[ARTICLE] International Market Access Strategy for Electrical Medical Devices and IVDs: National Differences and the Added Value of "CB Scheme" and "NRTL Listing Report"

This blog article focuses on the international market access strategy for medical electrical equipment, notably electrical medical devices including in vitro diagnostic medical devices (IVDs) and explains the relevance and benefits of establishing an IEC 60601 or IEC 61010 test report and certificate, following the CB (Certification Body) scheme test procedure, and respecting the national differences. In addition, the purpose of NRTL (Nationally Recognized Testing Laboratory) listing report along with its requirements and benefits are summarized.

Manufacturers of electrically-driven medical devices and IVDs may face different regulatory requirements depending on the intended device market strategy. Due consideration of the applicable international market requirements during and after the development phase of the medical electrical equipment is therefore essential.

As part of the global market access strategy for medical electrical equipment, medical device and IVD manufacturers must comply with the “State-of-the-Art” (SOTA) concept. This is normally achieved through the application of relevant harmonized standards within the European Union, or of Food and Drug Administration (FDA) recognized standards for the United States of America, taking into consideration the device classification and intended use of the device/system.

General Considerations on International Market Access for Medical Electrical Devices and IVDs

First of all, medical device manufacturers should begin by determining the target countries in which they intend to place their medical devices on the market. Based on the country, it should be assessed if any national differences are applicable. Identified national differences should be considered early during the development of the medical device. This approach, known as “frontloading”, can enable substantial cost savings compared to conducting this process at an advanced development stage.

For instance, IEC 60601-1:2005+AMD1:2012+AMD2:2020 (3.2 Edition) and IEC 61010-1:2010+AMD1:2016 (3.1 Edition) contain a variety of national differences in applicable regulatory requirements.

Notably, the following country-specific IEC 60601-1 versions are applicable depending on the target country and type of medical electrical equipment at stake:

• ANSI/AAMI ES60601-1:2005/A2:2021 (United States)
• CAN/CSA-C22.2 NO.60601-1:14 (Canada)
• SI 60601 Part 1 (Israel)
• JIS T 0601-1:2017 (Japan)
• MFDS No. 2020-12 (Republic of Korea)
• BS EN 60601:2006 A1 (United Kingdom)

The following country-specific differences of IEC 61010-1 are applicable depending on the target country and type of in vitro diagnostic:

• CAN/CSA-C22.2 NO.61010-1+Amd1 (Canada)
• EN 61010-1:2010/A1:2019 (CENELEC)
• UL 61010-1 (3^rd) AM.1 (United States)

The identified applicable national differences based on the target markets should be considered during the development and testing (verification) of electrical medical devices and IVDs.

It is important to note that FDA only recognizes the ANSI AAMI ES60601-1 standard, meaning that if the medical electrical equipment manufacturer plans to obtain market approval/clearance in the USA, they need to comply with the national differences for the USA presented therein.

Figure 1: Screenshot of ANSI AAMI ES60601-1 of FDA-recognized standard database

Furthermore, manufacturers should bear in mind that ANSI AAMI ES60601-1 3.1 Edition will be superseded by 3.2 Edition by 17 December 2023 according to the information provided by FDA, and therefore that after that date FDA will only accept submissions complying with 3.2 Edition.

With regard to the 61010-1 standard, the FDA recognizes the ANSI UL 61010-1 3^rd Edition and IEC 61010-1 Edition 3.1.

Figure 2: Screenshot of ANSI UL/ IEC 61010-1 of FDA-recognized standard database

In a second step, medical device and IVD manufacturers should contact an external test laboratory to plan and conduct the required tests (e.g., as per IEC 60601-1 or IEC 61010-1) in accordance with the identified applicable national differences.

As an example – Canadian national difference (CAN/CSA-C22.2 No. 60601-1:14) requires, as stated in clause 8.6.4 “impedance and current-carrying capability”, compliance to CSA C22.2 No. 04. This implies a protective earth test current for cord-connected equipment of twice the rating of the attachment plug cap, or for permanently installed equipment, of twice the rating of the fuse for branch circuit, but not less than 40 A for 120 seconds.

In contrast, IEC 60601-1 3.2 Edition requires, according to clause 8.6.4 “impedance and current-carrying capability”, a protective earth test current of 25 A or 1.5 times the highest rated current of the relevant circuit for a maximum time of 10 seconds.

The Canadian national difference requirement in the above example is therefore stricter than the IEC 60601-1 3.2 Edition requirement. Depending on whether the equipment is cord-connected or permanently installed, the extent of the required construction (protective earth wire diameter) and compliance testing could be impacted.

Finally, please note, IECEE covers 23 categories of electrical equipment and testing services. Therefore, the CB Scheme is not limited to electrical equipment for medical use. As an example, three additional categories of electrical equipment are listed below, which are often used/ tested in combination with electrical medical devices and IVDs:

• Electromagnetic Compatibility (EMC)
• Safety Transformers and similar equipment (SAFE)
• Information Technology Audio Video (ITAV)

If it is intended to gain market access internationally, it is recommended to follow the IECEE (IEC System of Conformity Assessment Schemes for Electrotechnical Equipment and Components) CB (Certification Body) scheme of test procedure which facilitates the global market access.

What is the “CB scheme”?

The CB scheme is an international system for mutual acceptance of test reports and test certificates. Currently, 54 countries are member bodies taking part in CB scheme approach. Only certification body testing laboratories (CBTL) may issue CB test reports and certificates. All CBTLs can be viewed here.

Typically, the first page of an IEC 60601/ IEC 61010 test report indicates the test specification and the applied test procedure.

Figure 3: Example of IEC 60601 test report test specification

What are the implications for electrical (IVD) medical device manufacturers?

The CB scheme follows predefined requirements, and the medical device manufacturer and the external test laboratories are obliged to comply with specific rules, operational documents, and guidance.

For instance, the IECEE Operational Document OD-2055 Annex D requires IEC 60601-1:2005+A1:2012+A2:2020 compliance, in addition to a test report documenting compliance of usability in accordance with IEC 60601-1-6:2010+A1:2013+A2:2020. Any other applicable collateral standard (e.g., IEC 60601-1-3) shall also be considered.

Moreover, it must be noted that following the CB scheme does incur additional costs due to the additional requirements and certification fees (certificate) implied.

Last, it is important to know that according to clause 6.2.1 of IECEE OD-2020, only three amendment reports due to technical changes are accepted to the original issued test report and test certificate. After three amendments a new CB test report and certificate need to be requested and issued by the external test laboratory. Even upgrading the CB test certificate and report from an old edition to a newer edition of the standards requires a new CB test report and certificate.

Besides that, the CB scheme offers the following benefits to the medical device manufacturer:

1. It enables fulfilment of the criteria for obtaining market access in certain countries – it provides direct acceptance by the regulatory authorities in many countries and is accepted by numerous retailers, buyers and vendors worldwide
2. No additional duplicate testing is needed, and it is a globally approved and well-established procedure
3. Simplification of the roll-over process (changing the external test laboratory)
4. All CB certificates are listed in the IECEE database and are publicly accessible

Now, moving on to the NRTL listing report:

What is the “NRTL”?

Nationally Recognized Testing Laboratory (NRTL) are mainly U.S.-based test laboratories recognized by the OSHA (Occupational Safety Health Administration) according to the Code of Federal Regulation (CFR) 21 §1910.7 to perform certification for certain products (e.g., medical electrical equipment or in vitro diagnostic) to ensure they meet the constructional and general industry OSHA standards. The NRTL will issue a separate listing report for the medical electrical equipment/ in vitro diagnostic manufacturer.

OSHA requires NRTL testing and affixture of the NRTL safety mark for electrical products used in public buildings or workplaces (e.g., hospital, clinics, and laboratories) in the United States. This is regulated by the National Electric Code (NEC) §90.7, §110.2, and §110.3 (C), and may be subject to control by Authorities Having Jurisdiction (AHJ) during the installation of the medical electrical equipment/ in vitro diagnostic or during operation.

What are the implications for electrical (IVD) medical device manufacturers?

1. Electrical (IVD) medical device manufacturers require an external NRTL-recognized test laboratory. Currently, there are 21 listed NRTL-recognized laboratories
2. The NRTL listing report and certificate need to be requested, incurring additional costs
3. Initial factory inspection must be conducted by an NRTL inspector, and follow-up inspections at the factory site are needed every 3 or 6 months (additional initial and follow-up costs incurred)
4. Manufacturers need to update the NRTL mark on the type label, and within the technical documentation such as in the instructions for use

The NRTL listing report puts focus on general constructional requirements (cable routing, labeling, protective earth connection, list of critical components) and routine tests for manufacturing and production (grounding continuity test, dielectric voltage withstand test, and leakage current test). These aspects will be regularly inspected during the ongoing factory inspections.

In addition, if it is also intended to obtain market access in Canada, it is strongly recommended to directly apply for an NRTL listing report for Canada in parallel. The NRTL listing report approach requested by the Standards Council of Canada (SCC) is similar to that for the U.S., and one combined NRTL listing report can be established for both countries.

Besides that, the NRTL listing report offers the following benefits to electrical (IVD) medical device manufacturers:

1. It enables market access for the United States of America and Canada
2. The electrical (IVD) medical device will bear the NRTL mark, showing that the NRTL tested and certified the product (quality property)
3. Valid NRTL-certified medical electrical equipment, including electrical (IVD) medical devices, are listed in the related NRTL database

How can Medidee, now part of Veranex, support your company?

Our team of electrical safety specialists at Medidee can assist you in identifying the regulatory requirements, notably the applicable standards and national differences, for your target market(s). Moreover, Medidee can help you in determining if a test report according to the CB scheme and/ or NRTL listing report is mandatory in specific countries. In addition, we can support you in selecting the right external test laboratory depending on the intended global market access strategy and during the certification process and on factory inspection to ensure a smooth certification process of the medical electrical equipment or in vitro diagnostic.

Contact us to discuss your needs.

This article was written by Stefan Staltmayr and Dr Jérôme Randall.

by Joana Gomes

[ARTICLE] Combination Products: Similarities and Differences of EU and US Regulations

The success of novel combination products is much dependent on the regulatory intelligence and foresight to define the best strategy to place and maintain them on the market, through a deep understanding of how drugs, devices and their combination are regulated in the different target markets. 

This article aims to provide general guidelines for combination product manufacturers who may not be familiar with the EU and US regulations, or know one of these markets well and aim to access the other. 

Terminology and definitions 

The term “combination product”, commonly used to identify the category of medical products made of a combination of drug, device, and/or biologic, comes from the FDA definition given in 21 CFR 3.2 (e). 

In the EU, instead, the wording “integral product” is used to refer to devices incorporating a medicinal substance (Article 1 §8), and devices intended to administer a medicinal product (Article 1 §9), as defined in the Medical Device Regulation (EU) 2017/745 (MDR). Of note, the European Medicines Agency (EMA) has published a Q&A guidance document on this topic and the term “Drug Device Combination” (DDC) is also used. 

In 21 CFR 3.2 (e), the FDA defines the following types of combination products: 

1. single-entity combination product in which its constituent parts are physically, chemically, or otherwise combined or mixed and produced, as a single entity;
2. co-packaged combination product in which its constituent parts are packaged together in a single package or as a unit;
3. cross-labeled combination product in which its constituent parts are packaged separately and, according to the investigational plan or proposed labeling, are intended for use together to achieve the intended use, indication, or effect.

According to the MDR, the same products are categorized differently, as follows: 

1. devices incorporating a medicinal substance as an integral part which has an action ancillary to that of the device; 
2. devices incorporating a medicinal substance as an integral part which has an action principal to that of the device; 
3. devices intended to administer a medicinal product, placed on the market as a single integral product (i.e. placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable); 
4. devices intended to administer a medicinal product, placed on the market as a “non-integral product”. 

To provide some examples, a pre-filled syringe is a single-entity combination product in the US, and “a device intended to administer a medicinal product as a single integral product” in the EU. 

A drug-eluting stent is a single-entity combination product in the US, and “a device incorporating a medicinal substance as an integral part which has an action ancillary to that of the device” in the EU. 

In the US, insulin cartridges to be used with a reusable pen injector can be a co-packaged combination product, if the insulin cartridges are provided in the same package with the reusable pen, or a cross-labeled combination product, if provided separately. In the EU, the reusable pen injector is “a device intended to administer a medicinal product as a non-integral product”. 

Mode of Action to define how the product is regulated 

Interestingly, the term “mode of action” is used both in the US and in the EU, but its definition is provided only in 21 CFR 3.2(k), which states that the “mode of action is the means by which a product achieves an intended therapeutic effect or action”. 

Both in the US and in the EU, combination products are recognized to have more than one identifiable mode of action. Among the multiple modes of action, FDA defines as Primary Mode of Action (PMOA) “the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.” (21 CFR 3.2(m)). 

The MDR does not provide a definition, but rather distinguishes between “principal” and “ancillary” action of the medicinal substance to that of the device. 

Finally, the “primary” or “principal” mode of action is the key criterion used in both US and EU's regulatory frameworks to define how the product is regulated and by which Regulatory Authority. 

Combination Products regulated as medical devices 

Both in the EU and in the US, combination products with a device PMOA, also called device-led combination products, are regulated as medical devices. 

European Union

In the EU, this type of combination product includes “devices incorporating a medicinal substance as an integral part which has an action ancillary to that of the device”, and “devices intended to administer a medicinal product, placed on the market as a non-integral product”. They undergo conformity assessment procedures as any other medical device, as defined in Article 52 and set out in Annex IX to XI of the MDR. 

In terms of classification, “devices incorporating a medicinal substance as an integral part which has an action ancillary to that of the device” are class III medical devices, according to Rule 14, as defined in Annex VIII of the MDR.  

Instead, “devices intended to administer a medicinal product, placed on the market as a non-integral product” are classified differently depending on their intended purpose. Of note, the MDR up-classified some of these products: for example, inhalers were regulated under the Medical Device Directive 93/42/EEC (MDD) as class I devices, whereas they are now class IIa or class IIb devices under the MDR.

Finally, as part of the conformity assessment procedure, “devices incorporating a medicinal substance as an integral part which has an action ancillary to that of the device” require consultation by the Notified Body of the relevant Medicinal Products Authority (National Competent Authority or EMA), to seek their Scientific Opinion. This consultation process should be taken into account when planning the CE marking of such products or when planning a significant change to an already CE-marked product, as it greatly impacts the timelines for completion of the conformity assessment procedure. 

United States

In the US, as a general rule, FDA requires a single application to streamline regulatory interactions with the Agency and the marketing application type generally coincides with the PMOA of the combination product. Hence for a device-led combination product, a single application should be submitted to the Center for Devices and Radiological Health (CDRH) which acts as “lead center”.

A Premarket Approval (PMA) is required for class III device-led combination products; a De Novo Classification Request applies for novel device-led combination products for which general controls alone, or general and special controls, provide reasonable assurance of safety and effectiveness for the intended use (class I and class II); a Premarket Notification (510(k)) applies when the substantial equivalence of the device-led combination product can be demonstrated against a predicate product. 

Of note that, as part of the single application, sufficient information should be provided on the drug constituent part and may include nonclinical pharmacology, toxicology and clinical pharmacology (including pharmacokinetic) data and chemistry, manufacturing, and controls (CMC) information. 

Combination Products regulated as drugs 

Both in the EU and in the US, combination products with a drug PMOA, also called drug-led combination products, are regulated as drugs. 

European Union

In the EU, “Devices incorporating a medicinal substance as an integral part which has an action principal to that of the device” and “devices intended to administer a medicinal product, placed on the market as a single integral product” are regulated as medicinal products under Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. 

In this context, Article 117 of the MDR introduces an amendment to Directive 2001/83/EC, requiring that the Marketing Authorisation Application (MAA) includes the results of the assessment of the conformity of the device part with the relevant General Safety and Performance Requirements (GSPRs) set out in Annex I of the MDR. This translates into two cases: 

• if the device part classifies as a class I medical device, then the evidence of conformity to the relevant GSPRs is provided as part of the manufacturer's EU Declaration of Conformity; 
• if the device part classifies in any other way (i.e. class Im, class Is, class Ir, class IIa, class IIb, and class III), then the evidence of conformity to the relevant GSPRs is provided either as the CE certificate issued by a Notified Body (if the device is CE marked), or as the so-called Notified Body Opinion. In the latter case, careful planning of the submission of the Technical Documentation of the device part to the Notified Body must be done to ensure sufficient time for review by the Notified Body and obtain the Notified Body Opinion, to be included as part of the MAA.  

United States

In the US, for a drug-led combination product, a single application should be submitted to the Center for Drug Evaluation and Research (CDER) which, acts as “lead center”.

For a new drug-led combination product, the single application is a New Drug Application (NDA); for drug-led combination products that are the generic version of already-approved drug-led combination products, the Abbreviated New Drug Application (ANDA) is, in general, the most appropriate pathway. It's worth noting that the ANDA is based on providing sufficient information to demonstrate that the proposed product is bioequivalent to the Reference Listed Drug (RLD). To do so, the ANDA of a drug-led combination product should also include sufficient information to demonstrate that the device constituent part is compatible for use with the final formulation of the drug constituent part. 

At Medidee, now part of Veranex, we have a long track record of providing expertise and technical knowledge to the Medical Device industry. Our Regulatory, Clinical and Quality support for combination products covers all product development stages, to the particular benefit of Pharma companies developing drug-delivery combination products, who may lack a medical device-oriented vision of the regulatory framework.

If this is something you are currently working on, do not hesitate to check our full offering of Combination Products Services, or to reach out directly for expert support. 

This article was written by Rima Padovani (PhD, RAC) and Bruno Strappa (MSc). 

by Joana Gomes