In-Vitro Diagnostic Medical Device Regulation
- Expanded scope to include companion diagnostics
- Classification systems has been altered to risk-based system to more closely match other international markets
- All non-EU based manufacturers are obligated to appoint an Authorized Representative
Table of Contents
- The Regulation: IVDR 2017/746/EU
- Technical Documentation
- Path to EU Market Entry: Conformity Assessment Procedures
- Notified Bodies under the IVDR
- Authorized Representatives under the IVDR
- Clinical Evidence and Performance Evaluation
- Clinical Performance Studies
- Person Responsible for Regulatory Compliance
- Risks of Non-Compliance
Devices falling under the In Vitro Diagnostic Medical Device Regulation (IVDR) 2017/746 are 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:
- concerning a physiological or pathological process or state;
- concerning congenital physical or mental impairments;
- concerning the predisposition to a medical condition or a disease;
- to determine the safety and compatibility with potential recipients;
- to predict treatment response or reactions;
- to define or monitoring therapeutic measures.
Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices; ‘medical device’ means ‘medical device’ as defined in point (1) of Article 2 of Regulation (EU) 2017/745.
The following products are excluded from the IVDR scope:
- 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;
- invasive sampling products or products which are directly applied to the human body for the purpose of obtaining a specimen;
- internationally certified reference materials;
- materials used for external quality assessment schemes.
The Regulation: IVDR 2017/746
The Regulation (EU) IVDR 2017/746 (In Vitro Diagnostic Medical Device Regulation – IVDR) has been adopted on the 5th April 2017. It will apply to in-vitro diagnostic medical devices after the transitional period of 3 years (May 2020).
Whereas the IVD Directive 98/79/EC specifies Notified Body involvement for only a few high risk IVDs listed in Annex VII, the IVD Regulation introduces risk-based classification Class A to D, based on IMDRFrules and similar to Health Canada and TGA classification rules
The outcome is that the conformity assessment process for CE marking for the majority of IVDs will now necessitate involvement of a Notified Body, as opposed to self-declaration by the manufacturer under the IVDD
The majority of IVDs currently self-certified will now require the services of a Notified Body in the conformity assessment process to ensure the safety and performances of IVDs placed on the EU market.
Under the IVDR, Devices are divided into classes A, B, C and D, taking into account the intended purpose of the devices and their inherent risks
Class D: High Public health and Personal risk i.e. Screening for transmissible agents and for high risk blood grouping for transfusion, transplantation, cell administration; life-threatening transmissible agents : Screening where possible high risk of propagation, and detection of infectious load where monitoring determines patient management e.g. Blood groups ABO, Rh, Kidd, Duffy, Kell; HIV1 and 2, HTLV I/II, Hep B and C, Chagas, screening blood for syphilis
Class C: Public health risk moderate – low; Personal risk low i.e. Testing for compatibility for transfusion, transplantation, cell administration, excluding high risk blood grouping; tests for Infectious disease / STI agents / cancer biomarkers / Companion diagnostics / genetic testing / TORCH screening / congenital disorders / monitoring high risk medicines/substances e.g. blood glucose / most self-test IVDs.
Class B: Public health risk Low; Personal risk moderate to low i.e. clinical chemistry tests, some specific self-test IVDs – Class B is also the default ruling where no other Rule applies.
Class A: Public health and personal risk low, e.g. Specimen receptacles; products for general lab use, accessories with no critical characteristics, buffers, washes, culture media, histological stains if intended for specific test; instruments intended for IVD procedures
Devices intended to be used for the following purposes are classified as class D: — detection of the presence of, or exposure to, a transmissible agent in blood, blood components, cells, tissues or organs, or in any of their derivatives, in order to assess their suitability for transfusion, transplantation or cell administration; — detection of the presence of, or exposure to, a transmissible agent that causes a life-threatening disease with a high or suspected high risk of propagation; — determining the infectious load of a life-threatening disease where monitoring is critical in the process of patient management.
Devices intended to be used for blood grouping, or tissue typing to ensure the immunological compatibility of blood, blood components, cells, tissue or organs that are intended for transfusion or transplantation or cell administration, are classified as class C, except when intended to determine any of the following markers: — ABO system [A (ABO1), B (ABO2), AB (ABO3)]; — Rhesus system [RH1 (D), RHW1, RH2 (C), RH3 (E), RH4 (c), RH5 (e)]; — Kell system [Kel1 (K)]; — Kidd system [JK1 (Jka), JK2 (Jkb)]; — Duffy system [FY1 (Fya), FY2 (Fyb)]; in which case they are classified as class D.
Devices are classified as class C if they are intended:
- for detecting the presence of, or exposure to, a sexually transmitted agent;
- for detecting the presence in cerebrospinal fluid or blood of an infectious agent without a high or suspected high risk of propagation;
- for detecting the presence of an infectious agent, if there is a significant risk that an erroneous result would cause death or severe disability to the individual, foetus or embryo being tested, or to the individual’s offspring;
- for pre-natal screening of women in order to determine their immune status towards transmissible agents;
- for determining infective disease status or immune status, where there is a risk that an erroneous result would lead to a patient management decision resulting in a life-threatening situation for the patient or for the patient’s offspring;
- to be used as companion diagnostics;
- to be used for disease staging, where there is a risk that an erroneous result would lead to a patient management decision resulting in a life-threatening situation for the patient or for the patient’s offspring;
- to be used in screening, diagnosis, or staging of cancer;
- for human genetic testing;
- for monitoring of levels of medicinal products, substances or biological components, when there is a risk that an erroneous result will lead to a patient management decision resulting in a life-threatening situation for the patient or for the patient’s offspring;
- for management of patients suffering from a life-threatening disease or condition;
- for screening for congenital disorders in the embryo or foetus;
- for screening for congenital disorders in new-born babies where failure to detect and treat such disorders could lead to life-threatening situations or severe disabilities.
- Devices intended for self-testing are classified as class C, except for devices for the detection of pregnancy, for fertility testing and for determining cholesterol level, and devices for the detection of glucose, erythrocytes, leucocytes and bacteria in urine, which are classified as class B.
- Devices intended for near-patient testing are classified in their own right.
The following devices are classified as class A:
- products for general laboratory use, accessories which possess no critical characteristics, buffer solutions, washing solutions, and general culture media and histological stains, intended by the manufacturer to make them suitable for in vitro diagnostic procedures relating to a specific examination;
- instruments intended by the manufacturer specifically to be used for in vitro diagnostic procedures;
- specimen receptacles.
Devices not covered by the above-mentioned classification rules are classified as class B.
Devices which are controls without a quantitative or qualitative assigned value are classified as class B.
Manufacturers shall draw up and keep up to date the technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III of the IVDR.
The Technical Documentation shall contain all evidences to demonstrate that an in vitro diagnostic device complies with the general safety and performance requirements specified in Annex 1 of the IVDR. The Technical Documentation is mandatory for all devices regardless of their classification (A, B, C or D).
Manufacturers shall keep the technical documentation, the EU declaration of conformity and, if applicable, a copy of the relevant certificate, including any amendments and supplements, available for the competent authorities for a period of at least 10 years after the last device covered by the EU declaration of conformity has been placed on the market.
Upon request by a competent authority, the manufacturer shall, as indicated therein, provide that technical documentation in its entirety or a summary thereof.
A manufacturer with a registered place of business outside the Union shall ensure that the authorized representative has the necessary documentation permanently available.
Manufacturers shall, upon request by a competent authority, provide it with all the information and documentation necessary to demonstrate the conformity of the device, in an official Union language determined by the Member State concerned.
The Member State in which the notified body is established may require that all or certain documents, including the technical documentation, audit, assessment and inspection reports, relating to the procedures referred to in paragraphs 1 to 10 be made available in an official Union language(s) determined by that Member State. In the absence of such requirement, those documents shall be available in any official Union language acceptable to the notified body.
Path to EU Market Entry: Conformity Assessment Procedures
Prior to placing a device on the market, manufacturers shall undertake an assessment of the conformity of that device, in accordance with the applicable conformity assessment procedures set out in Annexes IX to XI of the IVDR.
Class D Conformity Assessment Procedures
Class D- Option 1
Manufacturers of class D devices, other than devices for performance study, shall be subject to a conformity assessment as specified in Chapters I, II and III of Annex IX (Conformity assessment based on a quality management system and on assessment of technical documentation).
- In addition, for devices for self-testing and near-patient testing, the manufacturer shall follow the procedure for technical documentation assessment set out in Section 5.1 of Annex IX.
- In addition, for companion diagnostics the manufacturer shall follow the procedure for technical documentation assessment set out in Section 5.1 of Annex IX. Furthermore, the notified body shall consult a competent authority designated by the Member States in accordance with Directive 2001/83/EC of the European Parliament and of the Council or the EMA, as applicable, in accordance with the procedure set out in Section 5.2 of Annex IX.
Class D- Option 2
Manufacturers of class D devices, other than devices for performance study, may choose to apply a conformity assessment as specified in Annex X coupled with a conformity assessment as specified in Annex XI.
- For companion diagnostics, the notified body shall in particular consult a competent authority designated by the Member States in accordance with Directive 2001/83/EC or the EMA, as applicable, in accordance with the procedure set out in point (k) of Section 3 of Annex X.
For ALL Class D (regardless of above chosen path)
For devices for which one or more EU reference laboratories have been designated in accordance with Article 100, the notified body performing the conformity assessment shall request one of the EU reference laboratories to verify by laboratory testing the performance claimed by the manufacturer and the compliance of the device with the applicable Common Specifications, or with other solutions chosen by the manufacturer to ensure a level of safety and performance that is at least equivalent.
In case where no Common Specifications are available for class D devices and where it is also the first certification for that type of device, the notified body shall consult the relevant panel of experts referred to in Article 106 of Regulation (EU) 2017/745 on the performance evaluation report of the manufacturer.
Class C Conformity Assessment Procedures
Class C- Option 1
Manufacturers of class C devices shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, including an assessment of the technical documentation of at least one representative device per generic device group.
- In addition for self-testing and near-patient testing, the manufacturer shall follow the procedure for technical documentation assessment set out in Section 5.1 of Annex IX.
- In addition, for companion diagnostics, the notified body shall for every device follow the procedure for technical documentation assessment laid down in Section 5.2 of Annex IX, and shall apply the procedure for technical documentation assessment laid down in Sections 4.1 to 4.8 of Annex IX and shall consult the competent authority designated by the Member States in accordance with Directive 2001/83/EC or the EMA.
Class C - Option 2
Manufacturers of class C devices, may choose to apply a conformity assessment as specified in Annex X coupled with a conformity assessment as specified in Annex XI except its Section 5.
- For companion diagnostics the notified body shall in particular for every device consult a competent authority designated by the Member States in accordance with Directive 2001/83/EC or the EMA,.
Class B Conformity Assessment Procedure
Manufacturers of class B devices shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, and including an assessment of the technical documentation for at least one representative device per category of devices.
- In addition, for devices for self-testing and near-patient testing, the manufacturer shall follow the procedure for assessment of the technical documentation set out in Section 5.1 of Annex IX.
Class A Conformity Assessment Procedure
Manufacturers of class A devices shall declare the conformity of their products by issuing the EU declaration of conformity referred to in Article 17, after drawing up the technical documentation set out in Annexes II and III.
- However, if those devices are placed on the market in sterile condition, the manufacturer shall apply the procedures set out in Annex IX or in Annex XI. Involvement of the notified body shall be limited to the aspects relating to establishing, securing and maintaining sterile conditions.
Notified Bodies for In-Vitro Diagnostic Medical Devices under IVDR
Notified Bodies play a key role in supporting manufacturers to place only safe and compliant in vitro diagnostic medical devices on the EU Market. They are controlling the manufacturers by carrying out conformity assessment procedures and grant conformity certificates to in vitro diagnostic medical devices. There are certain expectations that a Notified Body must meet before being designated by the EU Authorities. A key aspect of their role is to audit the quality management system of the manufacturer and review the technical documentation of IVD As, B, C, D. Notified bodies will issue EU Technical Documentation Assessment Certificates, EU Quality Management System Certificate, EU Production Quality Assurance Certificate and EU Type Examination Certificates depending on the conformity assessment procedure selected.
All notified bodies which have been designated under Directive 98/79/EC need to be re-designated under the IVDR. Under the IVDR, the requirements that notified bodies must meet have increased drastically. Those notified bodies are also subject to a peer review every 3 years. As a result of this process, we expect that the number of notified bodies designated under IVDR will be very limited. Notified bodies which have been designated under the IVD can issue the IVDR conformity assessment certificates. Manufacturer can consult the list of designated notified bodies under IVDR in the European Commission´s directory of Notified Bodies (NANDO website).
Notified bodies shall conduct surveillance audit on at least an annual basis as well as unannounced audit of manufacturer and where applicable subcontractors and suppliers.
For class B and class C devices, notified shall draw up and keep up to date, a sampling plan for the assessment of technical documentation as referred to in Annexes II and III covering the range of such devices covered by the manufacturer’s application. That plan shall ensure that all devices covered by the certificate are sampled over the period of validity of the certificate.
Selecting the right Notified Body for your EU Compliance requirements can be a daunting task. Contact us for help in your Notified Body Selection needs!
Authorized Representatives for In-Vitro Diagnostics Regulation
An Authorized Representative is any person naturally or legally established in the European Union who is explicitly designated by the manufacturer to act on their behalf. This person may be addressed by authorities and bodies within the Community, instead of the manufacturer themselves, with regards to the requirements of this Directive.
What are the duties of an E.A.R?
The role of a European Authorized Representative is both varied and challenging. The main duties include, but are not limited to, the following:
- Providing a registered address within the European Union
- Keeping all technical documentation available for inspection by the European Authorities
- Completing notifications to European Authorities
- Completing any registrations to national databases
- Taking care of any incident reporting
- Representing the manufacturer towards the European Commission, Authorities and Notified Bodies
- Safeguarding and ensuring compliance with constant regulatory updates
- Consulting on European Regulations
Expanded responsibilities under the In-Vitro Diagnostics Regulation include:
- Designation of Person Responsible for Regulatory Compliance (PRRC)
Non-EU based manufacturers are obligated to appoint a European Authorized Representative to serve as their vigilance contact point and ensure continued compliance at all times.
Clinical Evidence and Performance Evaluation
The IVDR (article 56 and Annex XIII) reinforces the need for clinical evidence to demonstrate conformity with the relevant general safety and performance requirements.
Performance evaluation of a device is a continuous process by which data are assessed and analysed to demonstrate the scientific validity, analytical performance and clinical performance of that device for its intended purpose as stated by the manufacturer.
To plan, continuously conduct and document a performance evaluation, the manufacturer shall establish and update a performance evaluation plan. The performance evaluation plan shall specify the characteristics and the performance of the device and the process and criteria applied to generate the necessary clinical evidence.
The performance evaluation shall be thorough and objective, considering both favorable and unfavorable data.
The manufacturer shall assess all relevant scientific validity, analytical and clinical performance data to verify the conformity of its device with the general safety and performance requirements as referred to in Annex I. The amount and quality of that data shall allow the manufacturer to make a qualified assessment whether the device will achieve the intended clinical benefit or benefits and safety, when used as intended by the manufacturer. The data and conclusions drawn from this assessment shall constitute the clinical evidence for the device. The clinical evidence shall scientifically demonstrate that the intended clinical benefit or benefits and safety will be achieved according to the state of the art in medicine.
The clinical evidence shall be documented in a performance evaluation report. This report shall include the scientific validity report, the analytical performance report, the clinical performance report and an assessment of those reports allowing demonstration of the clinical evidence.
Demonstration of the clinical performance of a device shall be based on one or a combination of the following sources:
- clinical performance studies;
- scientific peer-reviewed literature;
- published experience gained by routine diagnostic testing.
Clinical performance studies shall be performed unless due justification is provided for relying on other sources of clinical performance data.
The clinical evidence and its assessment in the performance evaluation report shall be updated throughout the life cycle of the device concerned with data obtained from the implementation of the manufacturer’s Post Market Performance Follow Up plan in accordance with Part B of Annex XIII, as part of the performance evaluation and the post-market surveillance system referred to in Article 10(9). The performance evaluation report shall be part of the technical documentation.
Clinical Performance Studies
The purpose of clinical performance studies is to establish or confirm aspects of device performance which cannot be determined by analytical performance studies, literature and/or previous experience gained by routine diagnostic testing. This information is used to demonstrate compliance with the relevant general safety and performance requirements with respect to clinical performance. When clinical performance studies are conducted, the data obtained shall be used in the performance evaluation process and be part of the clinical evidence for the device.
Manufacturer/sponsor is responsible for the:
- Design of the Performance Study Plan CPSP
- Designation of principal investigator
- Obtaining the authorization from the Competent Authorities in accordance with Article 66 for the following studies:
- in which surgically invasive sample-taking is done only for the purpose of the performance study;
- that is an interventional clinical performance study as defined in point (46) of Article 2; or
- where the conduct of the study involves additional invasive procedures or other risks for the subjects of the studies,
- Performance studies involving Companion Diagnostic
- Application with ethical committee
- The non-EU manufacturer/sponsor may choose to appoint the Authorized Representative to seek authorization on his behalf to perform the performance studies.
- Serious adverse events occurring during the performance studies must be reported by the sponsor or the appointed Authorized Representative through the EUDAMED database
- The Performance study report should be incorporated in the technical documentation that has to be kept available by the manufacturer and his appointed European Authorized Representative established within the Union.
- Sponsor (or the authorized representative) shall notify the competent authorities of the ending of the clinical investigation, and submit a report.
Authorities are responsible to give authorization for the Performance Studies to start, after registration in the European Databank. Delegated acts may be taken by the commission to fine tune this procedure. The Performance Study will receive a single registration number (SRN) for better follow-up and data exchange between member-states.
Clinical investigation and evaluation are reviewed by the Notified Body when the conformity assessment procedure does include an assessment of the technical documentation.
Personal Responsible for Regulatory Compliance
Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of in vitro diagnostic medical devices. The requisite expertise shall be demonstrated by either of the following qualifications:
(a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to in vitro diagnostic medical devices;
(b) four years of professional experience in regulatory affairs or in quality management systems relating to in vitro diagnostic medical devices.
Micro and small enterprises within the meaning of Commission Recommendation 2003/361/EC (Micro and SMEs are those organizations which have less than 50 employees and a turnover of less than 10 million Euros) shall not be required to have the person responsible for regulatory compliance within their organisation but shall have such person permanently and continuously at their disposal.
The person responsible for regulatory compliance shall at least be responsible for ensuring that:
- the conformity of the devices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released;
- the technical documentation and the EU declaration of conformity are drawn up and kept up-to-date;
- the post-market surveillance obligations are complied with in accordance with Article 10(9);
- the reporting obligations referred to in Articles 82 to 86 are fulfilled;
- in the case of devices for performance studies intended to be used in the context of interventional clinical performance studies or other performance studies involving risks for the subjects, the statement referred to in Section 4.1 of Annex XIV is issued.
Manufacturer with a registered place of business outside the Union shall designate a sole authorized representative in order to place their device on the EU market (Art 11.1).
Failure to Comply: Risks of Non-Compliance
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