M&T Insights | Legal and Regulatory System for Drug-Device Combination Products

On July 23, 2021, the National Medical Products Administration (“NMPA”) issued the “Notice on Matters Concerning the Registration of Combination Products of Medicines and Medical Devices”(Notice No. 52 of 2021 of the NMPA) (hereinafter referred to as the “Notice No. 52”). The promulgation of Notice No. 52 was primarily aimed at adapting to changes in laws and regulations as well as the needs of industry development, and as a supporting regulation to the “Pharmaceutical Administration Law of the People’s Republic of China” and the “Regulation on the Supervision and Administration of Medical Devices”, it revised the “Notice on Matters Concerning the Registration of Combination Products of Medicines and Medical Devices” (Notice No. 16 of 2009 of the former State Food and Drug Administration, hereinafter referred to as the “Notice No. 16”). It is evident that combination products of medicines and medical devices, as a special yet common form of products, are increasingly drawing attention to their importance.

1. Definition of Drug-Device Combination Products

According to Article 1 of Notice No. 52, a drug-device combination product is defined as a product that is composed of both drugs and medical devices and is manufactured as a single entity.

However, when looking at the global scope, there are slight differences in the definitions of drug-device combination products among various countries. For example, the definition by the US FDA covers a broader range than that in our country. In addition to products where drugs and devices are combined into a single entity, combination packaging or drugs/biologics and medical devices that are intended for use together can still be managed as drug-device combination products. According to the Explanatory Note on the Draft for Public Comments of the Notice on Matters Related to the Registration of Drug-Device Combination Products (Revision Draft), the National Medical Products Administration (NMPA) considered that further research is still needed on how to regulate combination products that are not produced as a single entity. Therefore, Notice No. 52 continues to use the definition of drug-device combination products from Notice No. 16 and does not currently consider expanding the scope of drug-device combination products.

2. Attribute Definition of Drug-Device Products

2.1 Significance of Attribute Definition

In practice, the basic principle of the regulation of drug-device combination products in China is to manage them according to their product attributes. In other words, the registration, review, and approval department for a combination product is determined based on the attribute of the component that plays the primary role in the combination product. If there is an error in the definition of the product attribute, the same type of combination product may simultaneously enter both the drug and medical device registration procedures, or it may enter the wrong review and approval process. After being identified as incorrect by the competent authority, it will be required to exit the wrong review and approval process and reapply for registration, which will seriously affect the product registration progress. Moreover, the negative impact of an incorrect product attribute definition may run through all stages of product review, approval, and registration. Both the review process of the review center and the administrative approval process of the registration department of the drug administration will examine the product classification. If the competent authority determines that the attribute definition is incorrect, even if the product has actually passed the review, it cannot pass the registration application. Therefore, the definition of product attributes is the premise and foundation for the management of drug-device combination products.

2.2 Attribute Definition Provisions in Notice No. 52

Notice No. 52 is a further revision of Notice No. 16, which was issued by the former State Food and Drug Administration, based on the revision and implementation of the “Pharmaceutical Administration Law of the People’s Republic of China” and the “Regulation on the Supervision and Administration of Medical Devices”, and their supporting rules. The main content includes the revision of attribute definition:

（1）Drug-device combination products that primarily function as drugs shall be registered in accordance with the requirements for drugs. Those that primarily function as medical devices shall be registered in accordance with the requirements for medical devices. If the drugs or medical devices contained in the combination product have been approved for sale in China or the country (region) of production, the corresponding marketing authorization documents shall be submitted together with the registration application. The application materials for drug-device combination products can refer to relevant documents and guidelines.

（2）Applicants shall fully assess the attributes of the drug-device combination products they intend to register. If the management attribute of a drug-device combination product cannot be determined, the applicant shall apply to the Medical Device Standards Management Center of the National Medical Products Administration (hereinafter referred to as the “Standard Management Center”) for attribute definition before registration. It is worth noting that, compared with the now-defunct Notice No. 28 (which clearly defined the attribute definition functional department as the Standard Management Center), Notice No. 52 has strengthened the primary responsibility of the applicant. Specifically, Notice No. 52 has added the clause “Applicants shall fully assess the attributes of the drug-device combination products they intend to register.” For cases where attribute definition is applied, considering that there are some products that have not yet been approved for sale in China but have clear attributes, as well as other possible scenarios requiring attribute definition, the phrase “such products have not yet been approved for sale in China” in Notice No. 16 has been revised to “For drug-device combination products whose management attributes cannot be determined, as well as other scenarios requiring attribute definition,” so that applicants can submit attribute definition applications according to their needs.

（3）The Standard Management Center reviews the application materials for attribute definition of drug-device combination products that it accepts, proposes attribute definition opinions in accordance with procedures, informs the applicant in the drug-device combination product attribute definition information system, and promptly publishes the attribute definition results of drug-device combination products on its website.

2.3 Typical Product Examples

Antibacterial and anti-inflammatory medicated band-aids are among the most common drug-device combination products in daily life：The dressing in the coating layer of the band-aid exerts antibacterial and anti-inflammatory effects on the wound through pharmacological actions, whereas the adhesive tape part of the band-aid functions as a medical device, used for fixing and protecting the wound surface to promote healing. The combined action of these two components forms a drug-device combination product registered as a single entity. Although the composition structure of band-aids available on the market is essentially the same, the mode of action and intended use of the drug coatings in different band-aids vary. For instance, in band-aids containing antibacterial and anti-inflammatory drugs, the drugs exert their antibacterial and anti-inflammatory effects through pharmacological means, while the adhesive tape part covers and protects the wound through physical actions. Between the two, the antibacterial and anti-inflammatory effects of the drugs play a primary role in wound healing. Thus, the product is characterized as a drug-device combination product primarily based on the drug. On the other hand, there are some waterproof band-aids on the market whose drugs do not have antibacterial or anti-inflammatory functions and only promote wound healing through covering and protecting actions. Therefore, they are registered as medical devices. It can be seen from this that the different modes of action of products will directly affect the product registration category and the differences in administrative approval processes and regulatory models.

3. Regulatory Authorities

According to Article 6 of Notice No. 52, the Center for Drug Evaluation (CDE) and the Center for Medical Device Evaluation (CMDE) of the National Medical Products Administration (NMPA) have established a coordination mechanism. For drug-device combination products submitted for registration as drugs, the CDE takes the lead in the evaluation process. If joint evaluation is required, the registration application materials are transferred to the CMDE for concurrent evaluation. For drug-device combination products submitted for registration as medical devices, the CMDE takes the lead in the evaluation process. If joint evaluation is required, the registration application materials are transferred to the CDE for concurrent evaluation. For drug-device combination products undergoing joint evaluation, the CDE and the CMDE should collaborate on communication and consultation regarding the application products. Each center will issue an evaluation report on the safety, efficacy, and quality control of their respective parts and clearly state the evaluation conclusions. The leading unit will compile the information, make an overall assessment, and issue a comprehensive evaluation conclusion, which will then be submitted to the relevant business department of the NMPA for administrative approval.

According to the above provisions, the specific regulatory authority for drug-device combination products should be determined based on the attribute definition results of the drug-device combination products. If joint approval is required, the Drug Evaluation Center and the Medical Device Technology Evaluation Center will conduct a joint evaluation and report to the relevant business department of the National Medical Products Administration for administrative approval.

4. Good Manufacturing Practices (GMP) for Drug-Device Combination Products

Under the Chinese current regulatory framework, no specific GMP requirements have been established for drug-device combination products. Given the absence of dedicated GMP regulations for such products, it is highly likely that future guidelines will reference standards adopted by major Western jurisdictions, such as the US Food and Drug Administration (FDA) GMP rules for combination products. For a detailed overview of US GMP requirements for drug-device combination products, please refer to the section below.

5. Regulations under US Law

5.1 Definition

The concept of drug-device combination products is not unique to China. Within the regulatory framework of the US Food and Drug Administration (FDA), combination products (Combination Product) can take several forms:

（1）Products composed of two or more regulated components, such as drug/device, biological product/device, drug/biological product, or drug/device/biological product, which are combined or mixed through physical, chemical, or other means and produced as a single entity.

（2）Two or more separate products packaged together in a single package or as a unit, consisting of drug and device, device and biological product, or biological product and drug.

（3）Drugs, devices, or biological products packaged separately, according to their investigational plan or proposed labelling, are intended solely for use with an approved, separately specified drug, device, or biological product to achieve the intended use, indication, or effect. After approval of the combination product, changes to the labelling of the approved product are required, such as reflecting significant changes in the intended use, dosage form, utility, route of administration, or dosage.

(4) Any investigational drug, device, or biological product packaged separately, according to the proposed labelling, is intended solely for use with another separately specified investigational drug, device, or biological product to achieve the intended use, indication, or effect.

According to the FDA’s definition, a combination product refers to a product “composed” of a drug and device, biological product and device, drug and biological product, or drug, device, and biological product, where “composed” includes:

a. Mixed or combined into a single entity by any means;

b. Packaged together as two separate single-entity products;

c. A single product, according to its instructions or labelling, that is intended for use with another separate product.

Therefore, the FDA’s definition of drug-device combination products is broader than that in China. In addition to explicitly including biological products as components of drug-device combination products, it also allows for the management of combination products that are packaged together or intended for use with each other, without limiting them to combination products registered and produced as a single entity.

5.2 Regulatory Authorities and Attribute Definition of Drug-Device Products

The principle of attribute definition for drug-device products by the FDA is similar to the definition principle stipulated under China’s Notice No. 52. According to the “Federal Food, Drug, and Cosmetic Act”(FDCA), the attribute of a combination product is determined based on the product’s primary mode of action (PMOA).

Even in the FDA, the attribute definition of drug-device products remains challenging. As early as 1990, when the concept of “combination products” first appeared in the “Safe Medical Devices Act” (SMDA), the SMDA did not define PMOA. It was not until 2005 that the FDA filled this gap by defining and interpreting PMOA as follows: if a single mode of action of a combination product contributes the most to its overall intended therapeutic effect, that single mode of action will be identified as the PMOA. For example, if a biological product in a combination product plays the primary function, the product is regulated by the FDA’s Center for Biologics Evaluation and Research (CBER).

However, the PMOA principle cannot resolve all attribute definition issues for combination products. In certain specific situations, neither the FDA nor the applicant can determine which component of the combination product plays the primary role based on the PMOA principle. These special cases generally include situations where two or more products in the combination product each play an independent role or where two or more products each play a role that is not less significant than the others. For these situations where the PMOA principle is not applicable, according to 21 CFR § 3.4(b), the FDA will follow the following process to define the attribute of the combination product:

(1) Step One: The FDA will first search whether any of its centers (including CBER, CDER, and CDRH) has experience addressing similar safety and effectiveness issues for other combination products. If so, the FDA will designate that center as the regulatory authority for the combination product.

(2) Step Two: If none of the centers has relevant experience, the FDA will consider the most significant safety and effectiveness issues involved in the combination product and assign the product to the center that is most specialized and experienced in addressing that issue, which will then serve as the regulatory authority for the combination product.

5.3 GMP for Drug-Device Combination Products in the United States

In 2013, the FDA issued the cGMP (current Good Manufacturing Practices) regulations for combination products in 21 CFR Part 4, Subpart A. Under US law, separate cGMPs have been established for drugs, biological products, medical devices, and products involving cells and tissues, with each set of cGMPs varying according to the product category. However, 21 CFR Part 4, Subpart A does not establish a separate cGMP specifically for combination products. Instead, it requires that each component of a combination product comply with the cGMP regulations applicable to its respective category.

5.4 Comparison of Regulatory Systems for Drug-Device Combination Products between China and the United States

When comparing the regulations for drug-device combination products between China and the United States, we have identified the following differences:

(1) The definition of combination products under US law is broader. Under Chinese law, a combination product must be composed of drugs and medical devices and produced as a single entity. In contrast, under US law, a combination product can be either produced as a single entity or separately.

(2) There is little difference between the two countries’ laws in terms of attribute definition for combination products, as both adopt the principle of “the component that plays the primary role” to determine the attributes of combination products.

(3) Under Chinese law, the GMP regulations for combination products are still a blank slate, whereas US law requires each component of a combination product to follow its respective cGMP.

6. Conclusion

This article has discussed the regulatory system for drug-device combination products in China and the differences between the Chinese and US regulatory systems. Compared to the differences in the regulation of drug-device combination products between China and the United States, it is not difficult to see that China’s regulations on drug-device combination products are still relatively limited. The only relatively detailed Notice No. 52 is still at the level of defining the attributes of drug-device combination products. It cannot comprehensively cover all issues related to drug-device combination products. Further supporting measures are needed to improve other regulations on drug-device combination products in China.

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