Regulatory Status of Combination Products in the US, EU, and China

Table of Contents

Regulation of Combination Products in the US 

First of all, it is important to mention that since combination products contain elements subject to regulation under the different frameworks, different US regulatory agencies are involved in the assessment of such products. However, one of the agencies will be responsible for the assessment in general (a “leading center”). Consequently, the assessment of a combination product includes several steps requiring the involvement of several regulatory agencies. 

As described by the Food and Drug Administration (FDA or the Agency), the country’s regulating authority, at the very first stage of the submission process, a party interested in placing its combination product on the US market should analyze the regulatory status of the product and determine the appropriate agency to which an application should be initially submitted. It is important to mention that in case of any doubts, an applicant is entitled to request feedback from the regulating authority in the course of a pre-submission process. 

The centers that could be involved in the assessment process include the following ones:

• The Center for Drug Evaluation and Research (CDER), which is responsible for medicines;
• The Center for Devices and Radiological Health (CDRH), which is responsible for medical devices;
• The Center for Biologics Evaluation and Research (CBER), which is responsible for biological products respectively. 

The authority also mentions that to ensure the effectiveness of the regulatory procedures, all the aforementioned agencies are cooperating with each other in the course of Combination Product Agreement Meetings (CPAMs). 

Depending on the primary mode of action (PMOA) of the product, it should be assigned to the appropriate leading center which will be responsible for the overall review process, as well as for further postmarket surveillance and regulation. The PMOA determination is based on assessing the way the combination product operates and identifying its element responsible for the primary mode of action. 

As it was mentioned before, an applicant may request assistance in determining the regulatory status of the combination product in question. According to the respective guidance, the determination provided by the regulatory agency could be either binding or non-binding – in the form of clarification. The FDA states that an applicant seeking additional advice should get in touch with the Office of Combination Products (OCP). Once the regulatory nature of the product is clarified, an applicant may proceed with contacting the Product Jurisdiction Officer of the appropriate center. 

To ensure the effectiveness of the regulatory procedures related to combination products, as well as to simplify and accelerate the review process, the FDA encourages the parties involved to follow recommendations including, inter alia, the ones listed below:

• All submissions related to combination products should be filed to the appropriate lead center. If a party responsible for a product (a sponsor) has certain concerns about the determination of a lead center, it shall obtain clarification and classification from the OCP following the procedure described here above.
• The questions raised by a sponsor when asking for feedback should be clear and relevant. The FDA additionally emphasizes that such questions should be relevant in the context of the current product development stage. 
• Any request filed by a sponsor should be accompanied by the information sufficient for the FDA to assess the matter and provide its feedback. 
• All communications with the regulating authority should take place via the designated Point of Contact (POC). It is important to mention that this approach applies even in case the question falls outside the scope of responsibility of the appropriate lead center.  

In summary, the regulatory approach for combination products adopted in the US is based on determining the primary mode of action of the product and then assigning it to the respective center based on such determination. A leading center remains responsible for the review process in general, and all communications with the applicant. Under the general rule, an applicant should determine the regulatory status of its product itself but is also allowed to contact the authorities to get binding determination or additional advice to be considered. Due to the involvement of several regulatory agencies in the review process, its overall effectiveness depends on the actual effectiveness of cooperation and interactions among all the parties engaged. 

European Regulations of Combination Products 

The products of several elements different in their regulatory nature are also subject to special regulation in the European Union. The applicable legislation refers to the concept of Drug-Device Combination (DDC) which stands for medicinal products which contain one or more medical device(s) as an integral part of the composition, as well as medicinal products for which one or more medical devices (s) and/or device component(s) are necessary for use of the medicinal product. It is important to mention that the scope of this concept covers medical devices that are either integral or non-integral to the medicinal product. The latter applies in cases the products are co-packaged, or included in documentation but are supplied separately. 

The authority acknowledges that the number of marketing authorization applications (MAAs) related to the products comprised of both medicines and medical devices has increased significantly. In particular, such products are mostly used to ensure the proper dosage in case of self-administration of medicines outside the clinical environment. 

In terms of concepts and definitions used, it is important to mention that all combination products could be divided into two main groups:

1. Integral DDCs, that are subject to regulation under the Medical Devices Regulation 2017/745 (MDR), as set forth by articles 1(8) and 1(9) respectively. This category includes:
   1. Devices that when placed on the market or put into service incorporate, as an internal part, a substance that, if used separately, would be considered as a medicinal product, provided that the action of the substance is principal.
   2. Devices intended to administer a medicinal product, where they form a single internal product intended exclusively for use in the given combination and which is not reusable. Typically, these devices have measuring, metering, or delivery functions. 
2. Non-integral DDCs – the ones in which the aforementioned components are not integrated within the course of the manufacturing process but should be combined for administration. This category covers situations when the products are either supplied in a single package (co-packaged) or referred to each other in the documentation, even if the devices themselves are supplied separately. The authority additionally emphasizes that medical devices which are supplied as parts of non-integral DDCs should bear a CE marking.

Examples of medical devices that could be included in integral DDCs are single-dose prefilled syringes, pens, and injectors, or multi-dose pens and injectors containing a pre-filled cartridge, provided that another cartridge could not be used due to the design of the device. At the same time, oral administration devices, refillable pens and injectors, nebulizers, and vaporizers are non-integral DDCs. 

The EU legal framework for combination products is based on:

• Directive 2001/83/EC (the Medicinal Products Directive, MPD) and Regulation 726/2004/E; and
• Regulation (EU) 2017/745 on medical devices (the Medical Devices Regulation, MDR) which amends Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009, and which repeals Directive 93/42/EEC (the Medical Device Directive, MDD).

It is also important to mention that the list provided hereinabove is not exhaustive, as certain regulatory aspects related to combination products could be covered by other regulations and directives. 

In terms of regulatory considerations, the main principle for combination products states that the assessment of the suitability of a device for its intended purpose should take into account both the relevant quality aspects of the device itself and its use with the particular medicinal product. The level of regulatory scrutiny should depend on the risks associated with the product and its intended purpose, as well as indications for use. As a specific feature, it is important to mention that considerations for a medicinal product should include the assessment of impact caused by a medical device. 

Under the general rule, an application for marketing approval for a combination product should contain, inter alia, sufficient evidence demonstrating that its medical device part complies with the relevant General Safety and Performance Requirements (GSPRs). In certain cases, the involvement of a Notified Body duly designated to conduct conformity assessment of such devices could be required (if applicable due to the class of the device under the risk-based classification). 

As it was mentioned before, non-integral combination products should have a CE marking confirming that they comply with the respective regulatory requirements. Moreover, the applicant should also provide detailed enough information about the impact the medical device included in the product would cause on the medicine intended to be used with it. Should the applicant have any doubts regarding the regulatory status of the product, it may contact the authorities responsible for medical devices to obtain additional clarifications and advice. 

When applying for marketing approval, the applicant should provide information about the medical device in question in a structured way as prescribed by the electronic Common Technical Document (eCTD) format. In particular, the submission should cover all the aspects related to the safety and effectiveness of the product subject to review and each of the components thereof. Depending on the regulatory status of the medical device component, a Declaration of Conformity issued by the manufacturer, or a Certificate of Conformity issued by a Notified Body could be required to demonstrate compliance of the product with the applicable regulatory requirements. The information contained in the submission concerning the manufacturing process, applicable controls, and usability should be sufficient for the regulating authority to assess the safety- and performance-related factors. For instance, the applicant should provide detailed information about the platform used, as well as justification for its users based on the intended purpose of the product. 

However, due to the complexity of combination products and novel technologies used therein, it is important to assess the applicability of general principles on a case-by-case basis to ensure the safety and effectiveness of all the components of this. 

In summary, the approach for combination products adopted in the EU is based on a slightly more detailed classification of such products. Special attention should be paid to the impact caused by a medical device on the safety and effectiveness of a medicinal product it is intended to be used with. For instance, this applies in the case of medical devices intended to administer medicines – it is important to ensure the device component would not adversely impact the features and characteristics of the medicines administered. 

Combination Products Regulation in China 

Chinese legislation on healthcare products also provides special rules and regulations to be applied for combination products. According to the official definition, a drug-device combination product refers to a medical product that consists of a drug and a medical device and is produced as a single entity. The approach to be applied for combination products is similar to the one applied in other jurisdictions since it is also based on determining the primary mode of action – the way the product operates and causes its impact on the human body. A drug-device combination product that mainly functions as a drug should be submitted for review as prescribed by the applicable regulations for the medicinal products, while in the case of the medical device component causing the main impact, a regulatory framework for medical devices should be applied accordingly. Should any of the components of a combination product be already approved for marketing and use either in China or in its country of origin, the appropriate documentation should be duly provided by the applicant. 

The authority also mentions that it is the sole responsibility of the manufacturer to ensure the safety and effectiveness of the product when used for its intended purpose. Should the manufacturer have any doubts regarding the regulatory status of the product in general or any of the components thereof, it may contact the authority in charge of medicines or medical devices respectively to get additional clarifications. Thus, the very first stage of the application process should include the determination of the particular framework to be applied based on the primary mode of action of the product subject to review. Once this is completed, a party interested in placing a medical device on the market (a sponsor) may apply for marketing approval for each of the components. The way the respective authorities interact with each other ensures the timely and predictable review of the application submitted. In certain cases, the simultaneous review may take place, when one of the authorities which initially receives the submission transfers it to another one. At the same time, the leading authority (determined based on the primary mode of action) will be responsible for the review process in general, including preparation of the final report and evaluation summary, which later should be approved by another authority. 

As it was mentioned before, the registration flow is based on the defining attributes of drug-device combination products. As prescribed by the appropriate instruction, the procedure includes the following steps:

1. The applicant shall apply to the Standards Management Center via the drug-device combination product attribute definition information system. 
2. The aforementioned Center will carry out a preliminary review to ensure the application submitted meets the formal requirements and could be accepted. In case of any corrections needed, the applicant will have 5 business days to implement such corrections.
3. Once the application is considered completed and accepted, the Standards Management Center will review it and respond within 20 business days. Should it be identified that any additional materials are reasonably needed to complete the review, the applicant will have 60 business days to provide them, otherwise, the application will be returned. 
4. Should the manufacturer have any objections regarding the determination granted by the Standard Management Center, it is allowed to apply for re-examination. Such an application should be filed within 10 business days from the date the initial response has been received. It is important to mention that the content of such an application should be limited to the content of the initial one. The application for re-examination will be reviewed by the Standard Management Center within 20 business days to be calculated from the date of acceptance, and the response will be provided via the same information system. This system could be also used for all interactions with the Standard Management Center in the course of application review, including the matters related to the application status, notifications of corrections, and attribute definition results. 

Existing Chinese legislation on combination products also outlines the scope of documentation to be submitted by an interested party when applying for defining the attributes of drug-device combination products. 

As it was mentioned before, the application should be submitted via the appropriate information system. Such an application shall cover the following aspects:

1. Description of a product subject to review, including the name, composition (dose of the ingredients contained), combination method, intended use, contact site/contact time with the patient, and other details reasonably necessary for the authority to assess the safety and effectiveness of the product. 
2. Description of the mechanism of action together with the respective supporting data – this information will be used for determining the primary mode of action. 
3. The Instructions for Use (IFU) to be supplied with the product. 
4. Indication of the source of each component of the combination product. 
5. Applicant’s suggestions on the definition of attributes, accompanied by the relevant documentation and justification. 

The key purpose of the initial assessment of a combination product is to determine its primary mode of action which stands for the single mode of action of the combination product to achieve the most important therapeutic effect. Such a determination will be made based on the information to be provided by the applicant, including test data. 

In case there are similar products already placed on the market, the applicant shall provide information about such products as well, including details about their composition, intended use, and other characteristics. 

In summary, the approach employed in China is similar to the ones applied in other jurisdictions: it provides that several regulatory agencies will be responsible for the product review depending on its status. 

Irrespectively of the differences between national frameworks, the regulatory approach to combination products is based on determining the regulatory status of the product depending on its primary mode of action, followed by assigning it to the respective authority for review. The scope of review should cover both medicine and medical device components of the combination product to ensure the latter does not impact adversely the medicinal product and its characteristics.

Sources:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requesting-fda-feedback-combination-products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-documentation-medicinal-products-when-used-medical-device-first-version_en.pdf

https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20210727154135199.html

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