- Email: [email protected]
Performance evaluation of in vitro diagnostic medical devices: Methodology and differences compared to studies on other medical devices
Accepted Manuscript Performance evaluation of in vitro diagnostic medical devices: Methodology and differences compared to studies on other medical devices
Rosa Anna Grifa, Giacomo Pozzoli PII: DOI: Reference:
S0026-265X(17)30750-6 doi: 10.1016/j.microc.2017.08.004 MICROC 2884
To appear in:
Microchemical Journal
Received date: Revised date: Accepted date:
15 May 2017 1 August 2017 2 August 2017
Please cite this article as: Rosa Anna Grifa, Giacomo Pozzoli , Performance evaluation of in vitro diagnostic medical devices: Methodology and differences compared to studies on other medical devices, Microchemical Journal (2017), doi: 10.1016/j.microc.2017.08.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Performance Evaluation of In Vitro Diagnostic Medical Devices: methodology and differences compared to studies on other Medical Devices Rosa Anna Grifa*, Giacomo Pozzoli
IP
T
Institute of Pharmacology, Catholic University School of Medicine, largo F. Vito1, 00168 Rome, Italy
CR
*Corresponding author:
US
Dr. Rosa Anna Grifa
AN
Institute of Pharmacology, Catholic University School of Medicine
M
Largo F. Vito 1, 00168 Rome, Italy
phone: +39-06-30154367
ED
e-mail: [email protected]
AC
CE
PT
fax: +39-06-3050159
1
ACCEPTED MANUSCRIPT Abstract The aim of this article is to summarize the rules governing Performance Evaluation on In Vitro Diagnostic Medical Devices (IVDs) and to outline the main differences compared to studies on other Medical Devices (MDs) in the European Union (EU). In fact, the term “Performance Evaluation” is
T
exclusive to IVDs. For other MDs, the term “Clinical Evaluation” is used. However, the aim of both
IP
terms is the same: to demonstrate that a device meets the “Essential Requirements” of safety and
CR
performance. On the contrary, the methodology through performance evaluation for IVDs and clinical
US
evaluation for other MDs are performed, is different: UNI EN ISO 14155:2011 only for MDs and EN 13612:2002 only for IVDs. This difference is due to the fact that IVDs, unlike other MDs, do not
AN
generally come into contact with patients. Therefore, it can be difficult to demonstrate direct harm to
M
patients, unless the device itself causes deterioration in the state of health. Harm to patients is more likely to be indirect. However, in May 2017 two new regulations on MDs have been published, the first
ED
one concerning IVDs and the second one concerning other MDs. These new regulations may represent
PT
a real revolution. There will be very important changes to the requirements required to demonstrate clinical evidence. With regard to IVDs, clinical performance studies shall be carried out in the absence
CE
of clinical performance data. Moreover, performance studies should be in line with international
AC
standards, such as ISO 14155:2011, and the Declaration of Helsinki, and many others are the changes on the horizon.
Keywords: Performance evaluation, clinical evaluation, in vitro diagnostic medical devices, other medical devices, clinical evidence
2
ACCEPTED MANUSCRIPT 1. Introduction Despite the fact that the In Vitro Diagnostic Medical Devices (IVDs) industry has a considerable impact on the European economy, IVDs-related sector is surprisingly poorly known. Indeed, this industry comprises about 3,000 companies, employing over 75,000 workers, and produces more than
IP
T
40,000 different IVDs, providing an annual sales amount around € 11 billion, compared to € 100 billion
CR
for the entire Medical Devices (MDs) industry [1]. Therefore, it is important to explain what the term In Vitro Diagnostic Medical Device means, and to explain the current European IVD regulatory
US
framework.
According to the current IVD regulatory reference, Directive 98/79/EC, IVD is “any medical device
AN
that is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or
M
system, either used alone or in combination, intended by the manufacturer to be used in vitro for the examination of biological specimens, including blood and tissues, derived from the human body,
ED
principally or exclusively collected to gain information: concerning a physiological or pathological state, or
-
concerning a congenital abnormality, or
-
to determine the safety and compatibility with potential recipients, or
-
to monitor therapeutic measures”.
AC
CE
PT
-
The Directive 98/79/EC divides IVDs into four categories, according to the perceived risk associated with the relative danger to public health and/or patient treatment by an IVD failing to perform as intended. In particular, the four groups are:
List A:
Reagents and reagent products, including calibrators and control materials for: 3
ACCEPTED MANUSCRIPT -
determining the following blood groups: ABO system, rhesus (C, c, D, E, e) anti-Kell;
-
detection, confirmation and quantification of infection markers of HIV type 1 and 2, HTLV 1 and 2, and hepatitis B, C and D, in human specimens.
T
List B:
IP
Reagents and reagent products, including calibrators and control materials for: determining anti-Duffy and anti-Kidd blood groups;
-
determining irregular anti-erythrocytic antibodies;
-
detection and quantification in human samples of the following congenital infections:
AN
US
CR
-
rubella, toxoplasmosis;
diagnosing the hereditary disease phenylketonuria;
-
determining the following human infections: cytomegalovirus, chlamydia;
-
determining DR, A and B HLA tissue groups;
-
determining the tumoral marker PSA;
-
evaluating the risk of trisomy 21;
-
devices for the measurement of blood sugar.
AC
CE
PT
ED
M
-
Devices for self-testing.
All other IVDs.
The risk associated with their use decreases from the devices enclosed within the List A to those of the List B then to devices for self-testing and finally to all other IVDs. 4
ACCEPTED MANUSCRIPT In all cases, the manufacturer plays a key role, since He is responsible for identifying data relevant to the IVD and determining the types and amount of data needed to establish that the devices meet the Essential Requirements, documenting this process through the preparation of a technical dossier called “Technical File”. The latter includes documents related to device design, risk management,
T
manufacture, possible test reports, labels, instructions for use and “performance evaluation”. For "all
IP
other IVDs1”, the manufacturer is even allowed to self-declare it in the "declaration of CE conformity"
CR
contained in the “Technical File”. In fact, these devices do not require the involvement of a Notified Body. As far as IVDs for self-testing regards, the manufacturer must prepare a declaration of
US
conformity in a similar way to the general devices but a Notified Body review is also required. Finally,
AN
for List A and List B IVDs, the manufacturer must call on Notified Bodies before the product can be placed on the market [2, 3]. In addition, for List A IVDs, which presents higher risk than devices of List
M
B, the Notified Body must verify that the product meets the Common Technical Specifications (CTS)
ED
requirements for sensibility and specificity and must release each product batch before it can be placed on the European market. The batch release often requires performance evaluation studies [as illustrated
CE
PT
in Fig.1].
AC
2. Materials and Methods We conducted a systematic review of scientific literature, analysis of website of Competent Authorities, European Commission and Eurlex.
3. Results and Discussion
5
ACCEPTED MANUSCRIPT The term “Performance Evaluation” is exclusive to IVDs, whereas the term “Clinical Evaluation” is used for other MDs. However, the aim of both terms is the same: to demonstrate that a device meets the “Essential Requirements” of safety and performance. For other MDs, Clinical Evaluation must follow a defined and methodologically correct procedure based on: 1) a critical evaluation of scientific
T
literature; 2) or a critical evaluation of specific clinical investigations results carried out with the
IP
medical device in question; 3) or a critical evaluation of the combined clinical data provided by
CR
scientific literature and clinical investigations. Clinical Evaluation must be based on clinical data for all medical devices. Every medical device sold in Europe, regardless of its classification, must have a
US
Clinical Evaluation Report in its technical file. The international standard UNI EN ISO 14155:2011
AN
“Clinical investigation of medical devices for human subjects - Good clinical practice” describes the methods required for conducting clinical investigations. The above standard does not apply to IVDs1
M
[4]. For IVDs, Directive 98/79/EC requires that the manufacturer provides “clinical evidence”, in his
ED
technical documentation, that the IVD performs as claimed, whether these claims are of a technical, analytical or diagnostic nature. Such evidence can be shown by data already available to the
PT
manufacturer or by scientific literature or by data originating from performance evaluation studies in a
CE
clinical or other appropriate environment in accordance with the intended use. However, the terms “performance evaluation” and “performance evaluation study” are not defined in the Directive; instead,
AC
they are defined in the European harmonized standard, EN 13612:2002, “Performance evaluation of in vitro diagnostic medical devices”. This standard defines “performance evaluation” as an “investigation of the performance of any in vitro diagnostic medical device based on data already available, scientific literature and/or performance evaluation studies”. The standard, also defines “performance evaluation studies” as an “investigation of any in vitro diagnostic medical device intended to validate the performance claims under the anticipated conditions of use”. If a performance evaluation study is necessary and appropriate to support performance claims of the IVD, this standard “generically” 6
ACCEPTED MANUSCRIPT describes how the manufacturer can fulfill his obligation to conduct a scientifically correct performance evaluation study [5]. This is a considerable limit to this standard. In fact, it would be more correct to distinguish “analytical performance study” from “clinical performance study”. These definitions were provided in 2012 by the Global Harmonization Task Force (GHTF), a voluntary international group of
T
representatives from medical device regulatory authorities and trade associations that provide non-
IP
binding guide documents to regulatory authorities for use in the regulation of medical devices. It is
CR
important to clarify that the GHTF no longer exists, and the International Medical Device Regulators Forum (IMDRF), an organization composed only by officials from regulatory agencies, but not from
US
industry, around the world, has permanently replaced it. IMDRF is currently continuing the work on
AN
international medical device regulatory harmonization previously carried out by the GHTF. However, “analytical performance study” and “clinical performance study” definitions remain of actual
M
importance. The first one is defined as a “study undertaken to establish or confirm the ability of an IVD
ED
to detect or measure a particular analyte”. The “clinical performance study” is “a study undertaken to establish or confirm the ability of an IVD to yield results that are correlated with a particular clinical
PT
condition/physiological state in accordance with target population and intended user”. The purpose of a
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clinical performance study is to establish or confirm aspects of IVDs which cannot be determined by analytical performance studies, literature and/or previous experience acquired by routine diagnostic
AC
testing. According to the GHTF, since clinical performance of IVDs is the relationship between the testing results and the clinical conditions of patients, the clinical performance study design should take into account potential risks for patients and should follow appropriate ethical principles. It should be designed, conducted, analyzed and evaluated so that the best possible representation can be achieved with the target population in accordance with the intended use. To carry out appropriate studies for performance evaluation purpose, the GHTF has divided IVDs into three different categories:
7
ACCEPTED MANUSCRIPT Established and standardized tests whose analytical performance informations combined with scientific validity informations meet the clinical evidences requirements and are sufficient to demonstrate compliance with the Essential Safety and Performance Principles (EPs). These tests have clinical guidelines or consensus for their use and produce comparable results for the
IP
T
analyte regardless of the method or the manufacturer. Examples of this category include liver (e.g. AST, ALT, bilirubin) and kidney (e.g. creatinine,
CR
BUN) functional markers; electrolytes (e.g. sodium, chloride); metabolic markers (e.g. glucose,
US
calcium, albumin, total protein); hormones (e.g. hCG); blood gases and biochemical tests for the detection and identification of microorganisms.
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Established and non-standardized tests whose information about analytical performance in
M
conjunction with scientific validity information alone may not meet the clinical evidence
ED
requirements and may not be sufficient to demonstrate conformity with relevant EPs. These tests have clinical guidelines or consensus for their use but results obtained from different IVD
PT
medical devices might not be used interchangeably.
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Examples of this category include tests for infection disease (e.g. Rubella, Hepatitis C), hormones (e.g. estradiol), cardiac markers (e.g. troponin), tumoral markers (e.g. CEA, PSA)
AC
and cell markers (e.g. CD4, T-cells.)
Novel tests to whom information about analytical performance in conjunction with scientific validity information alone probably will not meet the clinical evidence requirements and will not be sufficient to demonstrate conformity with relevant EPs. These tests involve a new analyte, new technology, new target population, new application of an established technology, or a new intended use. Therefore, they are neither established nor standardized. 8
ACCEPTED MANUSCRIPT Examples of this category include tests for newly identified cardiac markers (e.g. high sensitivity CRP), tumoral markers (e.g. CTC), emerging infectious diseases (e.g. SARS, H1N1) and other pathogens. Finally, the GHTF defines the terms “performance evaluation” and “clinical evidence”. Performance
T
evaluation means “assessment and analysis of data to establish or verify the performance of an IVD2
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medical device”. Data are typically generated from studies (including, where appropriate, clinical
CR
performance studies using human specimens) or obtained from scientific literature”. Clinical evidence
US
means “compilation of the scientific validity, analytical performance and, where applicable, clinical performance” [as illustrated in Fig. 2] [6, 7, 8, 9]. The data drawn from the assessment of those
AN
elements constitute the clinical evidence for the device.
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4. Conclusions
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IVDs and other MDs have two harmonized standards, which are mutually exclusive, UNI EN ISO 14155:2011 only for clinical investigations on MDs and EN 13612:2002 only for performance
PT
evaluation on IVDs. However, there are several other significant differences between IVDs and other
CE
MDs.
In May 2017, key difference between these two categories of medical devices received a full and
AC
official recognition. Two new regulations on medical devices, the first one concerning IVDs, the latter concerning other MDs, were published in the European Official Journal. After their entry into application, on May 25, 2017, there will be a three-year transition period for MDs and a five-year transition period for IVDs. After the end of these transition periods, only the new rules will apply. Furthermore, these EU regulations, which, by definition, are “binding legislative acts”, must be applied in their entirety throughout the EU, contrary to the Directives that must be transposed into national laws. The two regulations, that adopt many principles established by the GHTF, may represent a 9
ACCEPTED MANUSCRIPT “Copernican revolution”, since they introduce several major changes. For example, there will be stricter requirements for the designation process of Notified Bodies. Additionally, Notified Bodies must perform unannounced manufacturer and supplier audits as part of their role in oversight. Another important change will concern the introduction of a new risk-based classification system for IVDs,
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ranging from Class A (lowest risk) to Class D (highest risk). Finally, in the regulation on IVDs, for the
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first time will be regulated the “Companion Diagnostics”. “Companion diagnostic” will be defined as a
CR
device essential for safe and effective use of a corresponding medicinal product through identifying, before and/or during treatment, patients who are most likely to benefit from that medicinal product; or
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patients likely to be at increased risk of serious adverse reactions as a result of treatment with the
AN
corresponding medicinal product. A Unique Device Identification system (UDI system) will be established allowing the identification and the traceability of devices [9, 10, 11]. There will be very
M
important changes to the requirements necessary to demonstrate clinical evidence. The manufacturer
ED
will have to specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. Therefore, he may rely on equivalent
PT
products only under very strict conditions. In the case of implantable devices and class III devices (high
CE
risk), clinical investigations shall be performed. As far as IVDs regards, clinical performance studies will be carried out unless it is justified to rely on other sources of clinical performance data. All these
AC
changes on the subject of clinical evidence will probably narrow the current regulatory gap between the United States of America (USA) and EU. In the USA, the Federal Drug Administration (FDA) classifies both IVDs and MDs as Class I, II, or III, based on the perceived level of regulatory control necessary to assure safety and effectiveness, with the lowest-risk devices in Class I and the highest in Class III. Class III devices (both IVDs and MDs) must undergo a demanding and expensive process, requiring clinical studies, known as “premarket approval application” (PMA) before they can be sold in the USA. The only class III devices that are not required to submit a premarket approval application are 10
ACCEPTED MANUSCRIPT the “preamendements” devices, i.e. the devices marketed in the USA prior to 1976, and devices equivalent to them [12]. FDA considers investigations concerning IVDs as clinical studies as other types of MDs and they are all regulated under the Investigational Device Exemption (IDE) regulation in Title 21 Code of Federal Regulations Part 812 (21 CFR 812) [13]. Unlike the EU, there are no
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distinctions between IVDs and other MDs. Finally, the term “performance evaluation” is exclusive to
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the European IVD regulatory framework.
CR
The new IVD EU regulation officially defines the term “performance evaluation” as “assessment and
US
analysis of data to establish or verify scientific validity, analytical and, where applicable, clinical performance of a device”. This definition, which is consistent with that of the GHTF, clearly
AN
distinguishes analytical performance from clinical performance. Consequently, clinical evidence means
M
“clinical data and performance evaluation results”. Moreover, according to the new regulation, the rules on performance studies should be in line with well-established international standards, such as the
ED
international standard UNI EN ISO 14155:2011 on good clinical practice for clinical investigations of
PT
medical devices for human subjects. This will facilitate the exchange of the results of performance studies between the UE and countries outside the UE. In addition, the rules should be in line with the
CE
most recent version of the World Medical Association Declaration of Helsinki on Ethical Principles for
AC
Medical Research Involving Human Subjects [10, 11].
11
ACCEPTED MANUSCRIPT References [1] In vitro diagnostic medical devices – Briefing November 2014. http://www.europarl.europa.eu/RegData/etudes/BRIE/2014/542151/EPRS_BRI(2014)542151_REV1_ EN.pdf
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[2] Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro
IP
diagnostic medical devices.
CR
http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:31998L0079&from=E [3] Sessione “Diagnostici in vitro e il corretto utilizzo dei dispositivi per test autodiagnostici nelle
US
farmacie alla luce dell'entrata in vigore del DM 16/12/2010”.
[4]
AN
http://www.salute.gov.it/imgs/c_17_paginearee_2561_listafile_itemname_25_ UNI EN ISO 14155: 2012.
ISO 13612: 2002.
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[5]
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http://iso.org
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http://iso.org
CE
[6] Global Harmonization Task Force - Clinical Evidence for IVD medical devices – Key Definitions and Concepts, November 2, 2012.
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http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n6-2012-clinical-evidence-ivdmedical-devices-121102.pdf [7]
Global Harmonization Task Force - Clinical Evidence for IVD medical devices – Clinical
Performance Studies for In Vitro Diagnostic Medical Devices, November 2, 2012. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n8-2012-clinical-performancestudies-ivd-medical-devices-121102.pdf
12
ACCEPTED MANUSCRIPT [8] Global Harmonization Task Force - Clinical Evidence for IVD medical devices – Scientific Validity Determination and Performance Evaluation November 2, 2012. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n7-2012-scientific-validitydetermination-evaluation-121102.
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[9] Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on
IP
medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC)
CR
No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. eur-lex.europa.eu › EUROPA › EU law and publications › EUR-Lex
US
[10] Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in
AN
vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.
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eur-lex.europa.eu › EUROPA › EU law and publications › EUR-Lex
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[11] Revisions of medical Device Directives.
http://ec.europa.eu/growth/sectors/medical-devices/regulatory-framework/revision_it
PT
[12] PMA Approvals.
PMAApprovals/
CE
https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/
AC
[13] Guidance for Industry and FDA staff – In Vitro Diagnostic (IVD) Device Studies – Frequently asked questions.
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ ucm071230.pdf
13
ACCEPTED MANUSCRIPT Figure Legends
Figure 1
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Procedures of Conformity Assessment
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Figure 2
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Performance Evaluation of IVDs
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ACCEPTED MANUSCRIPT
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Fig. 1
15
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ACCEPTED MANUSCRIPT
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Fig. 2
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ACCEPTED MANUSCRIPT Highlights
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CE
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ED
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AN
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T
Performance Evaluation is exclusive to IVDs. For other Medical Devices, Clinical Evaluation is used The aim of both terms is the same: to demonstrate that the device meets the Essential Requirements of safety and performance. Methods, however, are different: EN13612:2002 for IVDs and UNI EN ISO 14155 for other MDs. The new regulations change the requirements required to demonstrate clinical evidence. Clinical performance studies shall be carried out in the absence of clinical performance data. Moreover, performance studies should be in line with international standards, such as ISO 14155:2012, and the Declaration of Helsinki
17
Rosa Anna Grifa, Giacomo Pozzoli PII: DOI: Reference:
S0026-265X(17)30750-6 doi: 10.1016/j.microc.2017.08.004 MICROC 2884
To appear in:
Microchemical Journal
Received date: Revised date: Accepted date:
15 May 2017 1 August 2017 2 August 2017
Please cite this article as: Rosa Anna Grifa, Giacomo Pozzoli , Performance evaluation of in vitro diagnostic medical devices: Methodology and differences compared to studies on other medical devices, Microchemical Journal (2017), doi: 10.1016/j.microc.2017.08.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Performance Evaluation of In Vitro Diagnostic Medical Devices: methodology and differences compared to studies on other Medical Devices Rosa Anna Grifa*, Giacomo Pozzoli
IP
T
Institute of Pharmacology, Catholic University School of Medicine, largo F. Vito1, 00168 Rome, Italy
CR
*Corresponding author:
US
Dr. Rosa Anna Grifa
AN
Institute of Pharmacology, Catholic University School of Medicine
M
Largo F. Vito 1, 00168 Rome, Italy
phone: +39-06-30154367
ED
e-mail: [email protected]
AC
CE
PT
fax: +39-06-3050159
1
ACCEPTED MANUSCRIPT Abstract The aim of this article is to summarize the rules governing Performance Evaluation on In Vitro Diagnostic Medical Devices (IVDs) and to outline the main differences compared to studies on other Medical Devices (MDs) in the European Union (EU). In fact, the term “Performance Evaluation” is
T
exclusive to IVDs. For other MDs, the term “Clinical Evaluation” is used. However, the aim of both
IP
terms is the same: to demonstrate that a device meets the “Essential Requirements” of safety and
CR
performance. On the contrary, the methodology through performance evaluation for IVDs and clinical
US
evaluation for other MDs are performed, is different: UNI EN ISO 14155:2011 only for MDs and EN 13612:2002 only for IVDs. This difference is due to the fact that IVDs, unlike other MDs, do not
AN
generally come into contact with patients. Therefore, it can be difficult to demonstrate direct harm to
M
patients, unless the device itself causes deterioration in the state of health. Harm to patients is more likely to be indirect. However, in May 2017 two new regulations on MDs have been published, the first
ED
one concerning IVDs and the second one concerning other MDs. These new regulations may represent
PT
a real revolution. There will be very important changes to the requirements required to demonstrate clinical evidence. With regard to IVDs, clinical performance studies shall be carried out in the absence
CE
of clinical performance data. Moreover, performance studies should be in line with international
AC
standards, such as ISO 14155:2011, and the Declaration of Helsinki, and many others are the changes on the horizon.
Keywords: Performance evaluation, clinical evaluation, in vitro diagnostic medical devices, other medical devices, clinical evidence
2
ACCEPTED MANUSCRIPT 1. Introduction Despite the fact that the In Vitro Diagnostic Medical Devices (IVDs) industry has a considerable impact on the European economy, IVDs-related sector is surprisingly poorly known. Indeed, this industry comprises about 3,000 companies, employing over 75,000 workers, and produces more than
IP
T
40,000 different IVDs, providing an annual sales amount around € 11 billion, compared to € 100 billion
CR
for the entire Medical Devices (MDs) industry [1]. Therefore, it is important to explain what the term In Vitro Diagnostic Medical Device means, and to explain the current European IVD regulatory
US
framework.
According to the current IVD regulatory reference, Directive 98/79/EC, IVD is “any medical device
AN
that is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or
M
system, either used alone or in combination, intended by the manufacturer to be used in vitro for the examination of biological specimens, including blood and tissues, derived from the human body,
ED
principally or exclusively collected to gain information: concerning a physiological or pathological state, or
-
concerning a congenital abnormality, or
-
to determine the safety and compatibility with potential recipients, or
-
to monitor therapeutic measures”.
AC
CE
PT
-
The Directive 98/79/EC divides IVDs into four categories, according to the perceived risk associated with the relative danger to public health and/or patient treatment by an IVD failing to perform as intended. In particular, the four groups are:
List A:
Reagents and reagent products, including calibrators and control materials for: 3
ACCEPTED MANUSCRIPT -
determining the following blood groups: ABO system, rhesus (C, c, D, E, e) anti-Kell;
-
detection, confirmation and quantification of infection markers of HIV type 1 and 2, HTLV 1 and 2, and hepatitis B, C and D, in human specimens.
T
List B:
IP
Reagents and reagent products, including calibrators and control materials for: determining anti-Duffy and anti-Kidd blood groups;
-
determining irregular anti-erythrocytic antibodies;
-
detection and quantification in human samples of the following congenital infections:
AN
US
CR
-
rubella, toxoplasmosis;
diagnosing the hereditary disease phenylketonuria;
-
determining the following human infections: cytomegalovirus, chlamydia;
-
determining DR, A and B HLA tissue groups;
-
determining the tumoral marker PSA;
-
evaluating the risk of trisomy 21;
-
devices for the measurement of blood sugar.
AC
CE
PT
ED
M
-
Devices for self-testing.
All other IVDs.
The risk associated with their use decreases from the devices enclosed within the List A to those of the List B then to devices for self-testing and finally to all other IVDs. 4
ACCEPTED MANUSCRIPT In all cases, the manufacturer plays a key role, since He is responsible for identifying data relevant to the IVD and determining the types and amount of data needed to establish that the devices meet the Essential Requirements, documenting this process through the preparation of a technical dossier called “Technical File”. The latter includes documents related to device design, risk management,
T
manufacture, possible test reports, labels, instructions for use and “performance evaluation”. For "all
IP
other IVDs1”, the manufacturer is even allowed to self-declare it in the "declaration of CE conformity"
CR
contained in the “Technical File”. In fact, these devices do not require the involvement of a Notified Body. As far as IVDs for self-testing regards, the manufacturer must prepare a declaration of
US
conformity in a similar way to the general devices but a Notified Body review is also required. Finally,
AN
for List A and List B IVDs, the manufacturer must call on Notified Bodies before the product can be placed on the market [2, 3]. In addition, for List A IVDs, which presents higher risk than devices of List
M
B, the Notified Body must verify that the product meets the Common Technical Specifications (CTS)
ED
requirements for sensibility and specificity and must release each product batch before it can be placed on the European market. The batch release often requires performance evaluation studies [as illustrated
CE
PT
in Fig.1].
AC
2. Materials and Methods We conducted a systematic review of scientific literature, analysis of website of Competent Authorities, European Commission and Eurlex.
3. Results and Discussion
5
ACCEPTED MANUSCRIPT The term “Performance Evaluation” is exclusive to IVDs, whereas the term “Clinical Evaluation” is used for other MDs. However, the aim of both terms is the same: to demonstrate that a device meets the “Essential Requirements” of safety and performance. For other MDs, Clinical Evaluation must follow a defined and methodologically correct procedure based on: 1) a critical evaluation of scientific
T
literature; 2) or a critical evaluation of specific clinical investigations results carried out with the
IP
medical device in question; 3) or a critical evaluation of the combined clinical data provided by
CR
scientific literature and clinical investigations. Clinical Evaluation must be based on clinical data for all medical devices. Every medical device sold in Europe, regardless of its classification, must have a
US
Clinical Evaluation Report in its technical file. The international standard UNI EN ISO 14155:2011
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“Clinical investigation of medical devices for human subjects - Good clinical practice” describes the methods required for conducting clinical investigations. The above standard does not apply to IVDs1
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[4]. For IVDs, Directive 98/79/EC requires that the manufacturer provides “clinical evidence”, in his
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technical documentation, that the IVD performs as claimed, whether these claims are of a technical, analytical or diagnostic nature. Such evidence can be shown by data already available to the
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manufacturer or by scientific literature or by data originating from performance evaluation studies in a
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clinical or other appropriate environment in accordance with the intended use. However, the terms “performance evaluation” and “performance evaluation study” are not defined in the Directive; instead,
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they are defined in the European harmonized standard, EN 13612:2002, “Performance evaluation of in vitro diagnostic medical devices”. This standard defines “performance evaluation” as an “investigation of the performance of any in vitro diagnostic medical device based on data already available, scientific literature and/or performance evaluation studies”. The standard, also defines “performance evaluation studies” as an “investigation of any in vitro diagnostic medical device intended to validate the performance claims under the anticipated conditions of use”. If a performance evaluation study is necessary and appropriate to support performance claims of the IVD, this standard “generically” 6
ACCEPTED MANUSCRIPT describes how the manufacturer can fulfill his obligation to conduct a scientifically correct performance evaluation study [5]. This is a considerable limit to this standard. In fact, it would be more correct to distinguish “analytical performance study” from “clinical performance study”. These definitions were provided in 2012 by the Global Harmonization Task Force (GHTF), a voluntary international group of
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representatives from medical device regulatory authorities and trade associations that provide non-
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binding guide documents to regulatory authorities for use in the regulation of medical devices. It is
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important to clarify that the GHTF no longer exists, and the International Medical Device Regulators Forum (IMDRF), an organization composed only by officials from regulatory agencies, but not from
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industry, around the world, has permanently replaced it. IMDRF is currently continuing the work on
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international medical device regulatory harmonization previously carried out by the GHTF. However, “analytical performance study” and “clinical performance study” definitions remain of actual
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importance. The first one is defined as a “study undertaken to establish or confirm the ability of an IVD
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to detect or measure a particular analyte”. The “clinical performance study” is “a study undertaken to establish or confirm the ability of an IVD to yield results that are correlated with a particular clinical
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condition/physiological state in accordance with target population and intended user”. The purpose of a
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clinical performance study is to establish or confirm aspects of IVDs which cannot be determined by analytical performance studies, literature and/or previous experience acquired by routine diagnostic
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testing. According to the GHTF, since clinical performance of IVDs is the relationship between the testing results and the clinical conditions of patients, the clinical performance study design should take into account potential risks for patients and should follow appropriate ethical principles. It should be designed, conducted, analyzed and evaluated so that the best possible representation can be achieved with the target population in accordance with the intended use. To carry out appropriate studies for performance evaluation purpose, the GHTF has divided IVDs into three different categories:
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ACCEPTED MANUSCRIPT Established and standardized tests whose analytical performance informations combined with scientific validity informations meet the clinical evidences requirements and are sufficient to demonstrate compliance with the Essential Safety and Performance Principles (EPs). These tests have clinical guidelines or consensus for their use and produce comparable results for the
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analyte regardless of the method or the manufacturer. Examples of this category include liver (e.g. AST, ALT, bilirubin) and kidney (e.g. creatinine,
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BUN) functional markers; electrolytes (e.g. sodium, chloride); metabolic markers (e.g. glucose,
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calcium, albumin, total protein); hormones (e.g. hCG); blood gases and biochemical tests for the detection and identification of microorganisms.
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Established and non-standardized tests whose information about analytical performance in
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conjunction with scientific validity information alone may not meet the clinical evidence
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requirements and may not be sufficient to demonstrate conformity with relevant EPs. These tests have clinical guidelines or consensus for their use but results obtained from different IVD
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medical devices might not be used interchangeably.
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Examples of this category include tests for infection disease (e.g. Rubella, Hepatitis C), hormones (e.g. estradiol), cardiac markers (e.g. troponin), tumoral markers (e.g. CEA, PSA)
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and cell markers (e.g. CD4, T-cells.)
Novel tests to whom information about analytical performance in conjunction with scientific validity information alone probably will not meet the clinical evidence requirements and will not be sufficient to demonstrate conformity with relevant EPs. These tests involve a new analyte, new technology, new target population, new application of an established technology, or a new intended use. Therefore, they are neither established nor standardized. 8
ACCEPTED MANUSCRIPT Examples of this category include tests for newly identified cardiac markers (e.g. high sensitivity CRP), tumoral markers (e.g. CTC), emerging infectious diseases (e.g. SARS, H1N1) and other pathogens. Finally, the GHTF defines the terms “performance evaluation” and “clinical evidence”. Performance
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evaluation means “assessment and analysis of data to establish or verify the performance of an IVD2
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medical device”. Data are typically generated from studies (including, where appropriate, clinical
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performance studies using human specimens) or obtained from scientific literature”. Clinical evidence
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means “compilation of the scientific validity, analytical performance and, where applicable, clinical performance” [as illustrated in Fig. 2] [6, 7, 8, 9]. The data drawn from the assessment of those
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elements constitute the clinical evidence for the device.
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4. Conclusions
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IVDs and other MDs have two harmonized standards, which are mutually exclusive, UNI EN ISO 14155:2011 only for clinical investigations on MDs and EN 13612:2002 only for performance
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evaluation on IVDs. However, there are several other significant differences between IVDs and other
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MDs.
In May 2017, key difference between these two categories of medical devices received a full and
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official recognition. Two new regulations on medical devices, the first one concerning IVDs, the latter concerning other MDs, were published in the European Official Journal. After their entry into application, on May 25, 2017, there will be a three-year transition period for MDs and a five-year transition period for IVDs. After the end of these transition periods, only the new rules will apply. Furthermore, these EU regulations, which, by definition, are “binding legislative acts”, must be applied in their entirety throughout the EU, contrary to the Directives that must be transposed into national laws. The two regulations, that adopt many principles established by the GHTF, may represent a 9
ACCEPTED MANUSCRIPT “Copernican revolution”, since they introduce several major changes. For example, there will be stricter requirements for the designation process of Notified Bodies. Additionally, Notified Bodies must perform unannounced manufacturer and supplier audits as part of their role in oversight. Another important change will concern the introduction of a new risk-based classification system for IVDs,
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ranging from Class A (lowest risk) to Class D (highest risk). Finally, in the regulation on IVDs, for the
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first time will be regulated the “Companion Diagnostics”. “Companion diagnostic” will be defined as a
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device essential for safe and effective use of a corresponding medicinal product through identifying, before and/or during treatment, patients who are most likely to benefit from that medicinal product; or
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patients likely to be at increased risk of serious adverse reactions as a result of treatment with the
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corresponding medicinal product. A Unique Device Identification system (UDI system) will be established allowing the identification and the traceability of devices [9, 10, 11]. There will be very
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important changes to the requirements necessary to demonstrate clinical evidence. The manufacturer
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will have to specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. Therefore, he may rely on equivalent
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products only under very strict conditions. In the case of implantable devices and class III devices (high
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risk), clinical investigations shall be performed. As far as IVDs regards, clinical performance studies will be carried out unless it is justified to rely on other sources of clinical performance data. All these
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changes on the subject of clinical evidence will probably narrow the current regulatory gap between the United States of America (USA) and EU. In the USA, the Federal Drug Administration (FDA) classifies both IVDs and MDs as Class I, II, or III, based on the perceived level of regulatory control necessary to assure safety and effectiveness, with the lowest-risk devices in Class I and the highest in Class III. Class III devices (both IVDs and MDs) must undergo a demanding and expensive process, requiring clinical studies, known as “premarket approval application” (PMA) before they can be sold in the USA. The only class III devices that are not required to submit a premarket approval application are 10
ACCEPTED MANUSCRIPT the “preamendements” devices, i.e. the devices marketed in the USA prior to 1976, and devices equivalent to them [12]. FDA considers investigations concerning IVDs as clinical studies as other types of MDs and they are all regulated under the Investigational Device Exemption (IDE) regulation in Title 21 Code of Federal Regulations Part 812 (21 CFR 812) [13]. Unlike the EU, there are no
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distinctions between IVDs and other MDs. Finally, the term “performance evaluation” is exclusive to
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the European IVD regulatory framework.
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The new IVD EU regulation officially defines the term “performance evaluation” as “assessment and
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analysis of data to establish or verify scientific validity, analytical and, where applicable, clinical performance of a device”. This definition, which is consistent with that of the GHTF, clearly
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distinguishes analytical performance from clinical performance. Consequently, clinical evidence means
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“clinical data and performance evaluation results”. Moreover, according to the new regulation, the rules on performance studies should be in line with well-established international standards, such as the
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international standard UNI EN ISO 14155:2011 on good clinical practice for clinical investigations of
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medical devices for human subjects. This will facilitate the exchange of the results of performance studies between the UE and countries outside the UE. In addition, the rules should be in line with the
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most recent version of the World Medical Association Declaration of Helsinki on Ethical Principles for
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Medical Research Involving Human Subjects [10, 11].
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ACCEPTED MANUSCRIPT References [1] In vitro diagnostic medical devices – Briefing November 2014. http://www.europarl.europa.eu/RegData/etudes/BRIE/2014/542151/EPRS_BRI(2014)542151_REV1_ EN.pdf
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[2] Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro
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diagnostic medical devices.
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http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:31998L0079&from=E [3] Sessione “Diagnostici in vitro e il corretto utilizzo dei dispositivi per test autodiagnostici nelle
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farmacie alla luce dell'entrata in vigore del DM 16/12/2010”.
[4]
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http://www.salute.gov.it/imgs/c_17_paginearee_2561_listafile_itemname_25_ UNI EN ISO 14155: 2012.
ISO 13612: 2002.
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[5]
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http://iso.org
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http://iso.org
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[6] Global Harmonization Task Force - Clinical Evidence for IVD medical devices – Key Definitions and Concepts, November 2, 2012.
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http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n6-2012-clinical-evidence-ivdmedical-devices-121102.pdf [7]
Global Harmonization Task Force - Clinical Evidence for IVD medical devices – Clinical
Performance Studies for In Vitro Diagnostic Medical Devices, November 2, 2012. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n8-2012-clinical-performancestudies-ivd-medical-devices-121102.pdf
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ACCEPTED MANUSCRIPT [8] Global Harmonization Task Force - Clinical Evidence for IVD medical devices – Scientific Validity Determination and Performance Evaluation November 2, 2012. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n7-2012-scientific-validitydetermination-evaluation-121102.
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[9] Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on
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medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC)
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No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. eur-lex.europa.eu › EUROPA › EU law and publications › EUR-Lex
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[10] Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in
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vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.
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eur-lex.europa.eu › EUROPA › EU law and publications › EUR-Lex
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[11] Revisions of medical Device Directives.
http://ec.europa.eu/growth/sectors/medical-devices/regulatory-framework/revision_it
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[12] PMA Approvals.
PMAApprovals/
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https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/
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[13] Guidance for Industry and FDA staff – In Vitro Diagnostic (IVD) Device Studies – Frequently asked questions.
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ ucm071230.pdf
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ACCEPTED MANUSCRIPT Figure Legends
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Procedures of Conformity Assessment
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Figure 2
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Performance Evaluation of IVDs
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Fig. 1
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Fig. 2
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ACCEPTED MANUSCRIPT Highlights
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Performance Evaluation is exclusive to IVDs. For other Medical Devices, Clinical Evaluation is used The aim of both terms is the same: to demonstrate that the device meets the Essential Requirements of safety and performance. Methods, however, are different: EN13612:2002 for IVDs and UNI EN ISO 14155 for other MDs. The new regulations change the requirements required to demonstrate clinical evidence. Clinical performance studies shall be carried out in the absence of clinical performance data. Moreover, performance studies should be in line with international standards, such as ISO 14155:2012, and the Declaration of Helsinki
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