The Authorized Representative (AR)

A natural or legal person established in the EU explicitly designated by a non-European manufacturer who acts on behalf the manufacturer in carrying out certain tasks required in the applicable regulations.


The Notified Body (NB)

An organization or entity that has been appointed and accredited by a Competent Authority to assess and ensure conformance to the requirements set forth in the directives. An NB will be nominated based on designated requirements, such as knowledge, experience, independence and resources to conduct the conformity assessment.


The Competent Authority (CA)

A person or entity that has the authority to act on behalf of the government of the Member State to ensure that the requirements of the MDR and IVDR are transposed into national law and applied. Each Member State has a CA responsible for medical devices. Each Member State has a CA responsible for medical devices.


The Manufacturer

A natural or legal person who manufactures or fully refurbishes a device or has a device designed, manufactured or fully refurbished, and markets that device under its name or trademark.


Overview

Purpose (+) Scope

This post is about the key entities involved in the CE marking process under the MDR and the IVDR.

Type of Entities

Different types of entities are/can be involved thought the CE marking process 

  • A manufacturer
  • An authorised representative (AR)
  • An importer
  • A distributor
  • A notified body (NB)
  • A competent authority (CA) of a Member State

EU reference laboratories, the European Medicines Agency (EMA), and the EU Commission are voluntary not mentioned here as they intervene in particular cases.

Some of them are considered as Economic Operators (EOs) 

‘economic operator’ means a manufacturer, an authorised representative, an importer or a distributor;

Fig.1 – The IVD symbol

IVDs in the EU

In the EU, the IVDs are regulated by the Directive 98/79/EC (IVDD). In May 2022, a new law governing the IVDs will be fully applicable: The Regulation (EU) 2017/746 (IVDR). Passed the IVDR different transition periods, all IVDs in the European Economic Area (EEA) would need to comply with the requirements of the IVDR.

As a reminder, please note that all IVDs compliant with the EU requirements must carry the CE Mark (Fig. 2).

There no major differences between the definition of an IVD under the IVDD (Art.1.2.b) and the IVDR (Art.2(2)). Both texts define an IVD as the following:

“‘in vitro diagnostic medical device’ means 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.

Note that the IVDR specifies the following: “Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices”.

Fig.2 – The CE Mark

IVDs in the U.S.

The US Food and Drug Administration (FDA) defines IVDs in Title 21 of the Code of Federal Regulation (CFR) Part 809.3 as “products that are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.”

IVDs are devices as defined in Section 210(h) of the Federal Food, Drug and Cosmetic Act (FD&C Act) and can be also biological devices subject to Section 351 of the Public Health Service Act (PHS Act).

It is important to know that IVD products must be labelled “For In Vitro Diagnostic Use” (as per 21 CFR 809.10(a)(4)) or carry the IVD symbol.

The FDA proposes on its website a whole overview of how it regulates IVD products. See section Recommended Reading.

Research Use Only (RUO) Products

RUO means Research Use Only. It means that a given product is basically for that, for research such as basic laboratory research, performance investigation, design investigation, etc.

Norms and standards don’t apply here. Depending of the countries, the RUO products can be considered or not as ineffective IVDs. Therefore, depending of the countries and jurisdictions, the RUO products can be more or less regulated.

RUOs in the EU

RUO products are not subject to the IVDD not the IVDR. As they lack a clinical application, there are not qualified as medical devices by law.

The IVDD and the IVDR don’t define the term “Research Use Only” explicitly and no requirements are defined.

Manufacturers of RUO products should not apply the CE Mark of these products and clearly label them as “Research Use Only” and use the RUO label (Fig.3).

In the EU, a distinction is made between RUO products and IVDs for Performance Testing. IVDs introduced in European laboratories to establish their performance characteristics also are subject to the IVDD and IVDR. Such products cannot carry the CE Mark as their performance have not been established yet. IVDD and IVDR have specific performance documentation and notification requirements for these products.

For more information: The EU Commission has published a MEDDEV guidance concerning Research Use Only products. See section Recommended Reading. Note this guidance is not aligned with the IVDR and that a MDCG Guidance for RUO products is still under development at this moment.

Fig.3 – The RUO label

RUO in the U.S.

The 21 CFR 809.10 and 21 CFR 864 define four types of IVDs: General Purpose Reagent (GPR), Investigational Use Only (IUO), Analyte Specific Reagent (ASR) and Research Use Only (RUO). This is why in the U.S., RUOs are also called RUO IVDs – In contrast, in EU, only the term RUO prevails.

As per the 21 CFR, RUO products are IVD products in the laboratory research phase of development and not represented as effective IVDs (21 CFR 809.10(c)(2)(i)). In essence, RUO products are reagents, instruments, or systems under development and evaluated for their potential use as IVDs (Evaluation of design, performance, usability, etc.). 

RUO product are essentially unregulated in the U.S but must be labelled with the following statement: “For Research Use Only. Not for use in diagnostic procedures”. Labelling a product as such permits it to be used by researchers, who can evaluate usefulness for a specific diagnostic purpose. Beyond the labelling statement, FDA regulations do not mandate any other restrictions or limitations on RUO products, and RUO manufacturers do not have to register or list their RUO products with FDA or comply with manufacturing standards. RUO products can be offered for sale without any FDA clearance or approval. 

RUO products can be also used in conducting nonclinical laboratory research with goals other than commercial IVD product development and are used in basic life science research and not intended for further clinical diagnostic use development. In this case, these RUOs are used to carry out research and are not, themselves, the object of the research.

As good marketing practices, RUO products must never be represented as effective IVD products. And no specific disease, condition, or diagnostic performance claims can be made for RUO products. In the other side, an IVD product that is inappropriately labelled as RUO may be also considered misbranded or adulterated due to the lack of premarket notification (510(k)) or premarket approval (PMA) if distributed/or labelled for clinical diagnostic purpose. 

For more information, the FDA has published a guidance regarding IVD products labelled for Research Use Only. See section Recommended Reading.

Recommended Reading

Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only, FDA Guidance, 2013

IVD Guidance : Research Use Only products, MEDDEV. 2.14/2 rev.1, 2004

Overview of IVD Regulation, FDA website

Manufacturer IVD, EC website

Medical Devices – Sector, EC website

References

CFR Title 21

Directive 98/79/EC (IVDD)

Regulation (EU) 2017/746 (IVDR)

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