MDCG 2022-2 Guidance on general principles of clinical evidence

Medical Devices

Medical Device Coordination Group Document MDCG 2022-2

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MDCG 2022-2

Guidance on general principles of

clinical evidence for In Vitro Diagnostic

medical devices (IVDs)

January 2022

This document has been endorsed by the Medical Device Coordination Group

(MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is

composed of representatives of all Member States and it is chaired by a

representative of the European Commission.

The document is not a European Commission document and it cannot be regarded

as reflecting the official position of the European Commission. Any views expressed

in this document are not legally binding and only the Court of Justice of the European

Union can give binding interpretations of Union law.

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Medical Device Coordination Group Document   MDCG  2022-2 
 
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Table of Contents   
 
1.  Purpose ..................................................................................................................... 3 
2.  Scope ........................................................................................................................ 3 
3.  Introduction ............................................................................................................... 4 
4.  Definitions ................................................................................................................. 7 
5.  General principles of Clinical Evidence ................................................................... 12 
6.  Performance Evaluation .......................................................................................... 13 
6.1. Performance evaluation process ............................................................................. 13 
6.2. The role of risk management in performance evaluation ........................................ 15 
6.3. Performance Evaluation Plan .................................................................................. 18 
6.4. Scientific Validity ..................................................................................................... 20 
6.5. Analytical Performance ........................................................................................... 23 
6.6. Clinical Performance ............................................................................................... 24 
6.7. Clinical performance studies ................................................................................... 26 
6.8. Performance Evaluation Report .............................................................................. 27 
7.  Continuous update of the performance evaluation .................................................. 28 
7.1. Post-Market Surveillance (PMS) and Post-Market Performance Follow up 
(PMPF) .......................................................................................................................... 29 
Appendix I – Methodological principle for generation of clinical evidence ..................... 31 
Appendix II Required frequency for updates of reports ................................................. 32 
 
   

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1. Purpose

This document outlines the general principles of clinical evidence and provides

guidance on the continuous process of performance evaluation for in vitro diagnostic

medical devices (hereafter referred to as IVDs), as set out in Regulation (EU)

2017/746 – In Vitro Diagnostic Medical Device Regulation (IVDR).

This guidance describes the approach by which collection, generation and

documentation of supporting data for an IVD may be conducted prior to the placing

on the market or putting into service. As the performance evaluation will be updated

throughout the life cycle of an IVD, this document also addresses principles related to

post-market surveillance, such as post-market performance follow-up.

The target audience of this document is IVD manufacturers, investigators and study

sponsors. This document is also intended to inform regulators, notified bodies and

other stakeholders when considering clinical evidence provided by manufacturers.

This document has been elaborated by an expert group representing Member State

Competent Authorities and the European Commission, in consultation with all

relevant actors including notified bodies and manufacturers.

In order to promote global convergence, this document takes into account certain

concepts outlined in the Global Harmonisation Task Force guidance documents

(such as SG5/N7:2012).

2. Scope

This guidance should be applied to all products meeting the definition of an IVD per

Article 2(2) of the IVDR:

any medical device which is a reagent, reagent product, calibrator, control material,

kit, instrument, apparatus, piece of equipment, software or system, whether used

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

examination of specimens, including blood and tissue donations, derived from the

human body, solely or principally for the purpose of providing information on one or

more of the following:

a) concerning a physiological or pathological process or state;

b) concerning congenital physical or mental impairments;

c) concerning the predisposition to a medical condition or a disease;

d) to determine the safety and compatibility with potential recipients;

e) to predict treatment response or reactions;

f) to define or monitoring therapeutic measures.

It shall be noted that as of 2012, the International Medical Device Regulators Forum (IMDRF) took up the work and mission of

the Global Harmonization Task Force (GHTF).

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Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices;

As accessories for an IVD fall under the scope of the IVDR, this document also

provides guidance on these devices.

This document provides guidance on:

- General principles of Clinical Evidence,

- Performance evaluation process,

- The role of risk management in performance evaluation,

- Performance Evaluation Plan (PEP),

- Scientific Validity, Analytical Performance and Clinical Performance,

- Performance Evaluation Report (PER),

- Continuous update of the performance evaluation.

It is important to remind that per Article 1(3) of the IVDR, the following products are

not considered IVDs and are henceforth out of scope of this guidance:

a) products for general laboratory use or research-use only products,

unless such products, in view of their characteristics, are specifically

intended by their manufacturer to be used for in vitro diagnostic

examination;

b) invasive sampling products or products which are directly applied to the

human body for the purpose of obtaining a specimen;

c) internationally certified reference materials;

d) materials used for external quality assessment scheme.

Please note that this guidance does not elaborate on performance studies in detail

nor does it address the concept of equivalence in detail. In addition, this guidance

does not apply to in-house devices.

3. Introduction

Prior to placing an IVD on the market or putting it into service, the manufacturer must

demonstrate compliance with all applicable requirements of the IVDR, in accordance

with the appropriate conformity assessment procedure(s). Therefore, the

manufacturer must demonstrate that the IVD achieves its intended purpose in

accordance with the claimed performance over the lifetime of the device.

Article 56 (1) of the IVDR underlines that the manufacturer must specify and justify

the level of clinical evidence in view of the characteristics of the device and its

intended purpose. As such, defining the intended purpose of an IVD must be

considered a key driver behind the overall assessment. Accordingly, the full intended

During the normal stated conditions of use by the intended user in the intended environment (e.g. laboratories, physician’s

offices, healthcare centres, and home environments.)

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purpose should be clearly expressed in the intended purpose statement, reflected in

the instructions for use (IFU), and should include the specific elements outlined in

Annex I, 20.4.1 (c.):

(i) what is detected and/or measured;

(ii) its function (e.g. screening, monitoring, diagnosis or aid to diagnosis,

prognosis, prediction, companion diagnostic);

(iii) the specific information that is intended to be provided in the context of:

— a physiological or pathological state;

— congenital physical or mental impairments;

— the predisposition to a medical condition or a disease;

— the determination of the safety and compatibility with potential

recipients;

— the prediction of treatment response or reactions;

— the definition or monitoring of therapeutic measures;

(iv) whether it is automated or not;

(v) whether it is qualitative, semi-quantitative or quantitative;

(vi) the type of specimen(s) required;

(vii) where applicable, the testing population; and

(viii) for companion diagnostics, the International Non-proprietary Name (INN) of

the associated medicinal product for which it is a companion test.

In this context, it is relevant to distinguish analytes with specific indications (e.g.

specific diagnostic purposes) from those which may be relevant for multiple clinical

conditions and are consequently intended to assess physiological status rather than

a specific diagnostic indication. In such cases, the intended purpose should be

framed to appropriately reflect the IVD’s overall purpose, e.g. ‘as a marker of

inflammation’ rather than specifying specific causes of inflammation (unless

specifically diagnostic for these). Additional information regarding different clinical

contexts for the analyte should be captured in the scientific validity of the IVD and be

included in other sections of the IFU, e.g. the ‘summary and explanation of the test’

section.

The IVDR outlines that evidence for an IVD’s conformity is established by

demonstrating and substantiating the scientific validity, analytical performance and

clinical performance. Furthermore, the IVDR underlines that the necessary clinical

evidence should be based on a sufficient amount and quality of data in order to allow

a qualified assessment of whether the IVD is safe, performant and achieves the

intended clinical benefit(s), when used as intended. The IVDR notes that clinical

evidence may include data from devices which are claimed to be equivalent to the

device under assessment. The handling of equivalence should be defined in the

manufacturers QMS (Annex IX 2.2.c). Where data from equivalent devices is used, a

justification should be provided. It is important to underline that risk classification is

not the only factor which influences the level of clinical evidence needed. As a

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general principle, scientifically substantiated conclusions should be reached through

the use of a systematic and explicit appraisal of data that supports decisions made

and conclusions reached regarding sufficient clinical evidence.

To assist in demonstrating conformity with the IVDR, IVD manufacturers may make

use of harmonised standards, or the relevant parts of those standards, the references

of which are published in the Official Journal of the European Union. While the use of

harmonised standards is recommended, it is not the only means to demonstrate an

IVD’s conformity with the IVDR. When other approaches are employed, the

manufacturer must ensure that the necessary level of safety and performance is

achieved.

Where no harmonised standards exist or where the existing harmonised standards

are not sufficient, the Commission can adopt Common Specifications (CS) regarding

the requirements on performance evaluation and performance studies. IVDs

developed in compliance with CSs (fully or partially), are in presumption of conformity

with the requirements of the IVDR covered by the CS or parts thereof. Thereby,

manufacturers or study sponsors must comply with the CS unless it can be duly

justified that the adoption of a different solution ensures an equivalent level of safety

and performance.

It is important to underline that performance evaluation should be regarded as a

continuous process required not only to generate but also maintain the clinical

evidence needed to support an IVD’s intended purpose. It is with this essence the

IVDR requires that a lifecycle approach must be employed, whereby clinical evidence

is updated throughout the IVD’s entire lifecycle. Scientific developments and

improvements in state-of-the-art should be reviewed and assessed by the

manufacturer on a regular basis as part of their continuous and pro-active post-

market surveillance activities. Therefore, manufacturers must instate a procedure for

planned monitoring of scientific developments and changes in medical practice

relevant to the IVD(s). Any relevant new information, developments and progress in

the scientific field should trigger reassessments of the existing clinical evidence thus

ensuring safety and performance through a continuous performance evaluation

process.

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4. Definitions

The definitions elaborated within this section and utilised within this document are

intended to apply to IVDs according to the IVDR. A small number of terms which are

considered useful and defined below were taken from other sources than the IVDR.

Analytical

performance

The ability of a device to correctly detect or measure a

particular analyte.

Source: EU 2017/746 (IVDR), Article 2 (40)

Analytical sensitivity

The capability of the method to distinguish between two

close concentrations of the target marker/analyte.

Source: Iteration from several sources

Analytical specificity

The ability of an assay to measure in a sample a particular

target measurand in the presence of for example other

analyte/marker, matrix, interfering substances/organisms or

cross-reactive species/agents.

Source: Iteration from several sources

Certified Reference

Material/ Standard

Reference Material

Reference material, accompanied by a certificate, one or

more whose property values are certified by a procedure

which establishes its traceability to an accurate realization

of the unit in which the property values are expressed, and

for which each certified value is accompanied by an

uncertainty at a stated level of confidence.

Source: WHO TGS-8 definition: Quality control for in vitro diagnostic medical devices for

WHO prequalification

Certified reference

methods

Measurement method which has been certified to show

appropriate trueness and precision for its intended purpose

and has been officially defined as reference method by a

competent body.

Source: WHO TGS-8 definition: Quality control for in vitro diagnostic medical devices for

WHO prequalification

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Clinical Benefit

The positive impact of a device related to its function, such

as that of screening, monitoring, diagnosis or aid to

diagnosis of patients, or a positive impact on patient

management or public health.

Note: It should be recognized that the concept of clinical

benefit for in vitro diagnostic medical devices is

fundamentally different from that which applies in the case

of pharmaceuticals or of therapeutic medical devices, since

the benefit of in vitro diagnostic medical devices lies in

providing accurate medical information on patients, where

appropriate, assessed against medical information obtained

through the use of other diagnostic options and

technologies, whereas the final clinical outcome for the

patient is dependent on further diagnostic and/or therapeutic

options which could be available.

Source: EU 2017/746 (IVDR), Article 2 (37) and recital 64

Clinical evidence

Clinical data and performance evaluation results pertaining

to a device of a sufficient amount and quality to allow a

qualified assessment of whether the device is safe and

achieves the intended clinical benefit(s), when used as

intended by the manufacturer.

Source: EU 2017/746 (IVDR), Article 2 (36)

Clinical performance

The ability of a device to yield results that are correlated

with a particular clinical condition or a physiological or

pathological process or state in accordance with the target

population and intended user.

Source: EU 2017/746 (IVDR), Article 2 (41)

Device for

performance study

A device intended by the manufacturer to be used in a

performance study.

A device intended to be used for research purposes, without

any medical objective, shall not be deemed to be a device

for performance study.

Source: EU 2017/746 (IVDR), Article 2 (45)

Diagnostic

sensitivity

The ability of a device to identify the presence of a target

marker associated with a particular disease or condition.

Source: EU 2017/746 (IVDR), Article 2 (50)

Diagnostic

specificity

The ability of a device to recognise the absence of a target

marker associated with a particular disease or condition.

Source: EU 2017/746 (IVDR), Article 2 (49)

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False negative

A result where the device incorrectly indicates that the

specimen tested negative for the condition, attribute or

property under analysis.

False positive

A result where the device incorrectly indicates that the

specimen tested positive for the condition, attribute or

property under analysis.

Usability engineering

Application of knowledge about human behaviour, abilities,

limitations, and other characteristics to the design of and

interactions with an IVD medical devices (including

software) to achieve adequate usability.

Source: Modified from IEC 62366

Investigator

An individual responsible for the conduct of a performance

study at a performance study site.

Source: EU 2017/746 (IVDR), Article 2 (48)

Likelihood ratio

Likelihood of a given result arising in an individual with the

target clinical condition or physiological state compared to

the likelihood of the same result arising in an individual

without that clinical condition or physiological state.

Source: EU 2017/746 (IVDR), Article 2 (54)

Linearity

The ability to provide measured quantity values that are

directly proportional to the value of the measurand in the

sample.

Source:

ISO 18113-1

Measuring interval

(range)

A set of values of quantities of the same kind that can be

measured by a given measuring instrument or measuring

system with specified instrumental measurement

uncertainty, under defined conditions

Source: International vocabulary of metrology – Basic and general concepts and

associated terms (VIM) 3rd edition

Negative predictive

value

The ability of a device to separate true negative results from

false negative results for a given attribute in a given

population.

Source: EU 2017/746 (IVDR), Article 2 (53)

Performance

evaluation

An assessment and analysis of data to establish or verify

the scientific validity, the analytical and, where applicable,

the clinical performance of a device.

Source: EU 2017/746 (IVDR), Article 2 (44)

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Performance of a

device

Performance of a device means the ability of a device to

achieve its intended purpose as claimed by the

manufacturer. It consists of the analytical and, where

applicable, the clinical performance supporting that intended

purpose.

Source: EU 2017/746 (IVDR), Article 2 (39)

Performance study

A study undertaken to establish or confirm the analytical or

clinical performance of a device.

Source: EU 2017/746 (IVDR), Article 2 (42)

Performance study

plan

A document that describes the rationale, objectives, design

methodology, monitoring, statistical considerations,

organisation and conduct of a performance study.

Source: EU 2017/746 (IVDR), Article 2 (43)

Positive predictive

value

The ability of a device to separate true positive results from

false positive results for a given attribute in a given

population.

Source: EU 2017/746 (IVDR), Article 2 (52)

Predictive value

The probability that a person with a positive device test

result has a given condition under investigation, or that a

person with a negative device test result does not have a

given condition.

Source: EU 2017/746 (IVDR), Article 2 (51)

Risk

The combination of the probability of occurrence of harm

and the severity of that harm.

Source: Article 2(16) IVDR

Robustness

The robustness of an analytical procedure means the

capacity of an analytical procedure to remain unaffected by

small but deliberate variations in method parameters and

provides an indication of its reliability during normal usage.

Source: ICH Q2(R1)– Validation of analytical procedures

Scientific validity of

an analyte

The association of an analyte with a clinical condition or a

physiological state.

Source: EU 2017/746 (IVDR), Article 2 (38)

Specimen

Is a discrete portion of a body fluid or tissue taken from an

individual for examination, study or analysis of one or more

quantities or characteristics to determine the character of

the whole. This also includes other materials, for example,

hair, nails excretions, secretions, or a sample from the skin

surface.

Source: MDCG IVD Classification guidance

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State-of-the-art

Developed stage of current technical capability and/or

accepted clinical practice in regard to products, processes

and patient management, based on the relevant

consolidated findings of science, technology and

experience.

Note: The state-of-the-art embodies what is currently and

generally accepted as good practice in technology and

medicine. The state-of-the-art does not necessarily imply

the most technologically advanced solution. The state-of-

the-art described here is sometimes referred to as the

“generally acknowledged state-of-the-art”

Source: Modified from IMDRF/GRRP WG/N47 FINAL:2018

Summary of Safety

and Performance

(SSP)

Article 29 specifies the information, including data on

performance evaluation and respective conclusions, which

manufacturers have to provide to notified bodies for

validation and to make available to the public in the

“Summary of safety and performance” in the EUDAMED

database.

Source: EU 2017/746 (IVDR), Article 29

Metrological

Traceability

Property of a measurement result whereby the result can be

related to a reference through a documented unbroken

chain of calibrations, each contributing to the measurement

uncertainty. The metrological traceability chain is a

sequence of measurement standards and calibrations that

is used to relate a measurement result to a reference.

Source: International vocabulary of metrology – Basic and general concepts and

associated terms (VIM) 3rd edition

True negative

A result where the device correctly indicates that the

specimen tested negative for the condition, attribute or

property under analysis.

True positive

A result where the device correctly indicates that the

specimen tested positive for the condition, attribute or

property under analysis.

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Usability

Characteristic of the user interface that facilitates use and

thereby establishes effectiveness, efficiency and user

satisfaction in the intended use environment.

Note 1 to entry: all aspects of usability, including

effectiveness, efficiency and user satisfaction, can either

increase or decrease safety.

Source: IEC 62366:2015

WHO International

Standard

WHO provided international standard for the calibration and

validation of diagnostic and screening assays.

Use environment

Actual conditions and setting in which users interact with the

IVDs (e.g. self-tests).

Source: modified from 62366-1:2015

5. General principles of Clinical Evidence

Clinical evidence for IVDs is established through the collection of data as a result of a

performance evaluation. Performance evaluation covers the assessment and

analysis of data to establish and verify the scientific validity, analytical performance

and, where applicable, clinical performance of an IVD as per article 2 (44). Clinical

expertise and judgment is required at every step of the performance evaluation,

including the collection and appraisal of data arising from different sources. Each

indication and claimed clinical benefit specified in the intended purpose should be

assessed and have the appropriate supporting clinical evidence.

As defined in Article 2 (37) of the IVDR, clinical benefit is the positive impact of a

device related to its function, such as that of screening, monitoring, diagnosis or aid

to diagnosis of patients, or a positive impact on patient management or public health.

Preamble (64) of the IVDR further clarifies that the concept of clinical benefit for IVDs

is fundamentally different from that which applies in the case of pharmaceuticals or of

therapeutic medical devices, since the benefit of IVDs lies in providing accurate

medical information on patients, where appropriate, assessed against medical

information obtained through the use of other diagnostic options and technologies,

whereas the final clinical outcome for the patient is dependent on further diagnostic

and/or therapeutic options which could be available.

As a substantial percentage of healthcare decisions rely on information provided by

IVDs, results from IVDs can significantly influence patient diagnosis, management,

treatment and overall clinical outcomes. As such, the clinical evidence of an IVD

should demonstrate that the defined clinical benefit is achieved and that the IVD is

safe and in conformity with the applicable general safety and performance

requirements (GSPRs) set out in Annex I. The clinical evidence must also support the

intended purpose and performance of the IVD, as stated by the manufacturer, while

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addressing the residual risks to the patients, users or other persons associated with

the use of the device. As accessories fall under the scope of the IVDR, establishment

of the clinical evidence for an accessory used together with one or several IVD(s)

may be performed alongside the corresponding IVD(s) in question. To determine and

justify the level of clinical evidence, the amount and quality of supporting data should

be evaluated. According to the principles of evidence-based medicine, the body of

evidence should be assessed taking into the account strength, robustness, and

quality of data in order to draw meaningful conclusions. All in all, the clinical benefit of

the IVD should always outweigh the overall residual risk.

As part of the ‘lifecycle approach’ of a device, it is of utmost importance that the

generation and assessment of clinical evidence remains a continuous process during

the life-time of the device. The general methodological principles to be considered by

the manufacturer are listed in Annex XIII 1.2. of the IVDR and are further illustrated in

Appendix I of this guidance document.

6. Performance Evaluation

6.1. Performance evaluation process

Performance Evaluation is a structured, transparent, iterative and continuous process

which is part of the quality management system and is conducted throughout the life

cycle of an IVD. The general performance evaluation principles are laid down in

Article 56 and Annex XIII, Part A, 1 of the IVDR and can be summarised as follows:

1. Planning: establishment and maintenance of a performance evaluation plan

(PEP); identification of the approach and steps to generate the necessary

clinical evidence based on the characteristics of the device, its intended

purpose, etc.;

2. Data Establishment:

- Identification and evaluation of the available data in terms of its

suitability and relevance for demonstrating conformity with the relevant

GSPRs and intended purpose;

- Identification of whether additional scientific validity, analytical

performance or clinical performance data is required to demonstrate

conformity and identification of any unaddressed issues or gaps exist in

the data;

- Generation of scientific validity, analytical performance and clinical

performance data needed (e.g. to address gaps);

3. Analysis, conclusions and documentation: analysis and documentation of the

scientific validity, analytical performance data and clinical performance data.

Assessments and drawing of conclusions in the performance evaluation report

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(PER); drawing up of the summary of safety and performance (for Class C and

D).

4. Continuous monitoring and updates: Update the performance evaluation

report, the summary of safety and performance (for Class C and D) and other

associated documentation (e.g. Periodic Safety Update Report (PSUR))

throughout the life cycle of the IVD considering also data obtained from

implementation of the manufacturer's Post Market Performance Follow-up

(PMPF) report and through a continuous evaluation of the state-of-the-art.

This approach is illustrated in Figure 1.

Figure 1. Overview of the Performance Evaluation process

The performance evaluation of an IVD must consider the benefit-risk ratio in light of

the state-of-the-art. The three essential pillars of performance evaluation can be

summarised as:

- Scientific validity: the extent to which the analyte, or marker to be

determined by the IVD is associated with the targeted physiological state or

clinical condition.

- Analytical performance: demonstration of the IVD’s ability to correctly

detect or measure a particular analyte.

IVDR Art. 29

For IVD medical device software, analyte or marker should be understood as the association of the claimed intended purpose

with a clinical condition or physiological state.

In the case of IVD software, and broadly speaking, accurately, reliably and precisely produce the intended output.

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- Clinical performance: demonstration of an IVD’s ability to yield results

that are correlated with a particular clinical condition or a

physiological/pathological process or state in accordance with the target

population and intended user.

When planning the performance evaluation, the approach to demonstrating

compliance with the applicable requirements and methods can vary. For devices

where CS have been published, aspects of the clinical evidence requirements are

clearly defined. Some devices may have relevant existing standards, guidelines (e.g.

WHO international standards, best practice documents) and/or certified reference

materials or reference measurement procedures. The availability of these may assist

manufacturers when designing the PEP (see section 6.3) and can be utilised in

studies required to generate sufficient clinical evidence to demonstrate conformity.

For devices that do not typically have, for example, CS or certified reference

materials, planning activities to generate necessary clinical evidence may be more

challenging. In such cases manufacturers are reminded that the clinical evidence

must be sufficient to support the intended purpose of the device in the intended use

environment. If there are no comparative methods, different approaches may be used

if demonstrated to be appropriate, such as comparison to some other well-

documented methods or the composite reference standard. The depth and extent of

clinical evidence should also take into account considerations including the inherent

risks of the device and the state-of-the-art. It may be worth reflecting on the concepts

listed in section 6.8 when designing the PEP and any studies required to generate

sufficient clinical evidence.

Devices with, for example, new intended purposes, new analytes, new target

populations, or are based on new technologies or technical processes may not have

a large amount of existing evidence available due to their novelty. The availability of

existing evidence and current clinical practices to support the novel aspects should

be a key consideration when designing the PEP and any studies necessary to

generate sufficient clinical evidence.

6.2. The role of risk management in performance evaluation

The risk management system should be carefully aligned with and reflected in the

performance evaluation process of the IVD, considering the clinical risks to be

addressed as part of the performance evaluation, performance studies, and post-

market performance follow-up(s).

Due to their nature, in the majority of cases, deficiencies of IVDs do not directly lead

to physical injury or damage to the health of people. If any, these devices may lead to

indirect harm, rather than direct harm.

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The requirements to remove or reduce risks as far as possible must be fulfilled,

taking into account the generally acknowledged state-of-the-art in the field of

medicine. Risks for IVDs are often generated from a series of events which may

involve several factors such as inadequate design characteristics, immature

technology or usability, defects in manufacturing, unintentional misuse, improper

storage or maintenance of the IVD as well as medical decisions of the healthcare

professional or lay user based on the examination results.

Chain of events may lead to hazardous situations, e.g. reporting of an incorrect

examination result. As a consequence of a medical decision based on the result

provided by the device, action taken or not taken may result in the worst cases to

severe harms to the patients. In addition to the harm to patients, exposures of the

users (e.g. maintenance personnel, patients) to chemical, electronic,

electromagnetic, mechanical (non-exhaustive) should be accounted for.

Therefore, the risk analysis should always reflect the clinical use and medical

purpose of the IVD. For more examples on series of events leading to harm, see

Table 1.

Table 1. Examples of series of events leading to harm. The probability of occurrence of harm can be

combination of probability of the hazardous situation occurring and probability of hazardous situation

leading to the harm. Severity of harm is often dependent of intended purpose of the device.

Probability of the Occurrence of the Harm x Severity

Probability of the Hazardous situation

Probability of the Harm

Manufacturer risk control

measures

Clinical risk control measures

An event/A

defect

Hazard

Hazardous

situation

Clinical events

contributing or

mitigating the

hazardous situation

Harm and Severity

Poor sampling,

stability of the

reagent

degraded etc.

False

negative

result/Too

low

result/Wro

ng result

Healthcare

professional/layman

receives an

incorrect result

Asymptomatic

The result (not)

considered in the

context of clinical signs

and symptoms

Not identified patients

likely to benefit from the

corresponding medicinal

product

Result accepted as

correct

Treated/Untreated

Death

Life-threatening

illness or injury

Permanent

impairment of body

structure or function

Hospitalization or

prolongation of

hospitalization

Inappropriate

medical treatment

Unintentional illness

or injury or adverse

clinical signs

Minor harm not

leading to additional

medical treatment or

treatment, minor

inconvenience

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Cross

reaction, too

high amount of

sample

dispensed etc.

False

positive

result/Too

high

result/Wro

ng result

Healthcare

professional

/layperson receives

an incorrect result

Asymptomatic

The result (not)

considered in the

context of clinical signs

and symptoms

Not identified patients

likely to be at increased

risk of serious adverse

reactions as a result of

treatment with the

corresponding medicinal

product

Result accepted as

correct

Treated/Untreated

Death

Life-threatening

illness or injury

Permanent

impairment of body

structure or function

Hospitalization or

prolongation of

hospitalization

Inappropriate

medical treatment

Unintentional illness

or injury or adverse

clinical signs

Minor harm not

leading to additional

medical treatment or

treatment, minor

inconvenience

Degradation of

quality

control(s) ,

result cannot

be accepted

etc.

Delayed

result

Healthcare

professional do not

receive a result in a

timely manner

Emergency use, No

back-up

method/assay/instrumen

t/component in use

Asymptomatic

Delay of medical

intervention

Death

Life-threatening

illness or injury

Permanent

impairment of body

structure or function

Hospitalization or

prolongation of

hospitalization

Inappropriate

medical treatment

Unintentional illness

or injury or adverse

clinical signs

Minor harm not

leading to additional

medical treatment or

treatment, minor

inconvenience

Barcode

reading error,

a component

missing from

the kit etc.

No result

Healthcare

professional

/layperson do not

receive a result at

all

Emergency use, No

backup

method/assay/instrumen

t in use

Asymptomatic

Delay of medical

intervention

Death

Life-threatening

illness or injury

Permanent

impairment of body

structure or function

Hospitalization or

prolongation of

hospitalization

Inappropriate

medical treatment,

Unintentional illness

or injury or adverse

clinical signs

Minor harm not

leading to additional

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medical treatment or

treatment, minor

inconvenience

Test line

colour/bacteria

l growth result

interpretation

unclear etc.

Unclear

result

Healthcare

professional

/layperson receives

an unclear result/do

not receive a result

in a timely manner

Asymptomatic

The result (not)

considered in the

context of clinical signs

and symptoms

Result accepted as

correct

Result not accepted

Treated/Untreated

Inappropriate

medical treatment,

Unintentional illness

or injury or adverse

clinical signs

Minor harm not

leading to additional

medical treatment or

treatment, minor

inconvenience

Mechanical,

Electronic,

Electromagneti

c, Chemical

defect etc.

Electric

shock,

pain, blood

scratch,

eye

damage,

inconvenie

nce

Healthcare

professional/mainte

nance

person/layperson

hurts him/herself

using the device

Death

Life-threatening

illness or injury

Permanent

impairment of body

structure or function

Hospitalization or

prolongation of

hospitalization

Inappropriate

medical treatment,

Unintentional illness

or injury or adverse

clinical signs

Minor harm not

leading to additional

medical treatment or

treatment, minor

inconvenience

The manufacturer’s risk management system should define a scientific and practical

approach to support decision making. All known and foreseeable risks, and any

undesirable effects shall be minimised and be acceptable when weighed against the

evaluated potential benefits to the patients and/or the user arising from the intended

performance of the device during normal conditions of use.

Risks and risk control measures should be reflected in the performance evaluation

process for the device in line with an up-to-date lifecycle approach. For example, the

impact on the clinical evidence required to support the use of the device should be

considered when new risks are identified or when changes are implemented.

6.3. Performance Evaluation Plan

As highlighted above, the performance evaluation begins with the establishment of

the PEP. To generate the necessary clinical evidence, the PEP should specify certain

characteristics, performance of the device, the process and the criteria to be applied.

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When designing the PEP, manufacturers should take into account the following

factors (non-exhaustive) in view of the safety and performance requirements for the

device:

- the intended purpose (including for example the specific disorder, condition

or risk factor of interest that it is intended to detect, define or differentiate),

- the novelty and degree of innovation,

- the scientific validity of the analyte,

- the specification of methods,

- the assay technology,

- the state-of-the-art,

- the risk to the patient (e.g. due to an incorrect or delayed result from an IVD),

- the intended user(s),

- the disease state(s),

- the device classification,

- the degree of variability of the study subject population,

- prevalence of the clinical state,

- the availability of certified reference materials or certified reference methods,

- the target population,

- the stability of specimens, reagents, etc.

- availability of CS.

The requirements for the PEP are set out in the IVDR Annex XIII.

The manufacturer must plan, continuously conduct and document a performance

evaluation and should establish and update the performance evaluation plan (per

IVDR Annex XIII Part A 1), and the performance evaluation report with data obtained

from the manufacturer’s PMPF (per IVDR Annex XIII Part B 6). Identification and

specification of the applicable GSPRs should be clearly outlined within the PEP.

Additionally, an assessment of the benefit-risk ratio should be included in the PEP.

To determine the benefit-risk acceptability, pre-determined thresholds indicating and

specifying parameters and criteria should be used. This is required in order to

determine if the clinical benefits of the intended purpose outweigh the overall residual

risk.

Whilst they are neither analytical performance studies nor clinical performance

studies, testing conducted in order to prove compliance with the applicable GSPRs

(Annex I Chapter II point 10 onwards e.g. electromagnetic compatibility testing or

electrical safety testing), would need to be taken into account within the performance

evaluation and their results should be reflected in the performance evaluation report.

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Figure 2 (below) illustrates the flow of plans and reports within a performance

evaluation and describes the relevant information that is required in the development

process of an IVD.

Figure 2 Continuous performance evaluation process including flow of plans and reports.

The blue double arrows denote where plans are linked namely that the post market surveillance plan should

include PMPF plan (Annex III 1b), and that the performance evaluation plan shall include PMPF planning (Annex

XIII part A 1.1). A green double arrow is used to demonstrate that the PMPF report feeds back into the PE

process. (Annex XIII part B.7). The blue frame indicates risk management and continuous performance evaluation

process inter-dependency.

Appendix II of this guidance provides an overview of the required frequency of

updates for the different documents depending on the device class.

6.4. Scientific Validity

Scientific validity should be demonstrated and documented for each device. As

defined by IVDR Article 2(38), the ‘scientific validity of an analyte’ is the association

of an analyte with a clinical condition or a physiological state. In the case of IVD

MDSW, scientific validity should be demonstrated and documented for each device

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that provides information on and with respect to a clinical condition or a physiological

state. It is important to underline that for certain devices intended to be used

together, for example a reagent intended to be used with calibrators and controls, it

may be more appropriate to establish the scientific validity in the context of this

combination. As certain instruments may have an independent measuring function

which does not use any additional reagents,

scientific validity would also be required

unless due justification is given. Scientific validity may be demonstrated through the

use of existing data, where available, while taking into account the generally

acknowledged state-of-the-art. If the association of the analyte to a clinical condition

or physiological state is well established, evidence may be available in sufficient

quality and quantity to substantiate the scientific validity. In such cases, this

association may be appropriately demonstrated based on available information such

as peer reviewed literature, textbooks, historical data and experience. Where existing

evidence does not exist, is considered insufficient, or where there is a high degree of

novelty (such as new analytes and/or new intended purposes), it will be necessary to

provide a scientific rationale and to generate new or additional data. A gap analysis

should be conducted by the manufacturer in order to determine the additional

evidence required. For example, this may prompt the need to demonstrate scientific

validity through studies such as clinical performance studies.

When conducting literature reviews or other data retrieval methods, manufacturers

should employ a systematic approach to identify relevant available data:

1. Define a search protocol

before commencing data retrieval. The searching

strategy must be thorough and objective, i.e. it should identify all relevant

favourable and unfavourable data.

2. Conduct several searches with consolidated and relevant criteria or focus in

order to obtain all relevant and necessary data.

3. Ensure appropriate documentation is produced such that the methods can be

appraised critically, the results can be verified, and searches reproduced if

necessary.

Examples of existing data (without any particular order):

- appraised literature data,

- peer-reviewed data

- published clinical data (e.g. Summary of Safety and Performance (SSP),

Registries and databases from authorities),

- relevant information on the scientific validity of devices measuring the same

analyte or marker,

- proof of concept studies

See MDCG 2020-16 Rule 5b.

The search protocol is not a separate deliverable but is rather a part of the performance evaluation plan, the results of which

are embedded within the relevant reports.

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- relevant consensus expert opinions/positions from relevant professional

associations relating to the safety, performance, clinical benefits to patients,

design characteristics, scientific validity, clinical performance and intended

purpose of the device.

Examples of generating new evidence (without any particular order)

- Perform clinical performance study,

- Other studies (e.g. analytical performance studies or PMPF studies).

After finalising the collection and/or generation of evidence supporting the scientific

validity, the manufacturer should appraise and analyse the obtained data and reflect

it within the scientific validity report.

Figure 3 below highlights the different steps the manufacturer may take in order to

meet the requirements for establishing scientific validity.

Figure 3. Overview of the scientific validity steps

6.5. Analytical Performance

Per IVDR Article 2(40), the analytical performance focuses on the gathering of

evidence that the IVD in question reliably, accurately and consistently measures

and/or detects an analyte(s).

Proof of concept studies are usually smaller scale scientific studies to identify the fundamental association of the analyte with

the clinical condition/physiological state (GHTF/SG5/N7/2012). They are typically used in the feasibility stage of an IVD’s

development.

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The relevant performance characteristics, as part of the GSPRs and linked to the

analytical features of the IVD should be supported by existing evidence or by

generating new evidence. As a general rule, the analytical performance should

always be demonstrated on the basis of analytical performance studies. Data from

published experience gained by routine diagnostic testing may be considered as

supportive evidence to the analytical performance.

The manufacturer should verify that all different specimen types and specimen

sampling conditions that are indicated in the IVD’s intended purpose are assessed

and demonstrated.

To ensure stability, this examination should also include, where

applicable, the required devices for specimen collection, the indicated specimen

storage and transport conditions.

Information on the timeframe between the specimen collection, storage conditions

and its analysis should be provided and reflected in the analytical performance

report. This includes but is not limited to duration between collection, storage and

analysis, temperature limits and recommended number of freeze/thaw cycles. This is

especially pertinent for IVDs that use methods with time-critical analysis.

Analytical performance indicators are typically considered similar or even identical

across IVDs. These indicators may depend on the assay technology and the

intended use environment. The importance and weighting of different indicators listed

in the IVDR’s Annex I Section 9.1 and Annex II section 6.1 should be considered on

a case by case basis, as not all may be applicable. However, all omissions should be

clearly outlined and justified.

Examples of analytical performance indicators include:

- analytical sensitivity,

o limit of blank (LoB),

o limit of detection (LoD),

o limit of quantitation (LoQ),

- linearity,

- measuring interval/range: LoQ as the lower limit and linearity as the upper

limit,

- analytical specificity,

o testing against interferents and cross-reacting substances in the

presence of other substances/agents in specimen,

- accuracy,

a) trueness of measurement,

b) precision,

o intermediate precision,

o repeatability,

Please note that national provisions on informed consent/ethics approval prior to specimen collection and use may be

applicable.

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o reproducibility,

- carryover and cross contamination,

- instrument comparison,

- cut-off value(s),

- use environment,

- stability.

For IVD MDSW the following characteristics may be taken in to account:

- confidentiality,

- integrity,

- reliability,

- generalisability,

- expected data rate or quality,

- usability engineering.

Identification of gaps during the analytical performance assessment could trigger the

need for the generation of new or additional evidence. In the case of software this

may include, for example, to demonstrate generalisability of a software with real-life

datasets.

6.6. Clinical Performance

As per Article 2 (41) of the IVDR, clinical performance means the ability of a device to

yield results that are correlated with a particular clinical condition or a physiological or

pathological process or state in accordance with the target population and intended

user.

The clinical performance aims to demonstrate that the IVD can achieve clinically

relevant outputs through predictable and reliable use by the intended user(s). The

manufacturer should demonstrate that the IVD has been tested for the intended

use(s), target population(s), use condition(s), operating- and use environment(s) and

with all the intended user group(s). Indicators of clinical performance vary and

depend strongly on the intended purpose and performance claims.

The IVDR sets out that clinical performance may not be required for certain devices

in Article 2 (39). For example, clinical performance data may not be expected for non-

sterile specimen receptacles, microscopy glass slides, or some general reagents. In

such cases and where due justification is given, a clinical performance report would

not be expected. Nevertheless, the remaining aspects of the performance evaluation

report including other elements of clinical evidence would still be required unless due

justification is given.

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For markers that are not specific to a particular condition but are adequately defined

by scientific validity to be relevant in multiple clinical settings, separate clinical studies

for each clinical setting/indication would not be expected.

For those devices demonstrating clinical performance, the following principles are

highlighted as potential sources of clinical performance data:

- data from scientific peer-reviewed literature,

- data from published experience gained by routine diagnostic testing,

- data from clinical performance studies,

- other sources of clinical performance data.

Clinical performance can be characterised by the demonstration and evaluation of

applicable aspects of clinical performance for the device in question, such as (non-

exhaustive):

- diagnostic sensitivity,

- diagnostic specificity,

- positive predictive value,

- negative predictive value,

- number needed to treat/diagnose (average number of patients that need to be

treated/diagnosed in order to have an impact on one person),

- number needed to harm/misdiagnose (number of patients that need to be

diagnosed/ treated in order have an adverse effect on one patient),

- positive likelihood ratio,

- negative likelihood ratio,

- odds ratio,

- usability /user interface.

Other parameters may be determined by the manufacturer to be applicable when

demonstrating the clinical performance characteristics of the IVD in the intended use

environment(s) and may be included in the clinical performance report.

It is important that aspects of clinical performance are assessed in terms of their

statistical relevance, e.g. inclusion of confidence interval(s) and interpretation of the

impact on robustness of the result with regards to the intended purpose. Where due

to specific device characteristics demonstration of conformity with GSPRs based on

clinical data is not deemed appropriate, a performance evaluation is still required and

a justification shall be provided and documented in the PEP and the corresponding

PER.

6.7. Clinical performance studies

When determining what data is needed to demonstrate the safety and performance

of IVDs, it is important to consider available existing data and how to bridge any

deficits. In the event that data is not available in either sufficient quality or quantity it

will need to be generated.

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Clinical performance studies are considered necessary to establish or confirm

compliance with the relevant GSPRs as regards an IVD’s clinical performance which

cannot be determined by scientific validity, analytical performance studies, literature,

previous experience gained by routine diagnostic testing or other performance

studies. Clinical performance studies should be conducted in line with well-

established international guidance in this field, such as the international standard ISO

20916 on clinical performance studies using specimens from human subjects

regardless of the classification of the device, unless due justification is provided in

accordance with Annex XIII 1.2.3. For example, the manufacturer could justify that

the use of ‘other sources of clinical performance data’ may be appropriate, if this can

be supported by either literature and/or data from published experience gained by

routine diagnostic testing.

Clinical performance studies should always be designed in a manner which specifies

the clinical evidence the study intends to generate whilst accounting for potential

risks, considering appropriate ethical requirements and ensuring compliance with all

applicable legal and regulatory requirements.

The Clinical Performance Study Plan

(CPSP) should define the rationale, objectives, design, proposed analysis,

methodology, monitoring conduct and record-keeping of the clinical performance

study (IVDR Annex XIII 2.3.2).

As clinical performance studies should be tailored to the specified intended

population, the manufacturer must assess and justify the use of any samples within

their performance study in view of the intended purpose and type of IVD.

Clinical performance studies conducted under the IVDD should be considered as

‘other sources of clinical performance data’ per Annex XIII 1.2.3 as they wouldn’t

meet the requirements of Annex XIII 2.3.

. It should be noted that an assessment of

quality and completeness of the data is essential to identify any potential gaps. This

data should be supported by either literature and/or data from published experience

gained by routine diagnostic testing.

It must be noted additional requirements must be met by the manufacturer for certain

performance studies, such as studies which require ‘surgically invasive sample-taking

only for the purpose of the performance study’, that are ‘interventional clinical

Recital 66 IVDR Corrigendum to Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on

in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (Official Journal of

the European Union L 117 of 5 May 2017)(L117/11, 3.5.2019)

For example, the IVDR sets out a requirement for data management. This refers to the process of how data will be captured

and managed. Where relevant, it would be appropriate to state how the requirements of the General Data Protection Regulation

(GDPR) – Regulation (EU) 2016/679 are being met within the data management process.

If applicable, monitoring plans should be established in order to monitor the study conduct and progress, this will ensure

integrity of data, and adequate qualification of study conduction personnel.

Please note that national provisions on informed consent/ethics approval prior to specimen collection and use may be

applicable.

Unless the requirements of section 2.3 are appropriately justified.

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performance studies’ or which ‘involve additional invasive procedures or other risks

for the subjects of the studies’.

When clinical performance studies are conducted, the data obtained should be

documented in a clinical performance study report (Annex XIII 2.3.3), used in the

performance evaluation process and be part of the clinical evidence for the IVD.

6.8. Performance Evaluation Report

The manufacturer should compile evidence, determine the benefit-risk and document

the performance evaluation and its output in the PER. The manufacturer should

assess all relevant scientific validity, analytical and clinical performance data to verify

the applicable conformity of its device with the general safety and performance

requirements as referred to in Annex I. Annex XIII, Section 3 makes reference to

studies other than clinical performance studies, these other studies could be

analytical performance studies or PMPF studies that should be documented by

analogy to clinical performance studies and reflected in the PER.

The amount and quality of data collected should allow the manufacturer to make a

qualified assessment whether the IVD will achieve the intended clinical benefit(s) and

safety, when used as intended by the manufacturer. The data and conclusions drawn

from this assessment constitute the clinical evidence and should take into account

the following considerations:

- the intended users,

- the state-of-the-art,

- the nature, severity and the evolution of the condition being diagnosed or

treated,

- the adequacy of the estimation of associated risk for each identified hazard,

- the number and severity of adverse events,

- the availability of alternative diagnostic devices and current standard of care.

The assessment may be guided by the following non-exhaustive questions:

- Does the data support the intended purpose, intended users indications,

device specifications, target groups, clinical claims and the relevant general

safety and performance requirements?

- Has the novelty and level of innovation/history on the market been evaluated

and considered?

- Have the risks been identified, mitigated and the effectiveness of the risk

control measures been verified?

- Have for example environmental conditions, interference factors, exogenous

factors and endogenous factors been evaluated?

- Has the quality of literature retrieved and reviewed been evaluated and has a

rationale for the selection process been provided?

Article 58(1) IVDR

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- Has there been a sufficient number of observations to draw scientifically valid

conclusions?

- Have any limitations within the observations been appropriately justified?

- Was the statistical approach including sample size appropriate to reach a

scientifically valid conclusion?

- Have the scientific validity, analytical and clinical performances been

demonstrated?

- Is data from performance studies or other sources sufficient to verify the safety

and performance, including clinical benefits (where applicable) of the device

when used as intended with respect to the state-of-the-art?

- Does the design and results of the performance studies support the clinical

evidence?

- Have all deviations from and all planned changes to the performance

evaluation plan been justified?

- Has the relevance of the information of the performance evaluation been

assessed and documented?

- Has the contribution of each data set to the performance evaluation been

weighted according to systematic criteria?

- Is the data set appropriate and takes into account the state-of-the-art of the

device?

- Is all supporting data fully traceable, documented and is integrity assured?

- Were all ethical, legal and regulatory considerations/ requirements taken into

account?

- Have all omissions been clearly outlined and justified?

7. Continuous update of the performance evaluation

As described previously, performance evaluation is a continuous process conducted

over the lifecycle of the IVD. The safety, effectiveness and performance of the IVD is

maintained by data which is actively and continuously monitored and collected by the

manufacturer. Such data may include, developments in the state-of-the-art, post-

market information such as complaints, PMPF data, direct end-user feedback or

newly published research, guidelines, harmonised standards.

In addition, changes to an IVD’s e.g. intended purpose, product design,

characteristics or technology should be evaluated and the clinical evidence of the

IVD should be updated or re-established before such changes are implemented.

Developments or changes in the state-of-the-art, harmonised standards or CS by

reference to which the conformity of an IVD is declared should be taken into account

as they may trigger further activities to update the clinical evidence.

This information should be subject to the performance evaluation process depicted in

Figure 1.

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7.1. Post-Market Surveillance (PMS) and Post-Market

Performance Follow up (PMPF)

In the context of continuous update of the performance evaluation, planning of

thorough post market surveillance activities are critical to detect signals and ensure

continued performance (e.g. monitor for possible shifts that may signify the

emergence of mutated strains not detected by a specific assay).

The IVDR sets out that a PMPF is required to confirm that the IVD’s safety,

performance, and clinical evidence throughout its expected lifetime is based on

factual evidence and that the benefit-risk ratio remains acceptable. In some cases,

PMPF can be justified as not required (Annex III 1b and Annex XIII Part B 8). If

PMPF is not deemed appropriate for a specific IVD, a justification should be provided

and documented within the performance evaluation report.

Post-market information such as data from the manufacturer’s post-market

surveillance system (e.g. serious incident reports, results from post-market

performance studies) should be reviewed on a regular basis and used to determine

the potential impact on the risks, clinical benefit and whether there is a need to

update the performance evaluation report of the IVD. A manufacturer must ensure

that appropriate methods, procedures and product specific appropriate triggers for

proactively collecting and evaluating safety, performance and scientific data with the

aim of conducting PMPF are included in the PMPF plan.

The performance evaluation documentation (PEP & PER) should be updated

accordingly as part of the PMPF and the clinical evidence for the IVD expanded as

appropriate. Both favourable and unfavourable data should be equally considered.

Activities and triggers should be identified to prompt a review of the PMPF. These

may include for example:

- Monitoring and analysis of data from post-market use,

- Assessment of published experience gained by routine diagnostic testing,

- Involvement in external quality control schemes,

- Identification of new mutations, strains or variants which may impact the

performance of the IVD,

- Inputs from post-market surveillance, including information on serious incident

reports and field safety corrective actions.

- Post-market performance studies.

Information gained through the review and assessment of PMPF data may be useful

to inform future developments of the device e.g. expansion of the intended purpose

or change in claims or design to improve effectiveness.

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Appendix I – Methodological principle for generation of clinical

evidence

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Appendix II Required frequency for updates of reports

Device

Class

Document

Required frequency of update

Article

All

Performance

Evaluation and

associated

documentation

Throughout the life cycle of the device.

From implementation of the

manufacturer's Post Market

Performance Follow up (PMPF) plan in

accordance with Part B of Annex XIII

and the post-market surveillance plan

referred to in Article 79

Continuously through product’s lifetime

based on input from PMS and PMPF

for all classes.

Article 56

(6)

All

Post Market

Surveillance Plan

As necessary

Article 79

All

Post-Market

Performance

Follow-Up (PMPF)

Continuously through product’s lifetime

based on input from post market

surveillance plan (Annex III)

As necessary, unless specific

justification is given.

Annex XIII

Part B

A & B

Performance

Evaluation Report

Continuously through product’s lifetime

based on input from PMS and PMPF

for all classes.

As necessary and as defined in the

PMS plan

Article 56(6)

A & B

Post Market

Surveillance

Report

When necessary and made available

to the notified body and the competent

authority upon request

Article 80

C & D

Performance

Evaluation Report

As necessary and at least annually

Article 56(6)

C & D

Periodic Safety

Update Report

(PSUR)

At least annually

Article 81

(1)

C & D

Summary of Safety

and Performance

(SSP)

As soon as possible, where necessary

Article 29

Article 56

(6)