Regulatory Perspectives of Combination Products
Combination products are innovative medical solutions that combine drugs, devices, and biologics, such as drug-eluting stents or pre-filled syringes. These products offer significant value to patient treatment by providing integrated options; however, they face a much more complex regulatory landscape as they must comply with both drug and device regulations. Combination products are defined differently across regulatory jurisdictions, reflecting their diverse regulatory requirements and classification approaches.
Under FDA Regulation 21 CFR 3.2(e), combination products in the US consist of two or more components (drug/device, biologic/device, drug/biologic, or device/biologic), which may be physically combined, co-packaged, or intended for joint use, with necessary labeling modifications upon approval. Similar products in Europe are referred to as integral products or drug-device combinations and regulated based on their primary mode of action, be that medicinal or medical device.
Regulatory Framework in the United States
In the US, regulation is overseen by the FDA's Office of Combination Products (OCP) which was created on December 24th, 2002, under the Medical Device User Fee and Modernization Act of 2002. OCP plays a crucial role in classifying products based on their primary mode of action (PMOA) and assigning them to one of three FDA centers: CDER, CBER, or CDRH. This determines the marketing authorization type, such as a New Drug Application (NDA) for drug PMOA, Biologic License Application (BLA) for biologic PMOA, or Premarket Approval Application (PMA) for device PMOA.
For instance, CDRH typically regulates drug-eluting stents, where the primary mode of action is the device function (physical support). CDER regulates prefilled syringes when the primary mode of action is the drug component. In some cases, separate applications for constituent parts may be required and coordinated with respective FDA centers. The process typically entails one marketing application, though separate applications for constituent parts may be permissible under some circumstances, coordinated with relevant centers.
Regulatory Framework in the European Union
EU regulatory approach differs from that of OCP by lacking a centralized office that categorizes products based on the primary mode of action. Instead, products are either classified as medicinal products under pharmaceutical legislation (Directive 2001/83/EC or Regulation (EC) No 726/2004) or as medical devices under the Medical Devices Regulation (MDR, Regulation (EU) 2017/745).
The US and EU classify combination products differently based on their primary mode of action (PMOA). In the US, the PMOA determines which regulatory center takes the lead—often allowing manufacturers to submit a single application- whereas the EU classifies products based on primary mode of action, resulting in dual regulatory pathways. A drug-eluting stent in the US is regulated as a device under CDRH. In the EU, it must comply with MDR regarding its medicinal substance, potentially leading to varying compliance requirements.
Future Perspective of Combination Product Regulation
The regulatory landscape for combination products continues to change rapidly as technology evolves. However, several emerging approaches show promise in improving the evaluation process for these products:
Computational Modeling and Simulation
Artificial Intelligence applications
Development of new standards and evidence-based research methodologies
New regulatory strategies for identifying and approving innovative or breakthrough products
As combination products increasingly incorporate digital health components, regulatory frameworks must adapt accordingly. Computer platforms, connectivity features, software, and sensors form integral parts of combination products. The regulatory standards continue to develop their position on how best to regulate digital health tools as part of combination products.
Conclusion
Combination products play a vital role in modern healthcare by offering comprehensive treatment solutions. However, their complex regulatory landscape requires manufacturers to navigate multiple frameworks effectively. As technology advances, the regulatory landscape for combination products will undoubtedly change as new tools and methodologies emerge to address their unique challenges. Manufacturers must remain updated on developments while engaging proactively with regulatory authorities for optimal navigation of these challenges.
At DDReg, we provide regulatory and pharmacovigilance services through a multifaceted approach that ensures the safety and efficacy of pharmaceutical products throughout their lifecycle. DDReg’s team of experienced pharmacovigilance professionals is well-versed in regulatory requirements and guidelines from health authorities, ensuring that all safety assessments comply with the latest regulatory standards. For professional advice and assistance in regulatory writing related queries.
Our team of skilled experts ensures compliance with regulatory requirements while prioritizing patient safety.
Missed our last blog? Catch it here: Understanding Benefits and Challenges of Outsourcing Pharmacovigilance Services
COO
5moLove this