With the development of science and technology, existing drug-device combination products are constantly refreshed by more and more innovative products, including the emerging digital drugs, tissue engineering medical products and drug-device integrated products. The number of drug-device combination product declaration is gradually increasing both at home and abroad. However, the diversity and complexity lying in drug-device combination products also highlight the problems in their declaration and registration.
In the irreversible trend that the innovative combination products keep emerging, China's drug administrators should always stand at the frontier and closely follow the development of domestic and foreign combination products, so as to draft scientific definition principles applicable to our drug-device combination products. In this way, we could provide scientific guidance and better supervision when the R&D of innovative drug-device combination products is getting more and more mature.
Property definition process for drug-device combination products
China has established a definition mechanism for drug-device combination products as early as 2009. According to the Circular on Matters Relating to Registration of Drug-device Combination Products promulgated by former China Food and Drug Administration (CFDA) in November 2009, if a drug-device combination product to be declared is not permitted to hit the market in China, before the declaration of registration, the applicant should apply for product property definition from the Center of Administrative Matters Acceptance Service and Complaint Reporting of NMPA (hereinafter referred to as the "Acceptance Center"). After receiving the applicant's application for property definition, the Acceptance Center shall organize relevant examiners to conduct definition and then inform the applicant of the result in written notice.
In 2015, the former CFDA made a procedure for drug-device combination products property definition. In 2016, the original procedure was simplified to consulting the Center for Drug Evaluation, NMPA ("CDE-NMPA") and the Center for Medical Device Evaluation, NMPA ("CMDE-NMPA") in letter with the Acceptance Center in the lead. With any discrepancy between the two centers, an expert meeting will interfere directly to make a decision. The improvement of property definition procedures for drug-device combination products essentially reduces the intermediate links, thus shortening the time period needed for issuing the definition results and improving the efficiency for definition. In 2019, the Medical Device Standardization Administration Center of NMPA took over the work of property definition for drug-device combination products.
In China, a drug-device combination product refers to such one that comprises drug and medical devices and is produced as a single physical work. The definition of product property is based on the definition of drug-device combination products and their major function modes, and the basic principle is that the product will not cause any administrative overlap of drugs and medical devices.
For the drug-device combination products in which drugs play the main role, the applicant shall declare for drug registration under the evaluation led by the CDE-NMPA; for the drug-device combination products in which medical devices play key roles (hereinafter referred to as "drug-contained devices") , the applicants shall declare for medical devices registration and shall be reviewed and evaluated under the leadership of CMDE-NMPA. For those needing a joint evaluation, the leading evaluation center shall hand over the needing parts in the registration declaration documents to a joint evaluation center for a synchronized evaluation. In view of the large differences between drugs and medical devices in the quality system, tests, declaration requirements and post-market supervision, in order to ease the burden on applicants, the latter are encouraged to conduct communication and consultation and product property definition in the early stage of the research and development of the products, so as to avoid any later non-compliance of registration path and declaration data preparation.
Property definition for 152 combination products finished
It's clearly specified in Circular on Matters Relating to Registration of Drug-device that: "Drug-coated stents, products including catheters with antimicrobial coating, drug-contained condoms, and drug-contained birth control rings shall be registered for administration as medical devices; products including the Band-Aids containing antimicrobial and anti-inflammatory drugs and TCM bandages for external use shall be registered for supervision as drugs. "But because of the variety of drug-device combination products, their definition and supervision modes are different among countries and regions. Along with the ambiguity and disputation existing in the main function of some products themselves, this will lead to discrepancy of regulatory modes in different countries or regions for some products. Thus, there are still a number of products making application for property definition every year.
Currently, products applied for property definition commonly include devices containing drug coatings or impregnated or combined with drugs, pre-filled drug dosing devices/systems, pre-filled biological products dosing devices/systems, devices with biological-products coatings or combined with biological products, liquid or gel products, for external use, etc.
In order to ensure the transparency of the definition results in drug-device combination products and guide the applicants to make proper declaration, NMPA published all the recorded results in product property definition. As of March 6, 2019, NMPA has published 12 announcements on the results of product property definition of drug-device combination products, showing that there are 152 cases completed in total. Among them, 87 ones were defined as drug-device combination products, accounting for 57.2% of the total; 65 ones were defined as non-drug-device combination products, accounting for 42.8% of the total. Among the 87 ones defined as the drug-device combination products, 46 ones have drug-oriented functions, accounting for 52.9% of the total; 41 ones were medical-device-oriented, accounting for 47.1% of the total.
Analysis of frequently asked questions on application materials
A Study on the Administrative Policy of Drug-device Combination Products, a project jointly carried out by several departments including the Device Center and Drug Center of NMPA, Nation Institutes for Food and Drug Control and the Acceptance Center, has provided a material list for drug-device combination products property definition application. However, there are still many problems lying in the materials submitted by the applicants, mainly including:
The basic product information submitted is incomplete. It is suggested that the applicants specify the basic product information in their property definition application materials. For a drug-device combination product imported for the first time, the applicant shall clearly state that whether the product has been approved for marketing by the exporting country (region) and whether the composition of the product, the use of each component (constituent), product schematic diagram and the product operation manual and label to be adopted are specified in the application materials. For the drug part of the combination product, the necessary information shall include the name of the drug, the supplier, and whether the product is registered in China or permitted to market in the producing country (region) with certifications; discrepancies shall also be specified for the marketed drug used in combination product and used separately in the intended use/indications, contact methods, dosage, contraindications and so on; for the medical device part of the combination product, the structure of the device should be specified. If the device has been marketed separately, relative marketing permission certification should be provided; discrepancies shall also be specified for the marketed device used in combination product and used separately in the intended use/range of applications, performance requirements and so on.
The basis for the drug-device combination product application is not strong enough. It is suggested that applicant give full consideration to the application basis of the drug-device combination products at the early stage of their research and development. Taking drug-contained devices as an example, any unreasonable addition of drugs or other active ingredients to medical devices is not encouraged, and any of those ingredients added shall be demonstrated to be based on a sound foundation for application. For example, antibiotic ingredients added to medical devices will bring about both benefits and risks at the same time because the antibiotic ingredients may contact directly with the local tissue through the contact with the equipment, sometimes even breaking through the body's blood-drug barriers, changing the original antibiotic ingredients contact methods of the devices. Therefore, at the research and development stage, it should be considered that in adding antibiotic ingredients, whether there is any corresponding problem such as those in history of clinical use and drug resistance, and whether the intended local antibiotic effect can be achieved. In addition, the research, development and production of drug-contained devices are mostly carried out by medical device research institutions or production enterprises, which are often short of professional and technical personnel in pharmacy related fields. Therefore, the development of drug-device combination products should conducted with more caution.
There are no supporting information for the functional mechanisms and major functional modes of the product. It is suggested that the applicants submit information specifying the functional mechanisms and major functional modes of the product in their property definition application materials. Some applicants stated in the application materials that the ingredients contained in the products were not active, but failed to submit sufficient supporting materials to prove such opinion. In the special inspection for the registration of sticking-type medical devices made in 2013, NMPA has specified that, for sticking-type products that only contain chemical constituents, TCM herbs (or natural plants) and their extracts, the intended objectives and functional mechanisms for adding such components shall be stated and verified whether the components are recorded in the pharmacopoeia or not. If the components contained exert pharmacological, immunological or metabolic effects, or the components contained cannot be proved not to exert such effects, the product shall not be registered and administrated as a medical device.
The combination mode of the drug part and the device part and the application methods or procedures of the product are not specified. It is suggested that the applicants specify the combination mode of the drug part and the device part of the product, as well as the application methods or procedures of the product in their property definition application materials, thus making it easier for the administrators to determine whether the product apply to the definition of drug-device combination products. For example, an anticoagulants-contained device for separating blood components was applied for property definition. According to the application methods provided in its instruction book, the anticoagulants produced and supplied by drug companies are provided in separate sterilization packages, and are put inside a suit with the anticoagulants-contained blood components separating device. In usage, the anticoagulants are extracted with a syringe and pre-filled to the separation device. From the application methods, we can see that the product does not apply to China's definition for the drug-device combination products. Therefore, the result is that the product does not fall into the category of drug-device combination products and should be declared separately. (Author: from Center for Medical Device Evaluation, NMPA)
In the irreversible trend that the innovative combination products keep emerging, China's drug administrators should always stand at the frontier and closely follow the development of domestic and foreign combination products, so as to draft scientific definition principles applicable to our drug-device combination products. In this way, we could provide scientific guidance and better supervision when the R&D of innovative drug-device combination products is getting more and more mature.
Property definition process for drug-device combination products
China has established a definition mechanism for drug-device combination products as early as 2009. According to the Circular on Matters Relating to Registration of Drug-device Combination Products promulgated by former China Food and Drug Administration (CFDA) in November 2009, if a drug-device combination product to be declared is not permitted to hit the market in China, before the declaration of registration, the applicant should apply for product property definition from the Center of Administrative Matters Acceptance Service and Complaint Reporting of NMPA (hereinafter referred to as the "Acceptance Center"). After receiving the applicant's application for property definition, the Acceptance Center shall organize relevant examiners to conduct definition and then inform the applicant of the result in written notice.
In 2015, the former CFDA made a procedure for drug-device combination products property definition. In 2016, the original procedure was simplified to consulting the Center for Drug Evaluation, NMPA ("CDE-NMPA") and the Center for Medical Device Evaluation, NMPA ("CMDE-NMPA") in letter with the Acceptance Center in the lead. With any discrepancy between the two centers, an expert meeting will interfere directly to make a decision. The improvement of property definition procedures for drug-device combination products essentially reduces the intermediate links, thus shortening the time period needed for issuing the definition results and improving the efficiency for definition. In 2019, the Medical Device Standardization Administration Center of NMPA took over the work of property definition for drug-device combination products.
In China, a drug-device combination product refers to such one that comprises drug and medical devices and is produced as a single physical work. The definition of product property is based on the definition of drug-device combination products and their major function modes, and the basic principle is that the product will not cause any administrative overlap of drugs and medical devices.
For the drug-device combination products in which drugs play the main role, the applicant shall declare for drug registration under the evaluation led by the CDE-NMPA; for the drug-device combination products in which medical devices play key roles (hereinafter referred to as "drug-contained devices") , the applicants shall declare for medical devices registration and shall be reviewed and evaluated under the leadership of CMDE-NMPA. For those needing a joint evaluation, the leading evaluation center shall hand over the needing parts in the registration declaration documents to a joint evaluation center for a synchronized evaluation. In view of the large differences between drugs and medical devices in the quality system, tests, declaration requirements and post-market supervision, in order to ease the burden on applicants, the latter are encouraged to conduct communication and consultation and product property definition in the early stage of the research and development of the products, so as to avoid any later non-compliance of registration path and declaration data preparation.
Property definition for 152 combination products finished
It's clearly specified in Circular on Matters Relating to Registration of Drug-device that: "Drug-coated stents, products including catheters with antimicrobial coating, drug-contained condoms, and drug-contained birth control rings shall be registered for administration as medical devices; products including the Band-Aids containing antimicrobial and anti-inflammatory drugs and TCM bandages for external use shall be registered for supervision as drugs. "But because of the variety of drug-device combination products, their definition and supervision modes are different among countries and regions. Along with the ambiguity and disputation existing in the main function of some products themselves, this will lead to discrepancy of regulatory modes in different countries or regions for some products. Thus, there are still a number of products making application for property definition every year.
Currently, products applied for property definition commonly include devices containing drug coatings or impregnated or combined with drugs, pre-filled drug dosing devices/systems, pre-filled biological products dosing devices/systems, devices with biological-products coatings or combined with biological products, liquid or gel products, for external use, etc.
In order to ensure the transparency of the definition results in drug-device combination products and guide the applicants to make proper declaration, NMPA published all the recorded results in product property definition. As of March 6, 2019, NMPA has published 12 announcements on the results of product property definition of drug-device combination products, showing that there are 152 cases completed in total. Among them, 87 ones were defined as drug-device combination products, accounting for 57.2% of the total; 65 ones were defined as non-drug-device combination products, accounting for 42.8% of the total. Among the 87 ones defined as the drug-device combination products, 46 ones have drug-oriented functions, accounting for 52.9% of the total; 41 ones were medical-device-oriented, accounting for 47.1% of the total.
Analysis of frequently asked questions on application materials
A Study on the Administrative Policy of Drug-device Combination Products, a project jointly carried out by several departments including the Device Center and Drug Center of NMPA, Nation Institutes for Food and Drug Control and the Acceptance Center, has provided a material list for drug-device combination products property definition application. However, there are still many problems lying in the materials submitted by the applicants, mainly including:
The basic product information submitted is incomplete. It is suggested that the applicants specify the basic product information in their property definition application materials. For a drug-device combination product imported for the first time, the applicant shall clearly state that whether the product has been approved for marketing by the exporting country (region) and whether the composition of the product, the use of each component (constituent), product schematic diagram and the product operation manual and label to be adopted are specified in the application materials. For the drug part of the combination product, the necessary information shall include the name of the drug, the supplier, and whether the product is registered in China or permitted to market in the producing country (region) with certifications; discrepancies shall also be specified for the marketed drug used in combination product and used separately in the intended use/indications, contact methods, dosage, contraindications and so on; for the medical device part of the combination product, the structure of the device should be specified. If the device has been marketed separately, relative marketing permission certification should be provided; discrepancies shall also be specified for the marketed device used in combination product and used separately in the intended use/range of applications, performance requirements and so on.
The basis for the drug-device combination product application is not strong enough. It is suggested that applicant give full consideration to the application basis of the drug-device combination products at the early stage of their research and development. Taking drug-contained devices as an example, any unreasonable addition of drugs or other active ingredients to medical devices is not encouraged, and any of those ingredients added shall be demonstrated to be based on a sound foundation for application. For example, antibiotic ingredients added to medical devices will bring about both benefits and risks at the same time because the antibiotic ingredients may contact directly with the local tissue through the contact with the equipment, sometimes even breaking through the body's blood-drug barriers, changing the original antibiotic ingredients contact methods of the devices. Therefore, at the research and development stage, it should be considered that in adding antibiotic ingredients, whether there is any corresponding problem such as those in history of clinical use and drug resistance, and whether the intended local antibiotic effect can be achieved. In addition, the research, development and production of drug-contained devices are mostly carried out by medical device research institutions or production enterprises, which are often short of professional and technical personnel in pharmacy related fields. Therefore, the development of drug-device combination products should conducted with more caution.
There are no supporting information for the functional mechanisms and major functional modes of the product. It is suggested that the applicants submit information specifying the functional mechanisms and major functional modes of the product in their property definition application materials. Some applicants stated in the application materials that the ingredients contained in the products were not active, but failed to submit sufficient supporting materials to prove such opinion. In the special inspection for the registration of sticking-type medical devices made in 2013, NMPA has specified that, for sticking-type products that only contain chemical constituents, TCM herbs (or natural plants) and their extracts, the intended objectives and functional mechanisms for adding such components shall be stated and verified whether the components are recorded in the pharmacopoeia or not. If the components contained exert pharmacological, immunological or metabolic effects, or the components contained cannot be proved not to exert such effects, the product shall not be registered and administrated as a medical device.
The combination mode of the drug part and the device part and the application methods or procedures of the product are not specified. It is suggested that the applicants specify the combination mode of the drug part and the device part of the product, as well as the application methods or procedures of the product in their property definition application materials, thus making it easier for the administrators to determine whether the product apply to the definition of drug-device combination products. For example, an anticoagulants-contained device for separating blood components was applied for property definition. According to the application methods provided in its instruction book, the anticoagulants produced and supplied by drug companies are provided in separate sterilization packages, and are put inside a suit with the anticoagulants-contained blood components separating device. In usage, the anticoagulants are extracted with a syringe and pre-filled to the separation device. From the application methods, we can see that the product does not apply to China's definition for the drug-device combination products. Therefore, the result is that the product does not fall into the category of drug-device combination products and should be declared separately. (Author: from Center for Medical Device Evaluation, NMPA)