication that alleges deficiencies 149

related to the identity, quality, durability, reliability, usability, safety or performance 150

of a medical device that has been released from the organization’s control or related 151

to a service that affects the performance of such medical devices 152

Source: ISO 13485:2016 153

Correction: action to eliminate a detected nonconformity 154

Note 1: A correction can be made in advance of, in conjunction with or after a 155

corrective action 156

Note 2: A correction can be, for example, rework or regrade 157

Source: ISO 9000:2015 158

Corrective action: action to eliminate the cause of a detected non-conformity or 159

other undesirable situation 160

Note 1 to entry: There can be more than one cause of non-conformity. 161

Note 2 to entry: Corrective action is taken to prevent recurrence whereas preventive 162

action is taken to prevent occurrence. 163

Note 3 to entry: There is a distinction between correction and corrective action. 164

Source: ISO 9000:2015 165

Economic operator: manufacturer, an authorised representative, an importer, a 166

distributor or the person combining different medical devices into one pack or 167

sterilizing a system or procedure pack with the intent to place them on the market. 168

Source: MDR: 2017, “person combining, or sterilizing” replaces reference to article 169

where these persons are mentioned. 170

Field safety corrective action: an action taken by a manufacturer to reduce a risk of 171

death or serious deterioration in the state of health associated with the use of a 172

medical device. Such actions should be notified via a field safety notice. 173

In assessing the need of the FSCA the manufacturer may use the methodology 174

described in the international standard ISO 14971. 175

FSCAs may include: 176

• Return of a medical device to the manufacturer or its representative; 177

• Device modification; 178

• Device exchange; 179

• Device destruction; 180

• Advice given by manufacturer regarding the use of the device (e.g. where 181

the device is no longer on the market or has been withdrawn but could still 182

possibly be in use e.g. implants). 183

Device modifications may include: 184

• Retrofit in accordance with the manufacturer's modification or design 185

change; 186

• Permanent or temporary changes to the labelling or instructions for use; 187

• Software upgrades including those carried out by remote access; 188

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• Modification to the clinical management of patients to address a risk of 189

serious injury or death related specifically to the characteristics of the device. 190

For example: for implantable devices it is often clinically unjustifiable to 191

explant the device; 192

• Corrective action taking the form of special patient follow-up, irrespective of 193

whether any affected un-implanted devices remain available for return; 194

• For any diagnostic device (e.g. IVD, imaging equipment or devices) the 195

retesting of affected patients, samples or the review of previous results; 196

• Advice on a change in the way the device is used (e.g. IVD manufacturer 197

advises revised quality control procedure -use of third -party controls or 198

more frequent calibration). 199

Source: IMDRF N14: 2017 200

Field safety notice: a communication sent out by a manufacturer or its 201

representative to the device users in relation to a Field Safety Corrective Action. 202

Note: An FSN can also be “non-safety” customer product information. 203

Source: GHTF N57 R8: 2006, note added. 204

In-vitro diagnostics: a medical device, whether used alone or in combination, 205

intended by the manufacturer for the in-vitro examination of specimens derived 206

from the human body solely or principally to provide information for diagnostic, 207

monitoring or compatibility purposes. 208

Note 1: IVDs include reagents, calibrators, control materials, specimen receptacles, 209

software, and related instruments or apparatus or other articles and are used, for 210

example, for the following test purposes: diagnosis, aid to diagnosis, screening, 211

monitoring, predisposition, prognosis, prediction, determination of physiological 212

status 213

Note 2: In some jurisdictions, certain IVDs may be covered by other regulations. 214

(GHTF/SG1/N071:2012) 215

Source: IMDRF GRRP WG/N47 FINAL: 2018 216

Harm: injury or damage to the health of people, or damage to property or the 217

environment 218

Source: ISO 14971:2019 219

Hazard: potential source of harm 220

Source: ISO 14971:2019 221

Label: written, printed, or graphic information either appearing on the medical 222

device itself, or on the packaging of each unit, or on the packaging of multiple 223

devices 224

SOURCE: GHTF/SG1/N70:2011 225

Lot: defined amount of material that is uniform in its properties and has been 226

produced in one process or series of processes 227

Source: ISO 18113: YYYY 228

Manufacturer: any natural or legal person with responsibility for design and/or 229

manufacture of a medical device with the intention of making the medical device 230

available for use, under their name; whether or not such a medical device is 231


designed and/or manufactured by that person themselves or on their behalf by 232

another person(s) 233

Source: GHTF/SG1/N055:2009 234

Market surveillance: the activities carried out and measures taken by competent 235

authorities [regulatory authorities] to check and ensure that devices comply with the 236

requirements set out in the relevant Union harmonisation legislation and do not 237

endanger health, safety or any other aspect of public interest protection 238

Source: MDR: 2017 239

Medical device: any instrument, apparatus, implement, machine, appliance, implant, 240

reagent for in vitro use, software, material or other similar or related article, 241

intended by the manufacturer to be used, alone or in combination, for human 242

beings, for one or more of the specific medical purpose(s) of: 243

• diagnosis, prevention, monitoring, treatment or alleviation of disease; 244

• diagnosis, monitoring, treatment, alleviation of, or compensation for, an 245

injury; 246

• investigation, replacement, modification, or support of the anatomy, or of a 247

physiological process; 248

• supporting or sustaining life; 249

• control of conception; 250

• cleaning, disinfection or sterilization of medical devices; 251

• providing information by means of in vitro examination of specimens 252

derived from the human body; 253

and does not achieve its primary intended action by pharmacological, immunological, 254

or metabolic means, in or on the human body, but which may be assisted in its 255

intended function by such means. 256

NOTE 1: Products which may be considered to be medical devices in some 257

jurisdictions but not in others include: 258

• disinfection substances; 259

• aids for persons with disabilities; 260

• devices incorporating animal and/or human tissues; 261

• devices for in-vitro fertilization or assisted reproduction technologies. 262

(Modified from GHTF/SG 1/N071:2012) 263

NOTE 1: For clarification purposes, in certain regulatory jurisdictions, devices for 264

cosmetic/aesthetic purposes are also considered medical devices 265

NOTE 2: For clarification purposes, in certain regulatory jurisdictions, the commerce 266

of devices incorporating human tissues is not allowed 267

Source: IMDRF GRRP WG/N47 FINAL: 2018 268

(National) Regulatory Authority: a government body or other entity that exercises a 269

legal right to control the use or sale of medical devices within its jurisdiction, and 270

that may take enforcement action to ensure that medical products marketed within 271

its jurisdiction comply with legal requirements. 272

Source: IMDRF/GRRP WG/N040:2017 273

Nonconformity: non-fulfilment of a requirement 274

Page 12 of 79

Source: ISO 9000:2015. 275

Post-market surveillance: systematic process to collect and analyse experience 276 gained from medical devices that have been placed on the market 277 Source: ISO 13485:2016 278

Note: for the purpose of this document, post-market surveillance includes the actions 279

taken by the manufacturer based on the analysed data. 280

Preventive action: action to eliminate the cause of a potential nonconformity or 281

another undesirable situation 282

Note 1 There can be more than one cause for nonconformity 283

Note 2 Preventive action is taken to prevent occurrence whereas corrective action is 284

taken to prevent recurrence 285

Source: GHTF N18: YYYY 286

(Medical Device) Registry: Organized system with a primary aim to increase the 287

knowledge on medical devices contributing to improve the quality of patient care 288

that continuously collects relevant data, evaluates meaningful outcomes and 289

comprehensively covers the population defined by exposure to particular device(s) 290

at a reasonably generalizable scale (e.g. international, national, regional, and health 291

system. 292

Source: IMDRF/Registry WG/N42FINAL:2017 293

Requirement: need or expectation that is stated, generally implied or obligatory 294

Source: ISO 9000: YYYY 295

Risk: combination of the probability of occurrence of harm and the severity of that 296

harm 297

Source: ISO 14971: 2019 298

Sample: one or more representative elements selected from a set to obtain 299

information about that set 300

Source: ISO 22716:2007 301

Sample size: number of sampling units in the sample 302

Source: ISO 772:2011 303

Serious Public Health Threat: Any event type which results in imminent risk of death, 304

serious injury or serious illness that requires prompt medical action. 305

A serious injury is either: 306

• A life-threatening illness or injury, 307

• A permanent impairment of a body function or permanent damage to a 308

body structure, 309

• A condition necessitating medical or surgical intervention to prevent 310

permanent impairment of a body function or permanent damage to a body 311

structure. 312

Source: IMDRF/N14: YYYY 313

Signal detection: The process of determining patterns of association or unexpected 314

occurrences that have the potential to impact patient management decisions and/or 315

alter the known benefit-risk profile of a device. 316

Source: IMDRF/Registry WG/N42FINAL:2017 317


318

Unanticipated: a condition leading to an event that was not considered in a risk 319

analysis performed during the design and development phase of the device. 320

Source: IMDRF N14: YYYY 321

Use error: User action or lack of user action while using the medical device that 322 leads to a different result than that intended by the manufacturer or expected by 323 the user 324 Note 1 to entry: Use error includes the inability of the user to complete a task. 325 Note 2 to entry: Use errors can result from a mismatch between the characteristics of 326 the user, user interface, 327 task, or use environment. 328 Note 3 to entry: Users might be aware or unaware that a use error has occurred. 329 Note 4 to entry: An unexpected physiological response of the patient is not by itself 330 considered use error. 331 Note 5 to entry: A malfunction of a medical device that causes an unexpected result 332 is not considered a use error. [SOURCE: IEC 62366-1:2015, 3.21, modified — Note 6 333 to entry deleted 334 User: the person, either professional or lay, who uses a medical device. The patient 335 may be the user. 336 Source: GHTF/SG1/N70:2011 337

338

3.1 Acronyms 339

CAPA corrective and preventive action 340

EQA external quality assessment (specifically referring to proficiency testing) 341

FSCA field safety corrective action 342

FSN field safety notice 343

GHTF Global Harmonization Task Force 344

IMDRF International Medical Device Regulators Forum 345

ISO International Organization for Standardization 346

IVD In-vitro diagnostics 347

IVDR In Vitro Diagnostics Medical Devices Regulation of European Union (see 348

bibliography) 349

MDR Medical Devices Regulation of European Union (see bibliography) 350

NRA National Regulatory Authority 351

QC quality control 352

WHO World Health Organization 353

4 Basic principles of post market surveillance 354

4.1 Rationale for post-market surveillance by device manufacturers 355

Pre-market assessment is recommended for any medical device prior to entry into 356

the marketplace in each country of intended use, based risk management principles. 357

This serves to reduce risk to public safety. While pre-market assessment of medical 358

devices can provide information on a product's safety, quality and performance, 359

there might be questions that cannot be fully answered in the pre-market 360

Pre-market

assessment as a

basis

Page 14 of 79

assessment stage or an issue may arise after the medical device is placed on the 361

market. 362

Although medical devices are designed, developed, manufactured and distributed 363

on the global market, residual risks regarding the medical device’s safety and 364

performance remain throughout the product life cycle. This is due to a combination 365

of factors, such as product variability, factors affecting the medical device’s use 366

environment, different user interaction, as well as unforeseen medical device failure 367

or misuse. Design and development activities of medical devices ensure that the 368

residual risks are acceptable before product release (i.e. pre-market). However, it is 369

important to collect and analyse information on the medical device during 370

production and post-production to meet requirements for monitoring of product 371

and processes and ensure the residual risk remains acceptable. Appropriate 372

processes for collecting and analysing the information on the production and post-373

production feedback allow for early detection of any undesirable effects. These 374

processes can also reveal opportunities for improvement. 375

Post-market surveillance is the process to enable manufacturers to perform such 376

monitoring, by collecting data from actual use of medical devices and analysing 377

these data. Based on the outcome of this analysis, the need for further actions can 378

be decided, e.g. feedback into the risk management process, or notifying national 379

regulators authorities (NRAs), making a correction and/or field safety corrective 380

action which would be notified to users through a field safety notice. 381

4.2 Post-market surveillance mechanisms 382

Post-market surveillance depends upon the information that can be/is to be 383

collected, see also Part II. The manufacturer shall first establish the objective of the 384

post-market surveillance activities for the specific device or group of devices. Then, 385

the manufacturer shall decide which sources are needed to fulfil these objectives. 386

Based on that, the data shall be collected and analysed. 387

Depending on the sources selected and the methods to be used to collect the data, 388

post-market surveillance is divided in reactive and proactive post-market 389

surveillance. 390

The most basic form of post-market surveillance, which shall always be performed, 391

is reactive post-market surveillance. Reactive post-market surveillance is done 392

through notification and evaluation of feedback. Feedback is evaluated to establish 393

if it constitutes a complaint, which in turn may require report as an adverse event – 394

so-called vigilance. Proactive post-market surveillance is detecting issues such as 395

through trainings, user support, scientific literature, conferences/tradeshows, 396

publicly accessible market surveillance information on NRA websites including field 397

safety notices, etc. 398

4.3 Post-market surveillance linked to risk management 399

Risk management of medical devices is a process that applies throughout all phases 400

of the lifecycle of a medical device. A risk management process should be 401

Manufacturers

conduct post-

market

surveillance

Post-market

surveillance

mechanisms


implemented by all manufacturers of medical devices. The standard ISO 14971:2019 402

on risk management for medical devices is recognised in most parts of the world as 403

the state-of-the-art process [REF]. The related technical report ISO/TR 24971 404

provides guidance on the application of the standard. Risk management should be a 405

continuous and iterative process, during which the hazards associated with the 406

medical device are identified. The associated risks are estimated and evaluated, 407

these risks are controlled, and the effectiveness of the controls is monitored. Post-408

market surveillance has an important role in this process. It provides the essential 409

link through which production and post-production information is gathered and 410

analysed, so it can be fed back into the risk management process when needed. A 411

schematic representation of the risk management process is provided in Figure 1. 412

413 Figure 1 – Risk management process for medical device manufacturers 414 (permission to seek clearance from ISO to reproduce this figure is in-progress) 415

416

417

As explained in ISO 14971, risk management is a complex subject, because each 418

stakeholder can place a different value on the acceptability of risks in relation to the 419

Page 16 of 79

anticipated benefits. The concepts of risk management are particularly important in 420

relation to medical devices because of the variety of stakeholders. 421

It is generally accepted that the concept of risk has two key components: 422

— the probability of occurrence of harm; and 423

— the consequences of that harm, that is, how severe it might be. 424

All stakeholders, including manufacturers, regulatory authorities, healthcare 425

professionals, healthcare institutions and patients need to understand that the use 426

of a medical device involves an inherent degree of risk. The acceptability of a risk to 427

a stakeholder is influenced by the stakeholder’s perception of the risk and the 428

benefit. Each stakeholder’s perception can vary depending upon their cultural and 429

socio-economic background, and many other factors. It is important to realize this 430

when deciding on the need for further actions, based on data gathered during the 431

post-market surveillance process. 432

5 Stakeholders’ roles in post-market surveillance and market surveillance 433

Post-market surveillance should be implemented by every manufacturer, at least in 434

its most basic form as a system to collect, analyse and react to feedback. Other 435

economic operators such as agents, distributors and authorised representatives play 436

an important supportive role to ensure feedback from users reaches the 437

manufacturer, including overcoming language barriers. National or regional 438

legislation can require the manufacturer to perform more elaborate post-market 439

surveillance, as only reacting to feedback will provide limited information on the 440

experiences with the medical devices in actual use. Therefore, it then leaves 441

information unused that could have been used to improve safety, quality and 442

performance. 443

Users and clients/patients (also implementers/procurers), manufacturers (and their 444

economic operators) and NRAs each play a role in the system of post-market 445

surveillance and market surveillance. 446

NRAs should raise awareness among users and clients/patients about the 447

importance of providing feedback to manufacturers to use for post-market 448

surveillance. Users and clients/patients will benefit from a medical device remaining 449

safe and effective during their lifetime. 450

Table 1 gives an overview of the different stakeholders’ roles in post-market 451

surveillance and market surveillance of medical devices, as described in Parts I-IV of 452

this document. 453

454

Table 1 – Stakeholders’ roles in post-market surveillance and market surveillance for devices, with 455

emphasis on feedback 456

How stakeholders

manage risks


Stakeholder Activity Details

I Users and clients/patients (see Part I of this document)

1. Observe.

2. Document.

3. Report.

4. Act on manufacturers advice.

Users, and their clients/patients should observe for issues with devices (both positive and negative).

Users should document the serial numbers/lot numbers (and expiry dates) of affected devices at the very least.

Users are encouraged to provide feedback to the manufacturer as soon as they become aware, and to inform their NRA at the same time.

II Manufacturers and their economic operators (see Part II of this document)

1. Implement a system for post-market surveillance, including handling feedback.

2. Classify feedback and establish if it is an adverse event that requires reporting to NRA.

3. If needed, undertake root cause analysis.

4. If needed, make a correction.

5. If needed, implement corrective actions.

Effective post-market surveillance system should include both active and passive collection of post-market information. Collecting and analysing feedback is critical.

Manufacturers must establish a documented procedure for a feedback system and must quickly classify feedback.

Such a feedback system will provide early warning of quality/safety problems and for input into corrective action/preventive action processes (as required by the ISO 13485 and ISO TR 20416).

The action taken by the manufacturer following the classification of feedback might be to report to the NRA. This is vigilance and should include details of any investigations conducted such as through root cause analysis.

Corrections and corrective actions may also be required to protect public safety.

III NRA (see Part III of this document)

1. Ensure user feedback is forwarded to manufacturers

2. Conduct risk assessment.

3. Collect vigilance reports, oversee manufacturer’s investigation and other actions.

4. Conduct or coordinate testing using a risk-based approach.

5. Collect other post-market information.

6. Take regulatory action, if needed.

7. Share information with other NRAs.

NRAs should forward user feedback forms to the manufacturer, with copy of local economic operator, and conduct risk assessment.

NRA should collect vigilance reports (initial, follow-up, final).

NRAs should coordinate testing using a risk-based approach; either reactive or proactive.

NRAs should strive to collect other forms of post-market intelligence.

NRAs may need to undertake their own regulatory action, if the manufacturer does not or does not in a timely manner.

NRAs should share information with other NRAs.

Regulatory controls should be phased in depending on available regulatory capacity and resources and using a risk-based approach.

IV WHO (if applicable, see Part IV of this document)

1. Provide support for post-market surveillance of WHO recommended devices.

WHO assures that WHO recommended devices continue to uphold their safety, quality and performance.

WHO provides support to manufacturers, NRAs and end users facing problems with WHO-prequalified devices.

WHO reserves the right to conduct follow-up inspections for WHO prequalified devices to ensure that adequate actions are taken and corrective actions/preventive actions, if needed, have been implemented following a complaint.

Page 18 of 79

Part I: PROVIDING FEEDBACK BY USERS AND 457

PATIENTS/CLIENTS 458

Overview of responsibilities 459

Feedback from users and patients/clients on the safety, quality, and performance of 460

medical devices including IVDs is the basic part for every post-market surveillance 461

system and providing feedback is of crucial importance. In this part of the document, 462

professional users including lay users/caregivers, and patients/clients/self-testers 463

will be indicated by users or otherwise specified, if appropriate. It is through the 464

users providing feedback on the use of medical devices that manufacturers capture 465

an essential part of the product's post-market data. This section describes the 466

responsibilities of users for post-market surveillance of medical devices. Although 467

users have no official responsibility in post market surveillance, most of the 468

information on the experience with the actual use of medical devices will come from 469

the users. As safe and effective medical devices are also important for users, they 470

should be encouraged to provide feedback and thereby take their role in the post-471

market surveillance process. 472

Users should use medical devices according to manufacturer’s instructions for use to 473

maintain their safety, quality, and performance. 474

The principles for the use of the medical device are clearly laid out in the 475

manufacturer’s instructions for use. This document is considered part of the medical 476

device, as without it, the user is unable to use the product safely and correctly. The 477

instructions for use describe proper storage, the actual use, disposal of medical 478

devices and warnings, precautions and contra-indications. Every user must ensure 479

proper storage of the medical devices according to the manufacturers’ instructions 480

for use, which can include climate-control of the storage area, and, if applicable, 481

should monitor and record the temperature of the storage facility. Furthermore, 482

users should ensure that the storage areas are protected from sunlight, water, and 483

excessive dust and dirt. 484

Users (in conjunction with appropriate technical expertise) should document their 485

feedback in a broad sense, and as fully as possible. Users do not have to perform 486

their own investigation. 487

Users should provide feedback by reporting all information at their disposal to the 488

manufacturer. Feedback should be sent to the manufacturer’s address as indicated 489

in the contact details on the labelling or otherwise to the place where the medical 490

device is bought/purchased, e.g. a pharmacy. Following the feedback from the user 491

to the manufacturer, other parties might also become involved, such as an NRA (see 492

Part III). 493

Users play a crucial

role

Appropriate use of

medical devices

Document

feedback

Providing

feedback

Part I: Users


Figure 2 gives an overview of the steps involved in providing feedback and 494

subsequent analysis by the manufacturer. 495

Figure 2 – Actions of users in relation to manufacturer’s post-market surveillance 496

497

1 Detect/observe 498

User feedback can be classified in positive or negative feedback. Positive feedback 499

may include for example experiences, suggestions for improvement, etc. 500

Negative feedback may include for example complaints, use errors, or abnormal use. 501

Users should be aware of issues that can indicate a problem that needs to be fed 502

back to the manufacturer. Underneath, some examples of points to consider are 503

included. 504

The user should examine the device upon delivery through physical inspection: 505

• Verify if labelling matches the labelling for the product on NRA’s website if 506

possible, or on the manufacturer’s website; 507

• Ensure manufacturer’s contact details are present; 508

• Check for any evidence of tampering of labels and/or packaging such as 509

cracks, abrasion, erosion, breaks, seal integrity; 510

• Check for problems with labelling including instructions for use; or need for 511

training, including inadequate instructions to the use; unclear, missing, worn 512

out, incorrect or inaccurate labels; are intended users required to be 513

adequately trained according to labelling and instructions for use. 514

Types of feedback

How and what to

detect

Page 20 of 79

• Check for manufacturing, packaging or shipping problems, including 515

defective components, defective medical devices, medical devices damaged 516

prior to use, damage to the materials used to construct the cover or outer 517

packaging of the medical device, compromised microbiological state (e.g. 518

sterility), of the medical device, missing listed components, and 519

• Verify if the correct product was delivered. 520

Users should request a certificate of analysis for the lot or serial number, if 521

applicable, and use this as a reference for the physical inspection of product name, 522

product code, lot number, expiry date, etc. 523

During routine use of medical devices, users should be aware of product problems, 524

such as: 525

• Patient-device incompatibility, interaction between the patient’s/client's 526

anatomy/physiology and the medical device that affects patient/client. 527

• Material integrity problem, including broken, cracked, degraded, deformed, 528

disintegrated, split/cut/torn, scratched materials/components. 529

• Use problem, including device handling, improper or incorrect procedure or 530

method, misassembled by users, off-label use. 531

• Misdiagnosis. 532

Certain feedback may be considered an adverse event. 533

Registries are increasing used, especially for implantable medical devices that are 534

used to collect data on clinical use and to assesses use in the device’s target patient 535

population. These are generally maintained by healthcare facilities, by healthcare 536

authorities including regional databases, and the relevant professional associations. 537

Manufacturers might request access certain data from a given registry at the 538

discretion of the registry owner. 539

Signal detection may be conducted using data collected in registries whereby 540

associations or unexpected occurrences can be detected that might impact patient 541

management and/or change the established benefit-risk profile of a device. 542

For IVDs, sources of data on the post-market information include external quality 543

assessment schemes (EQAS), also known as proficiency testing, and from quality 544

control (QC). 545

Where it exists, the data generated by an EQA schemes can be assessed to 546

determine if any observations should be reported as feedback. Although, the 547

primary purpose of EQA schemes is inter-laboratory comparison, these data can 548

provide very useful information about the performance of IVDs, especially when 549

many sites are using the same product (same or different lot numbers). EQA data 550

analysis may indicate use errors and abnormal use errors. 551

Users who participate in EQA schemes are encouraged to report feedback to the 552

manufacturer, if they report nonconforming results. EQA providers are encouraged 553

Registries

Quality monitoring

of IVDs

EQA schemes

Part I: Users


to report to manufacturers, if they detect a noticeable trend from their analysis of 554

EQA data. 555

Quality control (QC) is a process to detect whether performance requirements and 556

quality objectives for an IVD have been met. Typically, a user might use biological QC 557

material of a known reference result to test a sample of IVDs. It is critical to ensure 558

that traceability of values assigned to such control materials is ensured through 559

available reference measurement procedures or available reference materials of a 560

higher order. 561

Biological QC materials are usually contrived biological specimens that is optimized 562

for the product and is developed independently of the manufacturer. They are 563

provided to laboratories/testing sites using the given product by the product 564

manufacturer or another body responsible for quality. Ideally QC specimens should 565

be tested in each test run or testing session. WHO recommends the following 566

frequency of QC for monitoring quality by users: 567

• once weekly, preferably at the beginning of the week 568

• for any new operator (including trained staff who have not conducted 569

testing for some time) 570

• for each new lot of test kits 571

• for each new shipment of test kits 572

• when any environmental conditions (for example, temperature and 573

humidity) fall outside the range recommended by the manufacturer. 574

The results of QC specimens can be analyzed and results outside a pre-determined 575

acceptance range can be identified and investigated. This approach is typically 576

difficult for IVDs returning qualitative results such as rapid diagnostic tests or 577

qualitative nucleic acid tests. Any implementation of QC for quality monitoring 578

should be implemented using a risk-based approach. 579

580

For IVDs, using sentinel sites to perform user quality control monitoring can build 581

capacity and collect data. This data can be fed into the risk management framework 582

of the NRA and help to determine specific products that might require prioritization 583

for market surveillance, see Part II. 584

2 Document 585

Users should document any feedback related to use of medical devices at any facility 586

or testing site including as applicable product name and product code of the 587

affected medical device, affected lot numbers (and expiry dates) , affected 588

patients/clients (age, concomitant diseases, current treatments, etc.), 589

procedure/treatment the device was used for and any measures taken. 590

Users should use a customer feedback form, if possible, see Annex 1. 591

QC

Sentinel sites

Feedback forms

Page 22 of 79

Photographs of affected medical device and/or injuries should be taken to illustrate 592

the feedback, if possible. If useful, take photographs of the packaging and 593

instructions for use to document the problem(s). 594

Users should keep and appropriately store one or more of the affected medical 595

devices as retention samples for later inspection and testing, if possible. It is advised 596

that the user contacts the manufacturer or the place where the medical device is 597

bought/purchased on the number of samples needed for later inspection and testing. 598

It is recommended that reimbursement of the costs for such samples will be 599

provided. 600

The documentation step will describe in more detail the circumstances related to 601

the feedback and will enable the manufacturer to conduct their investigation. 602

Other methods of documenting and sending feedback can be considered. Use of 603

smartphone applications and web forms that directly send feedback to a centralised 604

database (usually maintained by the NRA) have been used with success, e.g. MHRA’s 605

Yellow Card Scheme. Emerging solutions such as blockchain technology which is 606

decentralized (data is not stored by any one entity), transparent (uses self-sovereign 607

identity so the reporter’s identity is secured by cryptography) and immutable (data 608

cannot be tampered with, all transactions are recorded) may be explored. 609

3 Implementation of IMDRF’s framework for "Unique Device Identification 610

(UDI) System for Medical Devices" might aid documentation of user 611

feedback. A machine readable (such as a bar code) and a human 612

interpretable code will be placed on the device which allows for the device 613

and the product level data to be identified. UDI may be added to electronic 614

health records and registries.Report 615

All feedback, that reasonably suggests that the medical device has or may have 616

caused or contributed to the death or serious deterioration in the health of a 617

patient/client should be reported by the user to the manufacturer as soon as they 618

become aware, while following national regulations. 619

Contact details for the manufacturer are displayed on the label or in the instructions 620

for use. If this information is not self-evident, report to the site where the device 621

was distributed, e.g. other economic operator (agent, distributer, supplier), health 622

care facility, pharmacy, etc. 623

An overview of the steps in providing feedback by users is shown in Table 2. 624

4 Act 625

Users will often be called upon to act on the contents of field safety notices 626

including actions such as: 627

• Quarantine at the request of NRAs; 628

• Return of device or destruction of the device (recall) at the request of 629

manufacturer; 630

Store samples

Immediate

feedback

Part I: Users


• Device modification such as changes to the instructions for use or other 631

labelling, software upgrades, clinical management (including retesting), etc. 632

633

Patient/clients might need to be made aware of FSCAs usually via press release – in 634 any case they should contact their healthcare facility. 635

Table 2 – Summary of steps in providing feedback by users 636

What How How it will help

Detect/ observe

Single event observed by user (patient/client); proceed to documentation and reporting of the event.

Accurate record-keeping, preferably using standardized site registers, inventory records, patient clinical files will contain the necessary information to fill the feedback form.

Collect positive experiences.

If the circumstances concerning the use of the medical device concerned are observed and documented, it will make it later easier to understand if the situation can be attributed to an operator, a particular lot number, a particular health care facility site etc.

Document It is preferred to use site registers and inventory records, document the problem, e.g., affected product code/serial number, affected lot numbers (and expiry dates), any measures taken etc.

To ascertain which lots and/or consignments are affected, and the scope of the effect.

If possible, retain and quarantine according to manufacturer’s storage conditions a reasonable number of medical devices from the same pack and/or lot as retention samples for later inspection and testing.

To allow for subsequent inspection of packaging for breeches that might impact stability and testing.

Report The user will communicate all feedback, including complaints to the manufacturer using a feedback form.

To allow manufacturer to initiate their customer feedback system, including evaluation for reporting to NRAs and commencing an investigation, including root cause analysis.

Act The user should follow any advice provided by the manufacturer on the use of the device, particularly any field safety notice.

To assure public safety, examples include retesting/review of patients that had the device used on them

637

Page 24 of 79

PART II: POST-MARKET SURVEILLANCE BY 638

MANUFACTURERS (and their economic operators: 639

authorised representatives, agents, and distributors) 640

This section describes the manufacturer’s post-market surveillance obligations and 641

focusses on the assessment of feedback to distinguish administrative issues from 642

technical issues product problems that could be adverse events. Other economic 643

operators (authorized representatives, agents, distributors) may be required to act 644

on behalf of the manufacturer. Therefore, an agreement should be in place 645

between the manufacturers and their related economic operators, such as agents, 646

distributors and importers, to receive feedback from customers and to forward this 647

feedback to the manufacturers in a timely manner. This may include translation of 648

feedback into the language used by the manufacturer. 649

Escalation of feedback is the first step, followed by further investigation, that could 650

indicate that corrective or preventive action is needed, which can include field safety 651

corrective actions. 652

Although this part is focussing on the role of the manufacturer, other economic 653

operators can play a crucial role in collecting feedback and forwarding this to the 654

manufacturer. By including these economic operators, more feedback might be 655

collected, thereby providing the manufacturer with more information on the safety, 656

quality and performance of the medical devices during actual use. 657

Basics for post-market surveillance 658

The manufacturer shall have a post-market surveillance plan in place, in which at 659

least the following steps shall be included: 660

1. scope of the post-market surveillance plan; 661

The manufacturer shall indicate for which specific medical device, medical 662

device type or family the plan is applicable. 663

2. objective of the post-market surveillance plan; 664

The manufacturer shall indicate what is to be achieved by the post-market 665

surveillance for that device. 666

3. responsibilities; 667

The manufacturer shall indicate responsibilities for all stages of the post-668

market surveillance process. 669

4. data collection; 670

The data collection shall be described. 671

5. data analysis; 672

The method for data analysis shall be described. 673

6. Using data in risk management and other processes; 674

A system shall be in place to feedback the data obtained from post-market 675

Part II: Manufacturers


surveillance into other processes, such as risk management, improvement, 676

clinical evaluation. 677

7. Consider and implement required actions. 678

Based on the data analyses and further analysis in the appropriate processes, 679

mainly risk management, required actions must be considered and 680

implemented, if needed. 681

Scope of the post-market surveillance plan 682

The manufacturer shall indicate for which products the post-market surveillance 683

plan is applicable, as for different devices, different approaches might be needed. 684

This can be due to differences in devices itself, risks associated with the device, but 685

also due to the differences in time on the market and associated experiences gained. 686

ISO TR 20416 provides more detailed guidance on this topic. 687

Objective of the post-market surveillance plan 688

The manufacturer shall indicate what the objectives are for post-market surveillance. 689

At a minimum for every post-market surveillance plan, the manufacturer shall 690

include the following objectives: 691

• Has any new hazard or hazardous situation been identified for the medical 692 device or similar medical devices or has the risk acceptability changed? 693

• Has any misuse of the medical device occurred? 694

• Are there any unforeseen side effects for the medical device or similar medical 695 devices? 696

• Is there a medical device malfunction that impacts the benefit-risk analysis? 697

The above-mentioned questions relate mainly to the observation of adverse events 698

that users will report to the manufacturer. 699

Other objectives can be addressed as part of post-market surveillance. These 700

objectives will provide the manufacturer with more information on the performance 701

of the device(s). Examples of other objectives are: 702

• Do users experience any usability issues? 703

• Are recurring malfunctions due to service/maintenance deficiencies? 704

• How does treatment affect the quality of life of the patient? 705

• Can user/patient training reduce the likelihood of malfunction? 706

• Are there any improvements that can be made to the medical device? 707

• Has state of the art changed after design and development of the medical device? 708

• Are indications or contra-indications appropriate to ensure safety and 709 effectiveness for the intended use of the medical device? 710

Responsibilities 711

Responsibilities and powers for post-market surveillance activities shall be defined 712

by the manufacturer. The manufacturer shall ensure the availability of resources 713

with the independence and competence for post-market surveillance activities. 714

Knowledge of

relevant standards

Page 26 of 79

Preferably, a team of people should be involved in post-market surveillance, 715

covering all expertise required for post-market surveillance. 716

Data collection 717

As stated before, reactive post-market surveillance, based on collecting feedback, 718

should always be in place. Based on the objectives, the manufacturer shall choose 719

the appropriate data sources to allow the fulfil the objectives of the post-market 720

surveillance plan. For example, to make sure that the medical device is still state-of 721

the-art, actively collecting data on similar devices and procedures from literature, 722

congresses and trade shows is required. The data sources selected should provide 723

reliable data, which need to be verified. 724

After the appropriate data sources have been selected, methods to collect the data 725

need to be in place, including the time span for which the data need to be collected. 726

When establishing the data collection method, it needs to be ensured that the data 727

collected can be analyzed in a meaningful way. 728

Data analysis 729

To be able to obtain useful information from the data collected through post-market 730

surveillance, the data need to be analysed. The data analysis should be considered 731

when setting up the data collection. The data analysis can vary from simple 732

qualitative analysis to advanced statistical analysis. Qualitative analysis will often be 733

required as an initial step for the analysis of a complaint. The data obtained from the 734

qualitative analysis of complaints can also be used for quantitative analysis. An 735

often-used method for quantitative analysis is trend analysis. Trend analysis can only 736

be performed if enough data for a sufficiently long period are available. 737

Using data in risk management and other processes 738

The data collected and analysed shall be used in the applicable other processes, such 739

as risk management, improvement and clinical evaluation. In this document, the 740

focus will be on the use of post-market surveillance data in risk management. By 741

using the post-market surveillance data in other processes, conclusions can be 742

drawn on the changes in risk, the need or possibilities to make changes to a medical 743

device or the need to obtain more clinical data. 744

Manufacturers should be familiar with standards such as ISO 13485 on quality 745

management systems, ISO 14971 on risk management and ISO TR 20416 on post-746

market surveillance, that outline the manufacturer’s requirements for compliance 747

with post-market surveillance aspects. 748

Considering and implementing required actions 749

Based on the outcome of further analysis of post-market surveillance data in other 750

processes, such as risk management, actions might be required to correct problems 751

or defects related to a medical device (correction), to remove cause of 752

nonconformity to avoid reoccurrence (corrective action) or to prevent occurrence of 753

additional issues (preventive action). The manufacturer shall consider the options to 754

remedy the unwanted situation and decide on the appropriate action and 755

implement that action. 756



See Figure 3 for details on actions taken by manufacturers. 757

Figure 3 - Actions of manufacturers for post-market surveillance 758

759

1 Receiving feedback 760

In the rest of this chapter, the focus will be on receiving and acting upon feedback by 761

the manufacturer, as this is the basic form of post-market surveillance that always 762

needs to be performed, irrespective of the available resources. 763

The manufacturer shall make it possible for users and patients/clients to provide 764

feedback as easily as possible. This means that the methods to submit feedback shall 765

be readily available in the area concerned and provide as little barrier as possible to 766

users and patients/clients to provide the feedback. The manufacturer shall 767

document all feedback received. As feedback might contain a complaint or report of 768

an adverse event, feedback should be analysed as soon as possible and feedback 769

that constitutes an administrative/technical complaint or an adverse event should 770

be escalated further. 771

Feedback may include: 772

• administrative/contractual complaints related to any aspect of the procurement 773

contract not fulfilled, for example, agreed delivery time not adhered to, agreed 774

guaranteed shelf life upon delivery not adhered to, incorrect product and/or 775

quantity delivered etc. 776

• technical complaints affecting the safety, quality or performance of a medical 777

device. 778

779

Initially, the manufacturer shall distinguish between administrative feedback and 780

technical feedback. Administrative complaints are not considered to be linked to a 781

safety, quality or performance issue, these are considered normal feedback and do 782

Emphasis on

feedback

Page 28 of 79

not require immediate action, but an analysis shall be done periodically on such 783

complaints. Technical feedback shall be further classified, see next section. 784

785

Information about such issues may become available in other sources of post-786

market information than through user feedback, for example through literature and 787

other scientific documentation). From within the production site and/or quality 788

management system such as through management review, high rates of non-789

conforming product, risk assessment, and other relevant clauses of ISO 13845 and 790

ISO 14971. 791

792

However, manufacturers should, if possible, employ other proactive sources for 793

post-market surveillance. Such sources can be aimed at obtaining other information 794

from users and patients/clients by using enquiries., which also allows more positive 795

feedback to be solicited. From scientific literature, the manufacturer can obtain 796

information on side-effects and complication, also from similar devices, but can also 797

provide insight into state of the art. 798

For equipment requiring regular servicing, service reports can provide insight into 799

performance of the equipment, including information on wear of parts using spare 800

parts and other observations. 801

User training is an opportunity to observe the users, understand their thought 802

process and challenges, and estimate the distribution of user skills. Feedback from 803

user training can also provide insight into new risks due to unforeseen user 804

interaction with the medical device and possibilities for improvement. 805

The manufacturer shall choose the appropriate sources in line with the objective of 806

the PMS-plan. Underneath, an overview of possible data sources is provided (ref. 807

ISO TR 20416): 808

• Complaints, including adverse events reported to the organization; 809

• Maintenance (including preventive maintenance / corrective maintenance and 810

repair / refurbishing); 811

• Installation; 812

• Returned medical devices; 813

• Explants; 814

• Medical device registries; 815

• Post-market clinical follow-up (PMCF) studies, and post-market performance 816

follow-up (PMPF) if IVD; 817

• Controlled market release phase; 818

• User training; 819

• Advisory notices; 820

• Scientific literature; 821

• Market surveillance activities by regulatory authorities and their related 822

publications and recommendations; 823

Other sources of

post-market

information



• Publicly accessible databases from regulatory authorities on adverse events and 824

advisory notices; 825

• Conferences, tradeshows, etc.; 826

• Regulatory requirements, standards, guidance and best practices; 827

• Social media; 828

• Public media; 829

• Medical device distribution and medical device tracking; 830

• Finished products, product quality information; 831

• Internal audits and external inspections. 832

Each data source may require a specific method of collecting that data and the 833

analysis of each data source might be different. For example, obtaining data from 834

scientific literature will require expert judgement, whereas extracting information 835

from maintenance records requires administrative work. 836

When more data are collected, a quantitative analysis can be performed. As already 837

mentioned in the paragraph on basics for post-market surveillance, the quality of 838

the data to be analysed shall be checked and the quality of the data needed can also 839

play a role in selecting the appropriate data sources. 840

841

Economic operators 842

For users and patients/clients, the contact details of the manufacturer might not be 843

evident, or it is not possible to send feedback through the channels made available 844

by the manufacturer. In that case, the users and patients/clients should go to the 845

site from where they obtained the device or where the device was used on them 846

(e.g. pharmacy, healthcare facility, etc.). By making it easier for users and 847

patients/clients to provide feedback, more feedback should be received, allowing 848

the manufacturer to get more data on the experiences gained during the actual use 849

of the device. 850

851

Implementation of IMDRF’s Unique Device Identification (UDI) System for Medical 852

Devices is intended to “facilitate unambiguous identification of the medical device 853

through distribution and use by providing a single global identifier that can be used 854

to link and integrate existing government, clinical, hospital, and industry databases”. 855

UDI will allow industry and regulatory authorities to more rapidly identify medical 856

devices involved in adverse events. UDI may be added to vigilance reports, and 857

registries. UDI (Device Identifier (UDI-DI) + Production Identifier (UDI-PI)) throughout 858

distribution and use. The framework for UDI implementation is promulgated in 859

IMDRF/UDI WG/N7FINAL:2013. 860

Users and manufacturers should be aware that software as a medical device, 861

including artificial intelligence is subject to this guidance, where applicable. 862

Unique device

identification

Page 30 of 79

2 Classify feedback and escalate where needed 863

All technical feedback shall be initially analysed to verify if it constitutes a complaint, 864

including any adverse event. Complaints can identify quality, safety and 865

performance issues that are of high risk and therefore might require immediate 866

action to protect public health and safety. 867

Categories of problems (technical feedback) are listed in Table 3. IMDRF has issued a 868

series of annexes and guidance on adverse event reporting terminology. WHO 869

recommends that this coding and classification be implemented, using the following 870

seven annexes for all vigilance reporting: 871

Annex A: Medical Device Problem 872

Annex B: Cause Investigation - Type of Investigation 873

Annex C: Cause Investigation - Investigation Findings 874

Annex D: Cause Investigation – Investigation Conclusion 875

Annex E: Health Effects - Clinical Signs and Symptoms or Conditions 876

Annex F: Health Effects - Health Impact 877

Annex G: Medical Device Component878

http://www.imdrf.org/workitems/wi-aet-annex-a.asp

http://www.imdrf.org/workitems/wi-aet-annex-b.asp

http://www.imdrf.org/workitems/wi-aet-annex-c.asp

http://www.imdrf.org/workitems/wi-aet-annex-d.asp

http://www.imdrf.org/workitems/wi-aet-annex-e.asp

http://www.imdrf.org/workitems/wi-aet-annex-f.asp

http://www.imdrf.org/workitems/wi-aet-annex-g.asp



Table 3 – Categories of problems reported as feedback, taken from IMDRF adverse event reporting Terminology guidance (annex A) 879

(permission to seek clearance from IMDRF to reproduce this figure is in-progress) 880

No. Problem category Description

A01 Patient-device incompatibility problem Problem related to the interaction between the patient and the device.

A02 Manufacturing, packaging or shipping

problems

Problem associated with any deviations from the documented specifications of the device that relate to nonconformity

during manufacture to the design of an item or to specified manufacturing, packaging or shipping processes (out of

box problem).

A03 Chemical problem Problem associated with any from the documented specifications of the device that relate to any chemical

characterization, i.e., element, compound, or mixture.

A04 Material integrity problem Problem associated with any deviations from the documented specifications of the device that relate to the limited

durability of all material used to construct device.

A05 Mechanical problem Problems associated with mechanical actions or defects, including moving parts or subassemblies, etc.

A06 Optical problem Problem associated with transmission of visible light affecting the quality of the image transmitted or otherwise

affecting the intended application of the visible light path.

A07 Electrical/electronic property problem Problem associated with a failure of the electrical circuitry of the device.

A08 Calibration problem Problem associated with the operation of the device, related to its accuracy, and associated with the calibration of the

device.

A09 Output problem Problem associated with any deviation from the documented specifications of the device that relate to the end result,

data, or test results provided by the device.

A10 Temperature problem Problem associated with the device producing unintended temperatures.

A11 Computer software problem Problem associated with written programs, codes, and/or software system that affects device performance or

communication with another device.

A12 Connection problem Problem associated with linking of the device and/or the functional units set up to provide means for a transfer of

liquid, gas, electricity or data.

A13 Communication or Transmission Problem Problem associated with the device sending or receiving signals or data. This includes transmission among internal

components of the device to which the device is intended to communicate.

A14 Infusion or flow problem Problem associated with the device failing to deliver or draw liquids or gases as intended (e.g. delivering drugs at

incorrect rate, Problems with drawing fluid from a system). This includes vacuum collection devices.

A15 Activation, positioning or separation Problem associated with any deviations from the documented specifications of the device that relate to the sequence

Page 32 of 79

problem of events for activation, positioning or separation of device. Note: Deployment is synonymous with activation.

A16 Protective measure problem Problem associated with any deviations from the documented specifications of the device that relate to the

implemented and inherited design features specific to devices used for reducing risks to patient or caregiver or

maintaining risks within specified levels.

A17 Compatibility problem Problem associated with compatibility between device, patients or substances (medication, body fluid, etc.)

A18 Contamination/decontamination

problem

Problem associated with the presence of any unexpected foreign substance found in the device, on its surface or in the

package materials, which may affect performance or intended use of the device, or problem that compromise effective

decontamination of the device.

A19 Environmental compatibility problem Problem associated with the surrounding conditions in which the device is being used such as temperature, noise,

lighting, ventilation, or other external factors such as power supply.

A20 Installation-Related Problem Problem associated with unsatisfactory installation, configuration, and/or setup of a specific device.

A21 Label, instructions for use or training

problems

Problem associated with device markings/labelling, instructions for use, training and maintenance documentation or

guidelines.

A22 Human-device interface problem Problem associated with an act or omission of an act that has a different result than that intended by the

manufacturer or expected by the operator.

A23 Use of device problem Problem associated with failure to process, service, or operate the device according to the manufacturer's

recommendations or recognized best practices.

A24 Adverse Event Without Identified Device

or Use Problem

An adverse event (e.g. patient harm) appears to have occurred, but there does not appear to have been a problem

with the device or the way it was used.

A25 No Apparent Adverse Event A report has been received but the description provided does not appear to relate to an adverse event. This code

allows a report to be recorded for administration purposes, even if it doesn't meet the requirements for adverse event

reporting.

A26 Insufficient Information An adverse event appears to have occurred but there is not yet enough information available to classify the device

problem.

A27 Appropriate term/code not available The device problem is not adequately described by any other term. Note: this code must not be used unless there is no

other feasible code. The preferred term should be documented when submitting an adverse event report. This

information will be used to determine if a new term should be added to the code table.

Source: IMDRF Adverse Event Reporting Terminology (IMDRF/AE WG/N43 FINAL:2020) 881



As soon as feedback is received, an assessment of technical feedback must be 882

performed by the manufacturer to establish the impact (scale and scope) of the 883

problem. The degree of risk will determine the timeline for action and who should 884

be informed. The requirement for root cause analysis will remain, irrespective of the 885

classification. 886

The manufacturer (or their economic operator, including the marketing 887

authorization holder) should send a vigilance report to the NRA, in the following 888

circumstances: 889

• When use of a medical device leads to: 890

o Death of a user, patient/client or other person (adverse event) 891

o Serious deterioration in health of a user, patient/client or other 892

person (adverse event) 893

o Indirect harm, such as misdiagnosis, delayed diagnosis, delayed 894

treatment, inappropriate treatment, absence of treatment or 895

transfusion of inappropriate materials. 896

• Discovery of a serious public health threat 897

• No death or serious deterioration in health occurs but the event might lead 898

to death or serious deterioration in health of a patient, user of other person 899

if it recurs. 900

In general, most technical feedback will be considered as adverse events. 901

Any adverse events that represent a serious public health threat 2should be 902

reported immediately and not later than 2 calendar days to the relevant NRAs. 903

National regulations might contain other timelines. Examples might be if an IVD used 904

for blood screening of infectious diseases is observed to return higher than expected 905

rate of false negative results, hacking of software (as a medical device) that changes 906

dosing of infusion pumps, dosing of therapeutic radiation, etc. 907

Other serious adverse events including death or serious deterioration in health that 908

occurred or may have occurred for the patient, end-user or other individual should 909

be reported within 5 days to the relevant NRAs. 910

A manufacturer vigilance reporting form can be found in Annex 2. 911

Further analysis is needed, see below. This might require the manufacturer to obtain 912

additional information from the person providing the feedback, to be able to 913

perform the analysis. 914

A system shall be in place for such events to be monitored for the frequency of 915

occurrence or change in the type/severity of the outcome following such an event. 916 2 Any event type, which results in imminent risk of death, serious injury, or serious illness that may

require prompt remedial action. Source: GHTF/SG2/N79R11:2009

What should be

reported

Page 34 of 79

This is known as trending and should happen periodically, e.g. on a monthly basis. 917

Based on this analysis, it might be necessary to undertake further action, changes to 918

manufacturing, update of the IFU etc. 919

In addition to the above immediate reporting of adverse events, all feedback should 920

be reported to the NRA as part of the annual/periodic summary post-market 921

surveillance reports, if required by national legislation. 922

A use error, as defined, might include slips, lapses, mistakes and reasonably 923

foreseeable misuse. 924

Examples include: 925

• Inserting a test strip backward into a glucose monitor 926

• Not engaging the handbrake on a wheelchair when using public transportation. 927

Issues occurring despite adequate proper instructions for use and proper design 928

according to manufacturer's analysis could be potential use errors. 929

The error may be due to a medical device being poorly designed, or it may have 930

been used in a situation that promoted incorrect usage (foreseeable misuse). By 931

reporting such near misses, it helps the manufacturer to reduce the chance of other 932

users making the same use error with similar or worse consequences. 933

An abnormal use error (see definition) is a conscious, deliberate act, or deliberate 934

omission of an act, by the user as a result of conduct that is beyond any reasonable 935

means of risk control by the manufacturer. 936

Examples include: 937

• Use of a medical device despite obvious packaging breech 938

• Failure to follow manufacturer’s instructions for clean care, i.e., use of 939

antiseptic 940

• Continued use of a medical device after the manufacturer’s stated expiry date 941

• Product analysis showing that the medical device was working according to 942

specifications; further investigation revealing that the user was inadequately 943

trained.3 944

Ideally, there should be no barrier to report abnormal use-errors to the health care 945

organization (safe reporting). This will allow the organization to take measures and 946

will also allow the manufacturer better insight into problems occurring during use. 947

Manufacturers might also receive feedback internally through their quality 948

management system. This does not typically need to be reported to the NRA, unless 949

a FSCA is implemented as a result. 950

3 This list does not purport to be definitive and each case should be handled individually.

Use error

Abnormal use

error



3 Undertake root cause analysis 951

For certain feedback, especially adverse events, the manufacturer should undertake 952

a root cause analysis to determine if the feedback can be independently verified and 953

a root cause can be established. All reasonable efforts should be made by the 954

manufacturer to determine if there is a causative link between the medical device 955

and the adverse event. 956

“Root cause analysis helps identify what, how and why something happened, thus 957

preventing recurrence. 958

• Root causes are underlying, are reasonably identifiable, can be controlled by 959

management [review] and allow for generation of recommendations. 960

• The process involves data collection, cause charting, root cause identification and 961

recommendation generation and implementation.”4 962

As stated above, a systematic approach should be used to determine the root 963

cause(s) of an adverse event by establishing a methodology for determining the 964

causes, then determining all probable causes and likelihoods for each cause (i.e., the 965

probability that the cause contributed to the adverse event or incident); and the 966

evidence for reported causes and likelihoods. 967

A variety of methods exists for root cause analysis. Manufacturers may also use 968

failure mode and effects analysis (FMEA). The following set of information is 969

required: 970

• Device involved (medical device, accessory or part) 971

• intended use of the device 972

• The event 973

• Effect of the event 974

• Cause of event 975

• Current control 976

• Recommended action 977

A fishbone diagram approach is useful as a guide to rule in or rule out the following 978

causes: material, methods, mother nature, measurement, man and machine5. 979

4 Decide if a correction is required 980

Following the investigation of the complaint, the manufacturer must consider if a 981

correction is required, whereby a correction (see glossary) refers to: 982

• Repair, modification, adjustment, relabeling, destruction, or inspection 983

(including patient monitoring) of a product without its physical removal to some 984

other location6. 985

4 Quoted from: Root Cause Analysis For Beginners, James J. Rooney and Lee N. Vanden Heuvel, QUALITY PROGRESS, JULY 2004, 45-53. https://mycourses.aalto.fi/pluginfile.php/652713/mod_resource/content/1/Root_Cause_Analysis_For_Beginn.pdf 5 https://www.cms.gov/medicare/provider-enrollment-and-certification/qapi/downloads/fishbonerevised.pdf

Page 36 of 79

986

The manufacturer might also consider other corrections: 987

• Additional surveillance of the device in use; 988

• Retraining; 989

• Explantation; 990

• Additional clinical review of patients/clients; or 991

• Retesting, if IVD. 992

The manufacturer may decide the nonconformity has little associated risk or is 993 unlikely to recur. In such cases the manufacturer may decide only to carry out a 994 correction. 995

The manufacturer might also decide that a field safety corrective action is required. 996

Such urgent information is notified to those responsible for the device or affected by 997

the problem through a field safety notice, see next section. 998

The manufacturer might decide that no action is required. 999

5 Take corrective action 1000

The difference between a correction and corrective action is that a correction is an 1001

action undertaken by the manufacturer to eliminate detected nonconformity – most 1002

typically this would be a product recall or modification to labelling. Whereas a 1003

corrective action is is to eliminate the cause of a corrective action – such as 1004

increased quality control stringency, manufacturing process modification, etc. These 1005

are both reactive in nature. A correction may be made in conjunction with a 1006

corrective action. 1007

Based on the results of root cause analysis for one or more complaints, corrective 1008

action and preventive action (CAPA) should be considered. GHTF’s Quality 1009

management system –Medical Devices – Guidance on corrective action and 1010

preventive action and related QMS processes (GHTF N18) provides additional 1011

guidance on CAPA. CAPA are often improvements made to the manufacturing 1012

process or the design of the medical device, or to the quality management system 1013

(QMS) to eliminate causes of nonconformities to prevent their reoccurrence, see 1014

also definitions. Any process for CAPA should use the outcome of the systematic 1015

investigation of reported adverse events (malfunction/failures). To ensure that 1016

corrective and preventive actions are effective, the systematic investigation of the 1017

adverse event is pivotal in identifying the corrective and preventive action to be 1018

undertaken. The degree of action taken should be dependent upon and related to 1019

the risk, size and nature of the problem and its effect(s) on product safety, quality 1020

and performance. 1021

Corrective action (see definition) should be handled according to ISO 13485, Section 1022

8.3. (control of nonconforming product) and 8.5.2 (corrective action), depending on 1023

6 https://www.fda.gov/medical-devices/postmarket-requirements-devices/recalls-corrections-and-removals-devices#:~:text=Under%2021%20CFR%20806%2C%20Medical,the%20Act%20caused%20by%20the

CAPA



whether a nonconforming device is involved or if action is taken to prevent 1024

recurrence of a nonconforming device. 1025

Preventive action (see definition) is a proactive process undertaken by the 1026

manufacturer to identify opportunities for improvement of the device in advance, 1027

before a problem is identified. Preventive action is taken when a potential 1028

nonconformity is identified as the result of quality control testing, and other 1029

relevant sources of information. Examples of preventive action include (but are not 1030

limited to): 1031

• Reviews of contracts (with key suppliers), purchasing, processes, design 1032

• Supplier surveillance 1033

• Management review of quality management system 1034

• User training programmes, job aids 1035

• Benchmarking. 1036

5.1 Field safety corrective action 1037

A field safety corrective action (FSCA) is triggered by information about the 1038

occurrence of one or more problems with already distributed devices that poses an 1039

unacceptable increase in risk when that device is used. Such problems include 1040

malfunction or deterioration affecting the performance or operational 1041

characteristics of a device, as well as any inadequacy in the instructions for use 1042

which might lead or might have led to the death of a patient, user or other individual 1043

or to a serious deterioration in his/her state of health. The analysis of feedback on 1044

such occurrences is described in the previous paragraphs. 1045

In assessing the need for the FSCA, the manufacturer is advised to use the 1046

methodology described in the standard ISO 14971:2017 Medical devices - 1047

Application of risk management to medical devices. Implementation of risk 1048

management principles and activities within a quality management system is 1049

described in GHTF guidance “Implementation of risk management principles and 1050

activities within a Quality Management System” (GHTF/SG3/N15R8). 1051

Risk assessment is thus a key element of the manufacturer determining the need for 1052

an FSCA. Appropriate expertise must be used to determine the potential harm and 1053

the risk properly. 1054

FSCA may include: 1055

• Return of a type of device to the manufacturer or its representative (also 1056

known as recall) 1057

• Device modification 1058

• Device exchange 1059

• Device destruction7 1060

7 The NRA should ensure a record of disposal of affected product and inform the manufacturer so that they may reconcile product distributed and product destroyed.

What can trigger

FSCA

Assessing the need

for FSCA

Possible

actions

Page 38 of 79

• Advice given by the manufacturer regarding the use of the device 1061

Device modifications can include: 1062

• Retrofitting in accordance with the manufacturer's modification or design 1063

change 1064

• Permanent or temporary changes to the labelling or instructions for use 1065

• Software upgrades including those carried out by remote access 1066

• Modification to the clinical management of patients to address the risk of 1067

death or serious injury or death specifically to the characteristics of the device. 1068

The relative urgency of the FSCA should be communicated, consider introducing 1069

categories of urgency. 1070

A FSCA is communicated through a Field Safety Notice (FSN); see next page for 1071

details. 1072

The manufacturer is usually required to report any FSCA to the relevant NRAs where 1073

the medical device is supplied, according to the national regulations. It is advised to 1074

use IMDRF’s adverse event reporting terminology [IMDRF/AE WG/N43FINAL:2020 1075

and its annexes]. 1076

The manufacturer should issue a notification to NRAs of all the countries affected 1077

through a FSCA report, in line with national legislation. A format is proposed in 1078

Annex 5. The FSCA report should include the following information: 1079

• Name of the manufacturer; 1080

• Product name, product code and lot number of the affected device; 1081

Note: in the case that the FSCA related to certain lots only, an explanation 1082

why the other lots are not affected; 1083

• List of all affected countries; 1084

• Background information and reason for the FSCA, including a description of 1085

the device deficiency or malfunction, clarification of the potential hazard 1086

associated with the continued use of the device and the associated risk for 1087

the patient, user or other person and any possible risks to patients 1088

associated with previous use of affected device; 1089

• Relevant parts from the risk analysis; 1090

• Description and justification of the corrective and/or preventive action; 1091

• Advice on the actions to be taken by economic operators and users (include 1092

as appropriate): 1093

o Identifying and quarantining the device; 1094

o Method of recovery, disposal or modification of the device; 1095

o Recommended patient follow-up; 1096

o A request to pass any attached Field Safety Notice to all those who 1097

need to be aware of it. 1098

National regulations might require other items to be included. 1099

Communicating

FSCA

Reporting FSCA



A follow-up report should be submitted by the manufacturer to the NRA as per 1100

national legislation. 1101

The follow-up report should provide: 1102

• An update of the progress of reconciliation of the FSCA and estimated 1103

timescales for completion 1104

• Confirmation, where practicable, that users have received the FSN 1105


A final report should be submitted to NRAs of all the countries affected through a 1107

FSCA report, in line with national legislation. This should include information on the 1108

effectiveness of the action per country involved (e.g., percentage of devices that 1109

underwent the FSCA). 1110

If the FSCA includes return of affected stock to the manufacturer or an update of the 1111

instructions for use or a modification/update of existing medical devices on- or off-1112

site, records of completed actions should be fully reconciled against distribution 1113

records in order to maintain control of the progress of the FSCA. 1114

The final report should contain the following information: 1115

• A final assessment of the root cause of the problem and proposed action to 1116

reduce the chance of recurrence, e.g., redesign, update in the field, 1117

improved instructions for use etc. and the progress of the implementation of 1118

such actions; 1119

• The outcome of the reconciliation of the FSCA. 1120


5.2 Field safety notice (FSN) 1122

Field Safety Notices are an important means of communicating FSCA and safety 1123

information to users. They may also be used to provide updated information about 1124

how a medical device should be used. 1125

Manufacturers should inform affected users with copy to the relevant NRAs of any 1126

FSCA via FSN. Affected users will usually receive the FSN via their procurement 1127

agents or through in-country distributors who must inform all users within their 1128

region of supply. To be able to reach out to the affected users, the manufacturer 1129

and the other economic operators need to keep records to allow traceability of the 1130

medical devices to the users. 1131

The manufacturer should ensure that the FSN is distributed to all affected users and 1132

must keep track of confirmation of receipt of the FSN. A full, detailed distribution list 1133

with contact name and (email) address for each intended recipient must be kept and 1134

must be made available to WHO on request for pre-qualified devices. Further 1135

purchasing information requirements are specified in the guidance to ISO 13485 1136

[ref]. 1137

Follow-up

report

Final

report

Purpose

Distribution of FSN

Page 40 of 79

The manufacturer should use a standardized format for an FSN (see example in 1138

Annex 4). The FSN should be written on company letterhead and in English. It may 1139

be translated into required local languages by in-country distributors. 1140

The FSN should include the following items, see also GHTF Medical Devices Post 1141

Market Surveillance: Content of Field Safety Notices (GHTF N57): 1142

• A clear title like "Urgent Field Safety Notice" on the notice itself, and the 1143

subject line, if sent by email; 1144

• The intended audience: clear statement about the intended recipient of the 1145

notice; 1146

• Concise description of product, product code, lot number(s); 1147

• A factual statement explaining the reasons for the FSCA, including description 1148

of the problem; 1149

• A clear description of the hazards associated with the specific failure of the 1150

device and, where appropriate, the likelihood of occurrence, being mindful of 1151

the intended audience; 1152

• The recommended action(s) to be taken by the recipient of the FSN including 1153

any action(s) recommended for people that have previously used or been 1154

treated by affected device, including recalls; 1155

• Where appropriate, include timeframes by which the action(s) should be 1156

taken by the manufacturer and user; 1157

• Designated contact point for the recipient of the FSN to obtain further 1158

information. 1159

The FSN should not include any: 1160

• Comments and descriptions that downplay the level of risk; 1161

• Information that is intended to promote a manufacturer or their product's 1162

market visibility for the purposes of sales and marketing. 1163

It is recommended that manufacturers should provide a draft of the FSN to the NRA 1164

allowing a minimum of 48 hours for comment unless the nature of the FSCA 1165

dictates shorter timescale, e.g., for serious public health threat. 1166

In a very few cases, where an urgent FSCA is needed because of serious safety risks, 1167

the NRA may accept that prior consultation may not be possible. 1168

All types of reports related to complaints (including adverse events) should be kept 1169

on file by the manufacturer. These documents include: the initial, follow-up and 1170

final manufacturer adverse event investigation reports; root cause analysis reports; 1171

corrective action/prevention action plans; FSCA and FSN; and annual post-market 1172

surveillance summary reports. 1173

1174 During the post-market surveillance process, the manufacturer should update the 1175

Risk Management file including: 1176

• Risk analysis; 1177

Content and

format

No misuse

of FSN

Prior consultation

with NRA

Risk management



o intended use and identification of characteristics related to safety of 1178

device 1179

o identification of hazards 1180

o estimation of risks for the hazardous situation 1181

• Risk evaluation 1182

• Risk control 1183

o risk control option analysis 1184

o implementation of risk control measures 1185

o residual risk evaluation 1186

o risk/benefit analysis 1187

o risks arising from risk control measures 1188

o completeness of risk control 1189

• Evaluation of overall residual risk acceptability 1190

• Risk management report 1191

• Production and post-production information. 1192

1193

Vigilance reports and FSCA reports should mention the scope of updates made 1194

as a result of risk management activities. 1195

1196

Figure 4: schematic representation of handling feedback 1197

1198

Receive feedback

Administrative feedback

Technical feedback

Comnplaint?

Recording feedback

Periodic analysis and consider

follow-up actions

Recording feedback

Periodic analysis and consider

follow-up actions

Adverse event?

Ivestigate cause

Action required?

Perform action, eg. FSCA

1199

Page 42 of 79

Part III: MARKET SURVEILLANCE BY NRAs 1200

Overview of responsibilities 1201

Market surveillance is a set of activities conducted by the NRA to ensure that devices 1202

used in their market continue to meet safety, quality and performance requirements. 1203

In certain countries, the NRA may not be capacitated or have legislation to guide 1204

market surveillance activities. In such cases, NRA should be advised to appoint such 1205

person in the absence of legislation within their institution unless the NRA does not 1206

exist. Administrative arrangements can be done within the NRA to facilitate market 1207

surveillance. Certain activities such as ensuring users report feedback, and to receive 1208

and act on FSNs to minimise risk to public safety should be prioritized. 1209

Health authorities, including the NRA should raise awareness among users and 1210

clients/patients about the importance of providing feedback. NRAs should develop a 1211

system embedded with the law to enable receiving of feedback directly from users 1212

and their patients/clients, economic operators and manufacturers. 1213

The NRA should forward all feedback to the manufacturer. NRAs may conduct a risk 1214

assessment to ensure that registered/authorised devices are subject of the feedback, 1215

devices that are not would be considered unregistered and regulatory action may be 1216

undertaken as a result. 1217

The NRA should receive, review and act on vigilance reports received from 1218

manufacturers including via economic operators. The NRA may also receive directly 1219

feedback from users. The NRA oversees investigations undertaken by the 1220

manufacturer as described in the vigilance reports which should include a root cause 1221

analysis and analysis of impact on similar products. The investigation should be 1222

underpinned by risk management principles. 1223

NRAs use a risk-based approach to market surveillance of devices placed on their 1224

market according to a set of risk classification rules. Risk classes A through D were 1225

created for IVDs considering risk to the individual and risk to the public. The level of 1226

regulatory scrutiny will depend on the risk the device presents, risk to the public and 1227

the setting of intended use. 1228

In view of the resources required, a plan for market surveillance should be 1229

promulgated with resource (human and financial) requirements using a risk 1230

management framework. The market surveillance plan might include which devices 1231

will be prioritized for closer surveillance using a risk-based approach, including 1232

sampling intervals and instructions. It should also describe roles and responsibilities, 1233

include elements of monitoring and evaluation, timelines for the various activities 1234

and a budget. 1235

NRAs may establish a mechanism to arrange for testing of devices based on risk in 1236

order to ensure that they continue to meet their quality, safety and performance 1237

Forward post-

market

information

Plan market

surveillance

Risk based

testing

Part III: NRAs


requirements. Such testing should be conducted at a laboratory designated by the 1238

NRA, for the following reasons 1239

• Reactive testing with due cause; 1240

• Proactive testing based on risk management principles. 1241

It is acknowledged that testing capacity to cover all products types may not be 1242

possible or required and that any testing activities be guided by risk management. 1243

As part of the market surveillance plan, testing aspects such as where to collect, how 1244

to collect, who will collect, number of samples to be collected, and where to test 1245

(laboratories, depending on capacity) should be included. 1246

In certain circumstances, the NRA may investigate incidents where suspected 1247

falsified medical devices have been discovered. For-cause testing might also assist 1248

the NRA’s risk assessment for feedback about use of unregistered devices. For 1249

suspected substandard medical devices, the manufacturer is generally best placed to 1250

conduct the investigation as they have the means to trace all users who received the 1251

same or similar product. 1252

The NRA should take regulatory actions, as appropriate, to address any issues 1253

identified through vigilance reports, or through their own market surveillance 1254

activities. This includes overseeing any field safety corrective action undertaken by 1255

the manufacturer. Their ultimate objective is to ensure their citizens are protected 1256

The NRA should appoint a unit as responsible for market surveillance activities 1257

related to medical devices, including -market surveillance information exchange with 1258

other NRAs (confidentiality agreement to be signed). 1259

The implementation of market surveillance measures will depend on the maturity 1260

and capacity of the NRA to handle vigilance reports and notify manufacturers for 1261

their evaluation and action. In the early phases of the development of market 1262

surveillance, WHO can receive feedback from users for WHO recommended 1263

products and ensure that manufacturers are informed so they follow-up accordingly. 1264

Testing activities might be implemented later after vigilance reporting is well 1265

established. Figure 5 describes the various actions undertaken by the NRA. 1266

Figure 5 – Actions of regulators to oversee manufacturer investigation of feedback 1267 1268

Falsified devices

Take regulatory

action

Phased

implementation

Page 44 of 79

1269 1270

1 Forward feedback conduct risk assessment 1271

1272

The NRA may receive feedback directly from users and their clients/patients as 1273

described in Part I. NRAs will forward such feedback onto the manufacturer 1274

immediately. 1275

Upon receipt of feedback, the NRA will conduct a risk assessment to ensure public 1276

safety is immediately protected, which may include the following steps: 1277

1. Check if this product is registered, otherwise authorised for importation. 1278

2. Check the local representative has permission to import the product. 1279

3. Contact health facility where the issue/observation occurred with request 1280

for clarification of any details as required (minimum three attempts to 1281

contact). 1282

4. Determine if quarantine of affected product is warranted, consider a risk-1283

based approach whereby the absence of a device and a defective device is 1284

considered against a functioning device (is something better than nothing, 1285

or vice versa). 1286

5. Inform manufacturer, copy the local representative, as soon as the NRA 1287

become aware. This step may be in parallel or closely times with step 3. 1288

6. Continue dialogue with manufacturer to ensure timelines for their 1289

response(s) are followed. 1290

This step will also allow for enhanced detection of suspected falsified devices. 1291 1292

Forward

feedback

Risk

assessment

Part III: NRAs


2 Collect vigilance reports and oversee investigations 1293

Manufacturers of devices are obliged to report adverse events to the NRA. 1294

For device manufacturers (and other economic operators any observation that 1295

presents a serious public health threat should be reported immediately and not later 1296

than two calendar days of becoming aware to the relevant national regulatory 1297

authorities. 1298

Other adverse events including death or serious deterioration in health occurred or 1299

may have occurred for the patient, d-user or other individual should be reported 1300

within five calendar days of becoming aware to the relevant national regulatory 1301

authorities. 1302

These vigilance reports are a subset of all customer feedback reported by users to 1303

the manufacturer, see Part II. 1304

In brief, the manufacturer evaluates the feedback and determines if risk or harm has, 1305

or may have, occurred. Certain feedback is escalated to a complaint and if classified 1306

as an adverse event then a decision on the need to report to relevant NRAs is made, 1307

according to the national legislation in country of use. The manufacturer initiates a 1308

root cause analysis, and analysis of impact on similar products. 1309

The NRA may receive a series of vigilance reports from the manufacturer that 1310

contains a summary of the steps taken by the manufacturer to investigate the 1311

adverse event and initiate corrections and implement corrective actions. 1312

1. Manufacturer submits an initial manufacturer vigilance report to the NRA, as 1313

soon as the decision on reportability is made (immediately and not later 1314

than two days if serious public health threat, or five days if adverse event 1315

occurred or may have occurred), see also part II. 1316

2. The NRA should review the report for scientific rigor, evidence of 1317

documented procedures, timeliness and rationality. 1318

3. Follow-up manufacturer vigilance reports may be submitted when interim 1319

updates are required but should follow no more than 15 calendar days after 1320

the initial vigilance report is sent. 1321

Where appropriate, the manufacturer may initiate an FSCA which is notified to 1322

affected users through an FSN. The NRA should maintain a repository of FSNs and 1323

make these publicly available on the website. At the completion of the FSCA, the 1324

manufacturer should submit an FSCA report to the NRA. 1325

4. Manufacturer submits a final investigation report to the NRA, preferably 1326

within 15 days of the initial vigilance report or the last follow-up vigilance 1327

report. 1328

The NRA reserves the right to make any reasonable request for clarification of the 1329

investigation undertaken and possibly the conclusions drawn. 1330

The following aspects of the manufacturer’s vigilance and/or FSCA report might 1331

require clarification: 1332

Collect vigilance

reports

Oversee

manufacturer

investigations

Page 46 of 79

• Greater clarity on protocols used for functional testing of retained, and 1333

where possible returned, samples from affected lots; 1334

• Greater clarity of protocols used for physical inspection of retained, and 1335

where possible returned, samples from affected lots; and 1336

• Stability of product (all components) at different temperatures or humidity 1337

(claimed shelf life, in-use stability, shipping stability). 1338

The NRA should also review and determine their acceptability, at their discretion: 1339

• Suggested corrective/preventive actions; 1340

• Suggested actions for customers; 1341

• Risk management file updates. 1342

If the NRA determines that the investigation as detailed in the vigilance report is 1343

unacceptable, they should make these findings in writing to the manufacturer. It is 1344

suggested to present findings in tabular format with the following headings, or 1345

similar: topic, clarification(s), action(s) by manufacturer, etc. Any review of 1346

documentation should focus on evidence of implementation of any written 1347

procedures, and any data integrity concerns. The inspectorate may be requested to 1348

go on-site to review actual records of investigations. 1349

If any issue(s) cannot be accepted and/or resolved through desk review of 1350

documentation, the NRA may decide to take regulatory action until they are 1351

satisfied that product placed on their market does not present any safety issues. 1352

The NRA must be informed of any FSCA as soon as the manufacturer initiates it 1353

usually by sending the draft FSN for review and approval, see annex 4 for an 1354

example field safety notice format. This also applies to FSCA that were initiated 1355

based on user feedback generated in other justifications. 1356

3 Oversee testing 1357

The NRA has a mandate to conduct testing of devices that have been placed on the 1358

market, if appropriate. Annex 7 details how to conduct lot testing for IVDs. 1359

As previously mentioned, it is critical to establish a plan for testing as a market 1360

surveillance activity which is based on risk management. In particular, the better the 1361

user feedback system and the more compliant the quality management system of 1362

the manufacturer, the lesser the need for resource-intensive testing activities. 1363

Elements of the plan for testing as market surveillance include which devices to be 1364

collected based on risk assessment, where to collect, how to collect, who will collect, 1365

number of samples to be collected, where to test (laboratories, depending on 1366

capacity). If a country does not have the capacity to test all types of devices, they 1367

might rely on results generated by certified testing laboratories in other jurisdictions. 1368

Testing conducted by the NRA is not intended to replace the manufacturer’s quality 1369

control (QC) lot testing undertaken throughout the manufacturing process, and at 1370

final release of the product. 1371

NRA follow-up

Quarantine

and store

Part III: NRAs


The NRA should arrange for an appropriate number of samples of devices to be 1372

quarantined and stores according to the manufacturer’s instructions for use, until 1373

testing takes place. 1374

The following types of testing might be requested by the NRA: 1375

• Reactive testing, with due cause when a public health threat presents; 1376

• Proactive testing, without specific cause, to determine on-going compliance 1377

with regulatory requirements based on risk management principles. 1378

For-cause (reactive) testing may be conducted by the NRA when customer feedback 1379

doesn’t accord with the manufacturer’s investigation findings, on a case-by-case 1380

basis. It may also be applied to unregistered products that may have been widely 1381

used. It is considered as reactive market surveillance and may help to determine if 1382

the device in the hands of the user still meets the manufacturer's claims for safety, 1383

quality and performance as stated in instructions for use. Reactive testing provides 1384

additional information to assist the NRA on any decision to take regulatory action of 1385

its own. 1386

For any device that has undergone evaluation of clinical evidence to support safety, 1387

quality, and performance, any proactive testing should be considered using a risk-1388

based approach. 1389

It should be noted that testing of device pre-distribution to users will only provide 1390

information about product at the start of the life cycle when it is expected that well-1391

regulated devices should function according to their specifications. 1392

With the same above assumption, the testing of device post-distribution to users 1393

once they have been in use might bring additional information related to the 1394

fulfillment of the specifications related to stability. 1395

Implementing this post-distribution to user testing might validate if customer 1396

feedback systems are operational as one would expect that users should detect any 1397

adverse events and/or product problems related to use of the product. 1398

This approach to testing will not necessarily be able to detect quality issues if the lot 1399

has not been homogenously produced. Pre-distribution testing cannot detect 1400

stability issues that might lead to degradation of the device during shelf-life, 1401

including all components and accessories. 1402

Samples should be taken by appropriately trained and qualified NRA personnel (or 1403

otherwise delegated agency). Samples should be transported to the testing 1404

laboratory in such a way that the integrity of the devices is not adversely affected 1405

and that the appropriate storage conditions, as specified by the manufacturer, are 1406

maintained., if applicable temperature log monitors should be included within the 1407

transportation packing for the samples. 1408

A risk-based approach should be considered to minimise waste of resources and to 1409

leverage on the previous regulatory assessment decision. 1410

Reactive testing

Proactive testing

Limitations

Sampling

Page 48 of 79

For testing pre-distribution to users, each lot should be sampled initially. After a 1411

certain period of acceptable results (12 months or 10 lots, whichever comes first), 1412

the sampling frame may change from systematic sampling and testing of each lot, to 1413

random sampling of lots delivered to countries. The random sampling frame should 1414

be selected (every 5th lot). If any issue is observed with random pre-distribution 1415

testing, the NRA may elect to re-commence systematic testing of each lot. The 1416

decision about the sampling frame is therefore made using a risk-based approach. 1417

A testing laboratory should be identified to perform testing and should: 1418

• Be mandated by national authorities to perform testing for market 1419

surveillance of devices, and therefore have enough resources to conduct lot 1420

testing; 1421

• Strive to adhere to internationally recognized quality standards, e.g., ISO 1422

17025: General requirements for the competence of testing and calibration 1423

laboratories; 1424

• Participate in external quality assessment (EQA) schemes and act on results, 1425

as required. 1426

In this guidance, testing is generally comprised of two elements: 1427

• Physical examination, and 1428

• Functional testing. 1429

All samples should be physically examined, and any observations recorded. 1430

• Packaging, including defective components, defective devices, devices 1431

damaged prior to use, damage to the materials used to construct the cover or 1432

outer packaging of the device, compromised decontamination of the device, 1433

one or more of the listed components is missing. 1434

• Label, instructions for use or training problems, including inadequate 1435

instructions to the user and their patients/clients; unclear, missing, worn out, 1436

incorrect or inaccurate labels. 1437

• Material integrity problem, including broken, cracked, degraded, deformed, 1438

disintegrated, split/cut/torn, scratched materials/components. 1439

NRAs should apply international standards in force for the respective category of 1440

medical devices. 1441

The testing laboratory should present results in the report which would be sent to 1442

the requesting NRA. 1443

Figure 6 – Actions of regulators for testing in the context of market surveillance 1444

1445

Testing

laboratory

Physical

examination

Functional

testing

Part III: NRAs


1446

1447

4 Collect other post-market information 1448

If sentinel surveillance sites are established, these sites can collect information on 1449

safety, quality and performance of devices. 1450

If national device registries, mainly for implanted or other high-risk devices, are kept, 1451

this can provide useful information to detect signals. 1452

Post-market evaluation conducted by NRAs or other designated authority, this 1453

becomes post-market performance follow-up (in the context of IVDs). 1454

For all the above, the NRA passes the information to manufacturer from them to act 1455

upon. 1456

5 Decide if additional regulatory action is required 1457

Depending on the risk/benefit posed by an adverse event or product problem 1458

discovered in the post-market phase and/or potential for future harm, NRAs should 1459

consider the following possibilities8: 1460

• No action; 1461

• Perform additional surveillance of the device concerned in use; 1462

• Issue a safety alert giving advice to users; 1463

• Require the manufacturer to make appropriate changes in the design, 1464

manufacturing process or information/labelling supplied with the device; 1465

8 This list does not purport to be definitive and each case should be handled individually.

Sentinel sites

Signal detection

Post-market

evaluation

Page 50 of 79

• Mandate (enforce and monitor) a field safety corrective action (for example a 1466

device recall/withdrawal); 1467

• Send the data acquired to the manufacturer and store it in a database to help 1468

identify trends that require action. 1469

NRAs are required to prioritize regulatory action using the following questions: 1470

1. How much product was supplied? 1471

2. Where product is located? 1472

3. Remaining shelf life for product? 1473

4. Percentage of product remaining (if reagents, accessories, consumables)? 1474

5. Is the manufacturer providing timely updates on progress of recall? 1475

6. Is there an alternative product for users? 1476

NRA may request users to quarantine of product while the decision on 1477

recall/withdraw is made by the manufacturer. Only once the observation is 1478

confirmed at proceed to support manufacturer’s FSCA. 1479

NRA send out staff to look for products noted in a given FSCA. 1480

Economic operators must assist the manufacturer to conduct the recall. Therefore, 1481

any agreement for key suppliers should note that economic operator should help 1482

with FSCA. Centralised warehouses and other governmental storage facilities might 1483

also have a role would have distribution records that are useful to located affected 1484

users. 1485

Timelines should set for FSCAs to be closed-out. 1486

6 Share information 1487

Certain information should be made publicly available, including a searchable list of 1488

products that meet regulatory requirements (or are otherwise approved for 1489

importation). NRAs may consider making a searchable list of products that have 1490

been withdrawn/terminated/cancelled from the market publicly available, especially 1491

if they might present a serious risk to public health. 1492

All field safety notices for registered products should be maintained in repository by 1493

the NRA, if possible searchable list online. NRAs might offer an email subscription 1494

service whereby users can receive alerts on a current FSNs. 1495

IMDRF publishes a table that provides links to device safety information as published 1496

by IMDRF NCAR Exchange Members http://www.imdrf.org/safety/safety.asp 1497

Annex 5 provides an information exchange reporting form should be used by NRAs 1498

for sharing post-market data gathered through market surveillance. The reporting 1499

forms should be completed and the vigilance report and/or FSCA report and FSN 1500

attached. This is built on IMDRFs “Medical Devices: Post Market Surveillance: 1501

National Competent Authority Report Exchange Criteria and Report Form” 1502

(IMDRF/NCAR WG (PD1)/N14R4). 1503

http://www.imdrf.org/safety/safety.asp

Part III: NRAs


The IMDRF NCAR system is a way for NRAs to exchange confidential information 1504

about safety, quality and performance of devices where there is an anticipated or 1505

unanticipated serious public health threat, defined as: 1506

• Death of a patient, user or other person 1507

• Serious injury of a patient, user or other person 1508

• No death or serious injury occurred but the event might lead to death or serious 1509

injury of a patient, user or other person if the event recurs. 1510

Certain NRAs might request confidentiality agreements for such sharing of 1511

information, but the objective of the exchange is to ensure that information can be 1512

acted upon by the receiving NRA. 1513

This programme is used to exchange early information on significant concerns or 1514

potential trends that individual NRAs have observed, but that have not yet resulted 1515

in FSCA or recall. 1516

NRAs reserve the right to directly contact the manufacturer for additional 1517

information such as vigilance reports and/or FSCA report, and FSNs. 1518

1519

Page 52 of 79

1520

PART IV: SPECIFIC REQUIREMENTS FOR PRODUCTS 1521

RECOMMENDED BY WHO 1522

1 Role of WHO 1523

WHO makes recommendations on products based on the following forms of quality 1524

assurance procedures: 1525

• WHO prequalification 1526

• WHO Emergency Use Listing 1527

• Other products recommended/procurement by WHO. 1528

The findings of WHO Prequalification9 and Emergency Use Listing are used to 1529

provide independent technical information on safety, quality and performance of 1530

IVDs and other medical devices, principally to other United Nations (UN) agencies 1531

but also to WHO Member States and other interested organizations. 1532

WHO collects feedback on WHO recommended devices and oversees the evaluation 1533

and investigation conducted by the manufacturer. Manufacturers should report to 1534

WHO in the form of manufacturer vigilance reporting form as per Annex 2. 1535

Manufacturers of WHO recommended devices agree, and as a condition of WHO 1536

prequalification, to undertake the following post-market surveillance actions: 1537

• Actively encourage users and their patients/clients to report any feedback 1538

related to use of a device to manufacturers so that action can be taken, if 1539

needed. 1540

• Notify WHO of any problems relating to the product10 that have affected (or 1541

could have affected) the performance of the device, safety of the client, 1542

users, or any person associated with the product. 1543

• Any adverse event should be reported to WHO within 7 days of the 1544

manufacturer becoming aware. 1545

• WHO will request that the manufacturer provide further information 1546

relating to the incident, including details of the root cause analysis, any 1547

analysis of impact on similar products, any corrections made, and any 1548

correction action proposed. 1549

• Notify WHO of all events that require FSCAs such as withdrawal of devices 1550

from sale or distribution, physical return of a device to the manufacturer, 1551

device exchange, destruction of the device, device modification/s or 1552

9 Prequalification does not imply any approval by WHO of the product and manufacturing site(s).

Moreover, prequalification does not constitute any endorsement or warranty by WHO of the fitness of any product for a particular purpose, including its safety, quality, or performance.

10 Issues related to abnormal use do not need to be reported (see page 22 for details).

Beneficiaries

Reporting

investigation

finding

Part III: NRAs


additional advice provision to customers to ensure that the device continues 1553

to function as intended. 1554

• Submit information concerning all complaints, including any FSCA, carried out 1555

in the previous calendar year as part of the mandatory annual summary 1556

reporting. 1557

• Note: These actions do not replace the responsibilities of the manufacturer to 1558

report to NRA’s, see part 3. 1559

The outcomes of certain vigilance reports are notified through post-market 1560

information exchange to other NRAs and procurers/implementing partners such as 1561

non-governmental organizations as per Annex 5. WHO may act with regard to WHO 1562

recommended devices, as appropriate, including: 1563

• Post-market surveillance information exchange with NRAs 1564

• Publishing safety notices on WHO's website 1565

• Performance of additional surveillance of the device concerned 1566

• Removal of the product from the list of WHO recommended products (WHO 1567

prequalified devices, EUL, etc.), if needed 1568

• Inspection of manufacturing site to ensure that CAPA as a result of any 1569

complaint have been implemented. 1570

1571

Where WHO believes that the FSN does not fully meet the requirements as 1572

described in this document and explain the risk and how it will be removed/reduced, 1573

WHO may issue its own safety or advisory notice and send it to the relevant NRAs 1574

for further dissemination to users. 1575

1576

For recommended devices, WHO reserves the right to issue information notices for 1577

users in certain circumstances: if the manufacturer has not undertaken an 1578

appropriate FSCA within an appropriate time frame, if the manufacturer has not 1579

disseminated an appropriate FSN, and to give information to users about how to 1580

interpret the contents of FSN. WHO information notices may include any 1581

recommendations to programmes and implementing partners for alternative testing 1582

arrangements and to procurers for past, on-going or future purchase orders of 1583

affected or potentially affected products. 1584

1585 Figure 7 – Flow chart for reporting complaints related to WHO recommended 1586 devices1587

WHO safety

advisory notices

WHO

information

notices

Page 54 of 79

1588

1589 1590

1591

WHO reviews feedback

Sufficient information, feedback proceeds

Insufficient information, WHO request additional information

WHO sends feedback form to manufacturer

WHO informs relevant stakeholders

Manufacturer conducts investigation, if needed

Manufacturer submits initial report to WHO

Manufacturer submits FSCA report to WHO

Manufacturer submits draft FSN to WO for review/approval

Manufacturer issues FSN to affected users.

Manufacturer submits final investgation report to WHO

Feedback submitted to WHO

Draft

Annex 4: Adverse Event Manufacturer Investigation Reporting Form


Bibliography 1592

1.1 Reference documents 1593

The following reference documents have been used in preparing this document. Some documents 1594

are dated when a reference is made to a specific clause in that standard. Notwithstanding the 1595

reference to a clause, readers are encouraged to use the latest version of documents. 1596

Medical device post-market surveillance 1597

• EN 13975: 2003 Sampling procedures used for acceptance testing of in vitro diagnostic 1598

medical devices – Statistical aspects 1599

• ISO 9000:2005 Quality management systems — Fundamentals and vocabulary 1600

• ISO 13485:2016 Medical devices — Quality management systems — Requirements for 1601

regulatory purposes 1602

• ISO 13485:2016 Medical Device — A practical guide, Advice from ISO/TC210 1603

• ISO 14971:2019 Medical devices — Application of risk management to medical devices 1604

• ISO TR 20416: 2020 Medical devices — Post-market surveillance for manufacturers 1605

• ISO/TR 24971:2020 Medical devices — Guidance on the application of ISO 14971 1606

• ISO 15189: 2015 Medical laboratories — Particular requirements for quality and competence 1607

• ISO 17025: 2018 General requirements for the competence of testing and calibration 1608

laboratories 1609

Medical device vigilance 1610

• WHO Global Model Regulatory Framework for Medical Devices including in vitro diagnostic 1611

medical devices, WHO Medical device technical series, 2017 1612

• REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 1613

2017 on medical devices 1614

• REGULATION (EU) 2017/746 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 1615

2017 on in vitro diagnostic medical devices 1616

• GHTF/SG2/N54R8:2006 Medical Devices Post Market Surveillance: Global Guidance for Adverse 1617

Event Reporting for Medical Devices 1618

• GHTF/SG2/N008R4:1999 Guidance on How to Handle Information Concerning Vigilance 1619

Reporting Related to Medical Devices 1620

• GHTF/SG2/N57R8:2006 Medical Devices Post Market Surveillance: Content of Field Safety 1621

Notices 1622

• GHTF/SG3/N15R8:2005 Implementation of risk management principles and activities within a 1623

Quality Management System 1624

• MEDDEV 2 12-1 rev. 8 Vigilance European Commission Guidelines on a medical devices vigilance 1625

system 1626

Page 56 of 79

• IMDRF/NCAR WG (PD1)/N14R4 Medical Devices: Post Market Surveillance: National Competent 1627

Authority Report Exchange Criteria and Report Form” 1628

• GHTF SG2-n87-2012-xml-schema-electonic-transfer-adverse-event-data 1629

• GHTF/SG2/N36R7:2003 Manufacturer's Trend Reporting of Adverse Events 1630

• IMDRF/AE WG/N43 FINAL:2020 (Edition 4) IMDRF terminologies for categorized Adverse 1631

Event Reporting (AER): terms, terminology structure and codes 1632

• GHTF/SG3/N18:2010 Guidance on corrective action and preventive action and related QMS 1633

processes 1634

• GHTF/SG1/N071:2012 Definition of the Terms ‘Medical Device’ and ‘In Vitro Diagnostic (IVD) 1635 Medical Device’ 1636

• ISO 14199:2015 Health informatics — Information models — Biomedical Research 1637

Integrated Domain Group (BRIDG) Model 1638

1639

1640

1641

Draft



Annex 1 – Device Feedback Reporting Form 1642

PROVIDING FEEDBACK TO MANUFACTURERS ON MEDICAL DEVICES INCLUDING IVDS 1643

For device end-users – all types of feedback should be reported to the manufacturer (and local 1644

authorized representative) as soon as you become aware. You can find manufacturer’s contact 1645

details in the instructions for use. 1646

Providing feedback to the manufacturer is a critical role for users of medical devices. 1647

Adverse events may be:

• Death of the patient, end-user or any other person occurred or may have occurred

• Serious deterioration in health of the patient, end-user or any other person occurred or may have occurred

For IVDs:

• A false negative result

• A false positive result

• Non-reproducible results

• High or low readings, high- or low-test results

Product problems may be:

• Packaging – damaged, defective, suspect tampered

• Labelling– insufficient instructions for use, illegible

• Sampling – device doesn’t collect/transfer specimen

• Liquid – leak, splash

• Mechanical – misalignment, jam

• Electrical - unable to charge, power loss or fluctuation

• Data – capture, display, or storage affecting product functionality

• Software – network, program, algorithm, or security affecting product functionality

• Environmental – noise, temperature, humidity/ moisture, fungal/bacterial growth, or dust affecting product functionality

• Failure to calibrate

• Increased rate of invalid or unreturnable test results

• Obviously incorrect, inadequate or imprecise result or readings

• Unable to obtain reading

Note: this is not an exhaustive list of feedback that should be reported to the manufacturer

1. Contact details of the reporting organization/person 1648

Name of organization: Street Name and No.:

City and postcode: Country:

Name of contact person (for organization): Mobile telephone of contact person (for organization):

Position of contact person (for organization): Email of contact person (for organization):

Report date: Reporter’s report identifier:

Safe reporting: would you be willing to be contacted by the manufacturer for additional information? Be 1649 assured that reporting feedback is not an act of omission. 1650 1651 1652 1653

Page 58 of 79

2. Product details 1654

Product name/commercial name/brand name:

Product code/catalogue number(s):

Serial number(s): Model number(s):

Lot number/batch number(s): Expiry date(s):

Associated devices/accessories (lot numbers/expiry dates):

Instructions for use version number:

Authorized representative name:

Manufacturer name:

Authorized representative contact details (e-mail or telephone):

Manufacturer contact details (e-mail):

Please attach a copy of the instructions for use and photographs of the device and its labelling. 1655 1656 3. Event details 1657

1658

1659

1660

Event description (explain what went wrong with the medical device, and what was the health impact [death, life-threatening, indirect harm such as misdiagnosis or delayed diagnosis/treatment]).

Date of the observation/event:

% of device involved:

Number of devices involved:

Number of patients involved:

Operator/user at the time of the event/problem (please choose): ❑ Healthcare professional ❑ Patient/lay user ❑ Other (specify):

Has more than one user experienced the problem with the product? ❑ Yes ❑ No

Comments:

Date of report: Signature:

Disclaimer: The act of reporting an event is not an admission of manufacturer, user or patient liability for the event or

its consequences. Submission of an adverse event report does not, in itself, represent a conclusion by the

manufacturer that the content of this report is complete or confirmed, that the device(s) listed failed in any manner. It

is also not a conclusion that the device caused or contributed to the adverse event.

Draft



Annex 2– Manufacturer Vigilance Reporting Form 1661

For manufacturers (or their economic operator) – adverse events that represent a serious public 1662

health threat should be reported immediately and not later than 2 calendar days to the relevant 1663

NRAs and to WHO (e-mail: [email protected]). 1664

1665

For manufacturers (or their economic operator) - other adverse events including death or serious 1666

deterioration in health occurred or may have occurred for the patient, end-user or other individual 1667

should be reported within 5 days to the relevant NRAs and to WHO (e-mail: [email protected]). 1668

1669 MANUFACTURER VIGILANCE REPORTING FORM 1670

1671

Send to: 1672 Relevant National Regulatory Authorit/ies and 1673

World Health Organization, 20 Avenue Appia CH-1211, Geneva 27 Switzerland 1674 Email: [email protected] 1675

1. Report details 1676

Name of recipient organization (name of NRA):

Street Name and No.:

City and postcode:

Country:

Telephone:

Name and position of recipient contact person:

Email of contact person:

Identifier assigned by the manufacturer:

Report identifier assigned by NRA:

Date of this report:

Type of report:

□ Initial report

□ Follow-up report

□ Combined initial and final report

□ Final report

State any other NRAs who were also sent this report:

1677

Page 60 of 79

2. Reporter details 1678

Name of reporting manufacturer:

Street Name and No.: City and postcode:

Country: Telephone:

Name of contact: E-mail of contact:


Product name:

Product code/catalogue number(s):

Lot number/batch number/serial number(s):

Expiry date(s):



Please attach a copy of the instructions for use. 1680

4. Event/problem details 1681

Draft



Where observation/event happened:

Date(s) observation/event happened:

Date feedback reported to manufacturer (and/or economic operator) by user:

Event/problem description narrative (explain what went wrong with the product, and a description of the health effects [if applicable], i.e. clinical signs, symptoms, conditions as well as the overall health impact [death, life-threatening, indirect harm]), and the health/medical condition for which the device was being used):

IMDRF Medical device problem code(s) (annex A):

User at the time of the event/problem (please choose):

❑ Healthcare professional/lay provider ❑ Patient/client

❑ Other (specify):

Has more than one user experienced the problem with the product?

□ Yes □ No

Number of devices involved:

Number of patients involved:

IMDRF Clinical Sign Codes (annex E);

IMDRF Health impact codes (annex F):

5. Manufacturer’s preliminary comments (initial/follow-up reports) 1682

Manufacturer’s preliminary analysis of event:

IMDRF Type of Investigation (annex B):

IMDRF Investigation Findings (annex C):

Initial correction implemented by manufacturer:

Expected date of next report:

6. Results of the final investigation (final report) 1683

Page 62 of 79

Manufacturer’s analysis of event:

Any additional IMDRF Type of Investigation (annex B):

Any additional: IMDRF Investigation Findings (annex C):

IMDRF Investigation Conclusion (annex D):

Any additional corrections implemented by manufacturer: :

Corrective action/preventive action implemented by manufacturer:

Field safety corrective action by manufacturer:

Date field safety notice issued:

Field safety notice identifier:

Time schedule for implementation of the identified actions:

Final comments from the manufacturer:

Further investigations, including analysis of other impacted areas:

Is the manufacturer aware of similar events with this device with a similar root cause?

□ Yes □ No

If yes, state in which countries: If yes, number of similar incidents:

State which countries this report has been disseminated to:

7. Signature 1684

Name:

Signature:

Date:

Draft

Annex 5: Field Safety Corrective Action Reporting Form


Annex 3 – Field Safety Corrective Action Report 1685

FIELD SAFETY CORRECTIVE ACTION REPORT 1686

Send to: 1687 Relevant National Regulatory Authorities 1688

World Health Organization, 20 Avenue Appia CH-1211, Geneva 27, Switzerland 1689 Email: [email protected] 1690

1. Report details 1691

Date of this report:

Type of report:

□ Initial report

□ Follow-up report

□ Final report

FSCA reference number assigned by NRA:

Name of recipient organization:

Name of contact person:


Street and No.:

City and postcode:

Country:

Telephone:

2. Reporter details 1692

Name of manufacturer:

Street and No.:

City and postcode:

Country:

Telephone:



Identifier assigned by the manufacturer:

Page 64 of 79


Product name:

Product code (catalogue number):

Lot number/batch number/serial number:

Expiry date:



Please attach a copy of the instructions for use. 1694

4. FSCA description 1695

Background information and reason for the FSCA:

Description and justification of action (corrective/preventive):

Date feedback reported by manufacturer:

Advice on actions to be taken by distributor and the user:

Field Safety Notice attached:

□ Yes □ No

Status of FSN:

□ Draft □ Final

Time schedule for implementation of different actions:

List of countries this FSCA has been distributed to:

5. Comments 1696

6. Signature 1697

Name:

Signature:

Date:

1698

Draft

Annex 6: Example Field Safety Notice


Annex 4 – Example Field Safety Notice 1699

URGENT FIELD SAFETY NOTICE 1700

Product name: [insert name of the affected product] 1701

FSCA-identifier: [insert] 1702

Type of action: [e.g., return of device to supplier, device modification (including instructions for use), 1703

device exchange, device destruction, retrofit of device by purchaser of manufacturers modification 1704

or design change, advice given by manufacturer regarding use of the device and/or follow-up of 1705

patients, users, or others]. 1706

--------------------------------------------------------------------------------------------------------------------------- 1707

Date: dd/mm/yyyy 1708

Attention: [insert intended audience] 1709

Details on affected device: 1710

[Specific details to easily identify the affected device, e.g., product name, product code, lot number] 1711

Description of the problem: 1712

[A factual statement explaining the reasons for the FSCA, including description of the problem and a 1713

clear description of the potential hazard associated with the continued use of the MC device and the 1714

associated risk to the patient, user or other person.] 1715

Advice on action to be taken by the user: [include, as appropriate] 1716

• Identifying and quarantining the device; 1717

• Method of recovery, disposal or modification of device, including instructions for use and 1718

labelling; 1719

• Recommended patient follow-up; 1720

• Timelines; 1721

• Confirmation form to be sent back to the manufacturer. 1722

The above recommended action(s) are to be taken by all recipients of this FSN, including action(s) 1723

recommended for people that have previously used or been treated by affected devices. 1724

Transmission of this Field Safety Notice: [as appropriate] 1725

This notice needs to be passed on all those who need to be aware within your organization or to any 1726

organization where the potentially affected product has been transferred. Please be aware of this 1727

notice and resulting action for an appropriate period to ensure effectiveness of the corrective action. 1728

Contact person for further information: 1729

[Insert name, organization, address, contact details] 1730

The undersigned confirms that this notice has been notified to the appropriate National Regulatory 1731

Authorities. 1732

Signature: 1733

Page 66 of 79

Annex 5 – Post-Market Information Exchange Reporting Form for NRAs

Post-Market Information Exchange Reporting Form for NRAs

1. Report details

NRA report number:

Purpose of exchange:

□ Share information

□ Events leading or highly likely to lead to unanticipated public health threat

□ Observations from national trend analysis

□ Request information

□ Summary of query findings

Confidentiality: □ Yes □ No

Draft


2. Initiating NRA

Name of NRA:



Street and No.:

City and postcode:

Country:

Telephone:

3. Product details

Product name:

Product code (catalogue number):

Lot number/batch number/serial number:

Expiry date:



Manufacturer name:

Street and No.:

City and postcode:

Country:

Telephone:



Please attach a copy of the instructions for use.

4. Background information

Background information and reason for this report:

Is the investigation of the report completed?

□ Yes □ No

Attachments [insert FSN, FSCA reports etc.]:

□ Yes □ No

Page 68 of 79

5. Additional remarks

6. Details of responding NRA

Name of NRA:



Street and No.:

City and postcode:

Country:

Telephone:

7. Signature

Name:

Signature:

Date:

Draft


Annex 6 – Recommendations for specific end-user groups

Clinical laboratories For clinical laboratories, feedback from users (technicians and clinical analytical experts) will either be

related to technical operation of the analysers or to the results obtained.

If feedback relates to results obtained, these data should be made available to the manufacturer,

allowing the manufacturer to perform an investigation into the issue. It is also important to provide

details on the lot numbers of the consumables involved, and preferably, some samples will be kept apart,

to facilitate further investigation by the manufacturer.

Hospitals/Health care facilities As a lot of medical devices are mostly used in health care facilities, it is important for the manufacturer

to obtain feedback from the users in the healthcare facilities. Preferably, the manufacturer or other

economic operators involved, will discuss providing feedback as part of the purchase or even contracts.

The health care facilities should also consider how data they have can be made available to the

manufacturer. The manufacturer on the other hand should be aware that health care professionals have

limited time available and providing feedback other than incidents or adverse event, should be made as

easy as possible.

Primary care

See health care facilities. As primary care facilities will be relatively small, there will be limited staff

available to invest time in a system to provide systematic feedback to the manufacturer. The sales force

might be one of the best ways to obtain feedback from primary care facilities.

Self-testing Self-testing is most often performed the individual on themselves.

If observations are made during the performance of the test, not expert will be available to assist the

user. And as such tests are often purchased in drugstores or supermarkets, it is unlikely that sufficient

expertise is available there. Therefore, for feedback or advice, the labelling of the self-test shall contain

the contact details of the manufacturer or the distributor.

Implants Artificial intelligence

Page 70 of 79

Annex 7 – Lot testing for IVDs

1. Rationale

The NRA has a mandate to conduct testing of devices in their market place, if

appropriate.

Lot testing conducted by the NRA is not intended to duplicate the manufacturer’s quality control (QC)

lot testing undertaken throughout the manufacturing process, and at final release of the product.

Release of the product is the mandate of the manufacturer.

Despite the manufacturers’ obligation to test each lot during production and at release,

variations in the characteristics of each lot may occur due to differences in the lots of

key components (starting materials) used, different personnel involved in production

processes, variations in manufacturing processes, and a range of other variables.

For an IVD, lot sizes are varied, depending on how the manufacturing site configures their

operations. The EU standard EN 13975: 2003 Sampling procedures used for acceptance

testing of in vitro diagnostic medical devices – Statistical aspect defines the term lot as

follows: “A defined amount of material that is uniform in its properties and has been

produced in one process or series of processes. The material can be either starting

material, intermediate material or finished product”. In the context of these guidelines,

lot testing is focused on a commercially available test kit which is provided with a

unique lot number and where the single components are matched to this kit, e.g. micro-

plate or nitrocellulose membrane, antigen, conjugate, specimen diluent, etc.

For-cause lot testing conducted by a testing laboratory under the auspices of the NRA.

Pre-distribution (but post-shipment to country) as proactive market surveillance should

be considered using a risk-based approach. Its aim would be to ensure lot-to-lot

consistency against a baseline (reference) lot.

With the same above assumption, the testing of device post-distribution to users once

they have been in use might bring additional information related to the fulfillment of

the specifications related to stability.

Implementing this post-distribution to user testing might validate if customer feedback

systems are operational as one would expect that users should detect any adverse

events and/or product problems related to use of the product.

What is

meant by

“lot”?

Draft


1.2 Limitations

This approach to lot testing will not necessarily be able to detect quality issues if the lot

has not been homogenously produced. Pre-distribution lot testing cannot detect

stability issues that might lead to degradation of the product during shelf-life, including

all components and accessories.

1.3 Method

Samples should be taken by appropriately trained and qualified NRA personnel (or

otherwise delegated agency) from central medical stores (or similarly centralized

warehousing facility) for pre-distribution to users testing, and from user sites for post-

distribution to users testing. Samples should be transported to the reference testing

laboratory in such a way that the integrity of the test kits is not adversely affected and

that the appropriate storage conditions, as specified by the manufacturer, are

maintained. Temperature log monitors should be included within the transportation

packing for the samples.

A risk-based approach should be considered to minimise wastage of resources and to

leverage on the previous regulatory assessment decision.

For testing pre-distribution to users, each lot should be sampled initially. After a certain

period of acceptable results (12 months or 10 lots, whichever comes first), the sampling

frame may change from systematic sampling and testing of each lot, to random sampling

of lots delivered to countries. The random sampling frame should be selected (every 5th

lot). If any issue is observed with random pre-distribution lot verification testing, the NRA

may elect to re-commence systematic testing of each lot. The decision about the sampling

frame is therefore made using a risk-based approach.

Testing post-distribution to users carries a different risk as the product has already been

in use and depending on the through-put of the user site, it may or may not be close to its

expiry date. Therefore, the sampling frame does not need to include every lot delivered to

country but should rather be conducted twice per year.

A reference laboratory should be identified to perform lot testing and should:

Be mandated by national authorities to perform testing for market surveillance of devices,

and therefore have enough resources to conduct lot testing;

Strive to adhere to internationally recognized quality standards, e.g., ISO 15189: Medical

laboratories — Particular requirements for quality and competence or ISO 17025: General

requirements for the competence of testing and calibration laboratories;

Participate in external quality assessment schemes (EQAS), and act on results, as required.

Sampling

Sampling

frame

Reference

laboratory

Page 72 of 79

The staff performing the lot testing should be qualified and competent to undertake the

task and to demonstrate that they can perform the test procedure correctly.

The technical supervisor should:

• Ensure that technicians are blinded to the reference test results for the lot testing panel by

assigning the specimen vials with codes;

• Supervise the performance of the testing;

• Ensure that the testing results of subjectively read test kits are read independently by two

technicians;

• Collate the readings from each technician and sign off the data collection sheets at the end of

each testing day;

• Transcribe or verify that correct transcription of final results of lot testing into the testing report

to be provided to the NRA.

The technicians should:

• Perform the procedure according to the manufacturers’ instructions for use;

• Record any readings on the data collection sheet; and

• Store all data collection sheets in a folder.

The supervisor and technicians should not proceed with testing until they are confident regarding every

aspect of the testing procedure.

Quality assurance measures must always be in place and be adhered to.

The reference laboratory (in conjunction with the user) should be able to undertake an investigation of

perceived issues to eliminate all other possible causes that are not test kit-related (i.e. user-related,

poor quality assurance measures).

Lot testing is comprised of two elements:

• Physical examination, and

▪ Functional testing against a panel of well-characterized specimens, if IVDs, or a

recognized method, for other devices.

1.4 Physical examination

All samples should be physically examined, and any observations recorded.

• Packaging, including defective components, defective devices, devices damaged prior to

use, damage to the materials used to construct the cover or outer packaging of the device,

Testing staff

competencies

What is lot testing?

Draft


compromised decontamination of the device, one or more of the listed components is

missing.

• Label, instructions for use or training problems, including inadequate instructions to the

user and their patients/clients; unclear, missing, worn out, incorrect or inaccurate labels.

• Material integrity problem, including broken, cracked, degraded, deformed, disintegrated,

split/cut/torn, scratched materials/components.

1.5 Functional testing

• Sampling – device doesn’t collect/transfer specimen

• Liquid – leak, splash

• Mechanical – misalignment, jam

• Electrical - unable to charge, power loss or fluctuation

• Data – capture, display, or storage affecting product functionality

• Software – network, program, algorithm, or security affecting product functionality

• Environmental – noise, temperature, humidity/ moisture, fungal/bacterial growth, or dust affecting

product functionality

• Failure to calibrate

• Increased rate of invalid or unreturnable test results

• Obviously incorrect, inadequate or imprecise result or readings

• Unable to obtain reading

For testing IVDs, a set of clinically-derived reference specimens are constructed into a panel. Detail on

preparation of specimen panels and lot verification testing by the reference laboratory. The testing

should be conducted on a standardized panel.

1.6 Reporting testing results

The reference testing laboratory should present results in the report as defined in Annex 2 which would

be sent to the requesting NRA. The testing should be carried out using the same standardized panel as

the pre-distribution lot testing.

2 Collect other post-market information

Other sources of data on the quality and performance of IVDs on the market include external quality

assessment schemes (EQAS), also known as proficiency testing, and from quality control (QC)

programmes.

Where it exists, the data generated by an EQAS can be assessed. Although the primary

purpose of EQAS is inter-laboratory comparison, these data can provide very useful

information about the performance of IVDs.

EQAS

Page 74 of 79

EQAS data analysis may indicate not only operator-related errors (for example

transcription errors), but also errors related to the test itself, especially if large numbers

of laboratories/testing sites are using the same test kit.

A QC specimen is a specimen that has reactivity that is just above the cut-off for positivity

of a test kit. It is usually a manufactured specimen that is optimized for the test kit and

may be provided by a national authority to all laboratories/testing sites using the test kit

as part of a QC programme. All attempts should be made to procure and distribute QC

material to any site undertaking testing QC specimens should be tested in each test run

(for an immunochromatographic RDT, no more- than 10 tests per run). The results of

QC specimens can be graphically represented and results outside a pre-determined

acceptance range identified and investigated. This approach is typically not all that

useful for RDTs that generally are used in settings outside of the laboratories without

test kit controls and external QC specimens.

If sentinel surveillance sites are established, these sites could collect information on

safety, quality and performance of IVDs.

Model certificate of analysis for in vitro diagnostic medical devices (IVDs) Background A model certificate of analysis (CoA) is used by manufacturers of in vitro diagnostic medical devices (IVDs) to report the results of the final quality control for lot release, and state that the lot complied with the specifications stated in the instructions for use for the IVD. It may also be used by quality control laboratories that act on behalf of national regulatory authorities to conduct market surveillance. The items included are based on Technical Guidance Series for WHO Prequalification – Panels for quality assurance and quality control of in vitro diagnostic medical devices11, WHO guidance of post-market surveillance of in vitro diagnostics12, and WHO guidance for procurement of in vitro diagnostics and related laboratory items and equipment13. In addition, requirements of the International Standards Organization General requirements for the competence of testing and calibration laboratories - ISO/IEC 41 1702514 have been considered.

11 World Health Organization. Technical Guidance Series (TGS) for WHO Prequalification – Diagnostic Assessment. Panels for quality assurance and quality control of in vitro diagnostic medical devices (TGS-6). WHO/EMP/RHT/PQT/2017.10 http://apps.who.int/iris/bitstream/handle/10665/259408/WHO-EMP-RHT-PQT-2017.10-eng.pdf?sequence=1 12 World Health Organization. WHO guidance of post-market surveillance of in vitro diagnostics. 2015. ISBN 978 92 4 150921 3 http://apps.who.int/iris/bitstream/handle/10665/255576/9789241509213-eng.pdf?sequence=1 13 World Health Organization. Guidance for procurement of in vitro diagnostics and related laboratory items and equipment. 2017. 1SBN: 978-92-4-151255-8 http://apps.who.int/iris/bitstream/handle/10665/255577/9789241512558-eng.pdf;jsessionid=0BDFCB639EE408EC6686EA0DEEE73F2D?sequence=1 14 International Organization for Standardization. General requirements for the competence of testing and calibration laboratories. ISO/IEC 17025:2005.

QC

Sentinel sites

Draft


If any specific legal requirements exist in the country of issue or importation they should be respected when issuing the certificate.

Page 76 of 79

Table 1 outlines the specific elements for physical inspection and function testing for different assay formats.

Physical inspection Panel functional testing

Rapid diagnostic tests (RDTs)

secondary packaging primary packaging desiccant buffer vials specimen transfer devices lancets alcohol swabs, etc.

• 3 replicates of 5 positive serum/plasma specimens near to the cutoff claimed by the manufacturer;

• 3 replicates of 5 negative serum/plasma specimens;

• 3 replicates of 5 positive whole blood specimens; near to the cutoff claimed by the manufacturer;

• 3 replicates of 5 negative whole blood specimens.

Immunoassays (IAs)

secondary packaging primary packaging reagent vials, etc.

• 3 replicates of 5 positive serum/plasma specimens; near to the cutoff claimed by the manufacturer;

• 3 replicates of 5 negative serum/plasma specimens.

Nucleic acid testing (NAT) assays - quantitative


For IVDs used in a laboratory (conventional platform)15:

• 25 replicates at LoD claimed by manufacturer;

• 25 replicates at 2x LoD claimed by manufacturer;

• 25 replicates of 1000 copies/ml;

• 5 replicates of 10,000 copies/ml;

• 4 replicates of negative (normal human plasma). For IVDs used at point of care: Same as above.

Nucleic acid testing (NAT) assays - qualitative


For IVDs used in a laboratory (conventional platform):



• 24 replicates at LoD claimed by manufacturer;

• 24 replicates at 0.5x LoD claimed by manufacturer;

• 24 replicates at 0.25x LoD claimed by manufacturer;

• 5 replicates of negatives. Plus: Minimum of 3 replicates for the most common subtypes/genotypes16 at 2x LoD claimed by manufacturer. For IVDs used at point of care: Same as above.

A model of such certificate is shown in annex 7A.

15 For example, for a conventional NAT assay with an LOD of 45 copies/ml, the following concentrations would be

used: 10, 000 copies/ml (5 replicates), 1,000 copies/ml (25 replicates), 100 copies/ml (25 replicates), 50 copies/ml

(25 replicates), and negative dilutions (4 replicates).

16 For HIV-1 A, B, C, D, CRF02_AG and HIV-2 Group A

Draft


Annex 7A:

1. Laboratory issuing certificate of analysis:

Organization name:

Responsible Person (Surname, Given name): Position:

Street, Postcode, City, Country:

2. Reference for this certificate of analysis:

Identification number:

Date issued (dd/mm/yyyy):

3. Requestor of certificate of analysis:

Organization name:

Surname, Given name:


4. Sample details:

Registration number for this sample

Date sampled/received (dd/mm/yyyy):

Quantity sampled/received:

5. Product details:

Name of product:

Unique device identification (UDI-DI + UDI-PI):

Regulatory version:

Product code:

Lot number:

Date of manufacture (dd/mm/yyyy):

Date of expiry date (dd/mm/yyyy):

Packaging configuration (number of tests):

Contents of sample:

Page 78 of 79

6. Result of physical inspection: Date of inspection (dd/mm/yyyy):

Element inspected Result Accepted

x defective/x not defective Pass/Fail





Expand as needed Attach photographs of all inspected samples of reagents/kits. 7. Results of panel functional testing: Date of testing (dd/mm/yyyy):

Panel identification number Result Reference results Accepted

x detected/x tested Pass/Fail





Expand as needed Attach photographs of all testing results, if subjectively read assay format.

Draft

Annex 5: Post-Market Information Exchange Reporting Form for NRAs

8. Additional comments:

Including any invalid or unreturnable results.

9. Conclusion on compliance of the sample with the specifications:

Compliance statement:

Surname, Given name:


Date issued (dd/mm/yyyy):

Signature:

Documents

Guidance for post-market surveillance and market