Combination products are an integral part of healthcare as they provide innovative treatment options for complex diseases. They can be as simple as a first aid kit with vials & syringes or as complex as antibody-drug conjugates combined with drugs [1]. More often the development of combination products helps to enhance the function of an already approved product, in order to maximize patient care and safety. However, the regulatory landscape associated with these products is somewhat challenging due to their numerous combinations. This leads to a more unique regulatory approach.
More recently, the classification of these products has been difficult due to the increasing complexity of combination products. When comparing the regulatory framework between the US FDA and EMA, the US FDA manages combinations products through a dedicated Center, assigned by the Office of Combination Products (OCP), depending on the component of the product that provides the primary mode of action (PMOA). However, EMA segregates the different components of the product and implements different regulations for each of these components.
EMA: regulating drug-device combination products
In the EU, there are 2 directives that apply to drug-device combination products which determine their primary regulatory approach and framework. The Medicinal Products Directive (MPD) 2001/83/EC governs medicinal products and combinations that contain pharmacological & immunological actions, and the Medical Device Regulation (MDR) EU 2017/745 handles combinations that have a physical PMOA. If the medicinal product incorporates a device that forms the integral part of the combination product, it must also be evaluated in accordance with the MDR. Similarly, under the MDR, a combination product consists of a device which incorporates a substance as an integral part should also be evaluated under the MPD if it meets the following criteria [2]:
- It is considered a medicinal product under MPD if used separately,
- It must be liable to act upon the body;
- It must demonstrate ancillary action.
In order to support the regulatory approach for drug-device combination products, EMA also developed the “Guideline on the quality documentation for medicinal products when used with a medical device” guidance document in 2021 [3]. The guideline addresses that the Competent Authority (CA) is responsible for assessing device-specific safety aspects while also evaluating product’s safety, efficacy, and quality. Notified Bodies must evaluate the general device safety and performance requirements.
US FDA’s approach on combination product regulation
The US FDA’s OCP allocates combination products to its Centers: the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH). In January 2022, the US FDA released the ‘Principles of Premarket Pathways for Combination Products’ to provide information that would facilitate obtaining combination product approval by the FDA. This information includes what combination products are, interaction and communication between sponsors, Centers, and the FDA on regulation of combination products, and how the FDA reviews the combination products before granting market approval. Furthermore, the document provides guidance on how to determine which pre-market submission is appropriate for a particular combination product [4]. The following approval pathways are available for combination products depending on their PMOA:
Combination product | Applicable approval pathway |
Device-led | · Pre-market approval pathway (PMA) · De Novo Classification requests · Pre-market Notification (510(k)) submissions |
Drug-led | · New Drug Application (NDA) · Abbreviated New Drug Application (ANDA) |
Biologic-led | · Biologics License Applications (BLAs)-under section 351(a) · BLAs for biosimilar and interchangeable products- under section 351(k) |
The future of the regulatory landscape for combination products
As new tools and technologies develop and are increasingly incorporated into combination products, the regulatory approach for such products becomes more complex and requires more comprehensive support from regulatory authorities. A systematic regulatory review approach for combination products should focus on product design rational, PMOA, and evaluation (pre-clinical and clinical). However, due to differences in definitions and classification/designation of products, as well as complex PMOA, different regulations apply to the products. This is different for every country. A review article highlighted the difference in the regulatory approach towards combination products between the USA, EU, China, and Japan [5].
It is important to note that a more enhanced regulatory and pharmacovigilance system will be required to support novel combination products and related technologies. While on one hand, the complexities in the regulatory landscape for combination products present sponsors with many challenges, on the other hand it also brings areas for opportunities in terms of R&D, regulatory science and developing new standards and focusing on regulatory harmonization. Indeed, there is potential to revolutionize combination products and health care.
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References and further reading:
[1] US FDA. Combination Product Definition Combination Product Types. 2018
[2] Reis ME, Bettencourt A, Ribeiro HM. The regulatory challenges of innovative customized combination products. Frontiers in Medicine. 2022;9.
[3] EMA. Quality documentation for medicinal products when used with a medical device- scientific guideline. 2021
[4] US FDA. Principles of Premarket Pathways for Combination Products. 2022
[5] Tian J, Song X, Wang Y, Cheng M, Lu S, Xu W, Gao G, Sun L, Tang Z, Wang M, Zhang X. Regulatory perspectives of combination products. Bioactive Materials. 2022 Apr 1;10:492-503.