The regulatory pathway and corresponding regulatory requirements for combination products can often be unclear and daunting for drug makers and medical device manufacturers. Regulatory jurisdiction with respect to combination products (drug, device, and/or biologic) falls under one of the three FDA assigned lead centers: Center for Drug Evaluation and Research (CDER), Center for Biologic Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH), and is dependent on the combination product primary mode of action (PMOA). The US Food and Drug Administration’s (FDA) Office of Combination Products (OCP), established by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA), is the regulatory body responsible for covering the regulatory life cycle of combination products, including serving as a focal point for combination product issues, developing guidances, regulations, and standard operation procedures to clarify regulation of combination products.
The 21st Century Cures Act was signed into law by President Obama late last year, and promises to add some clarity and consistency into the way the OCP reviews combination products. For a better understanding of how these new regulations will impact regulatory review of combination products, I sat down with Diane Beatty, PhD; Managing Director, Regulatory Affairs and Product Development; and Jean Dehdashti, MSc, RAC; Scientist III, Regulatory Affairs & Product Development; both from Cardinal Health Regulatory Sciences.
Both Diane and Jean have spoken in a webinar on regulatory requirements for combination products. Watch that webinar on-demand by clicking here.
What constitutes a combination product?
A combination product is typically made up of two constituents: either a drug/device, a biologic/device, a drug/biologic, or a drug/biologic/device, where it is important to understand that from a regulatory perspective, that each constituent of a combination product maintains the regulatory requirements applicable to that particular constituent.
What makes the approval process for novel combination products, or novel indications of historically approved combination products, more complicated?
For two independently regulated constituents of a combination product, it might be challenging to decide which pathway is appropriate for your combination product. Specifically, which regulatory pathway leads your combination product development, approval, and postmarketing requirements: the drug pathway, the device pathway, or the biologic pathway? Depending on what kind of combination product it is, that may be exactly where the challenge lies.
How do you establish what the PMOA is for that particular combination product, and how do you define what the appropriate regulatory pathway would be? This information and the supporting scientific rationale play critical roles in establishing whether a combination product should be regulated as a drug combination product, as a device combination product, or as a biologic combination product, where each of these regulatory pathways have their own unique set of regulatory requirements, and regulatory interactions with FDA at their respective centers.
Further to that, it is important to note that there are three different categories of combination products based on how the products are combined and the mode of action of each constituent part, and as such, where the regulatory pathways are impacted based on what category the combination product falls into.
So the regulatory requirements are not standardized for all combination products, but are specific based on whether it’s a drug/device, a biologic/device, or a drug/biologic?
Those regulatory requirements are initially based on the combination product’s PMOA, which is the single mode of action that provides the most important therapeutic action of the combination product. FDA has standards that apply to combination products, but it’s not always clear how the product is designated or which review center has the primary regulatory jurisdiction. FDA has an algorithm for assigning the product designation and the corresponding primary review center, which guides the regulatory pathway.
There are three combination product categories: single entity combination products, co-packaged combination products and cross-labeled combination products. Not only do you have different constituents coming together, but they’re also packaged differently. This also adds an additional complicated layer to the regulatory pathway.
How has the 21st Century Cures Act changed the regulatory requirements for combination products?
Some of what the 21st Century Cures Act has codified is what has been in practice at the Agency already. For example, marketing submission under a single application is something that is already in practice by the FDA.
With respect to the OCP and Requests for Designation, the 21st Century Cures Act adds transparency to how OCP defines chemical action in the assessment of the PMOA, and as a result makes their jurisdictional decisions as far as whether it is a drug combination or a device combination. In addition, under the 21st Century Cures Act, a sponsor can now request the scientific rationale and evidence that the agency used to make a designation.
The 21st Century Cures Act also provides a means to Sponsors by which once a jurisdictional decision has been made, Sponsors can interact with OCP and gain further insight as to what the applicable regulatory requirements are for the combination product.
What can people expect to learn from your upcoming webinar?
We certainly know there is information out on the World Wide Web with respect to regulatory requirements and technical requirements. Predominantly, the information focuses on specific areas for combination products, like how to work with the OCP, cGMP compliance, implications of the 21st Century Cures Act, or requirements from a pre- and post- marketing perspective.
The objective of our webinar is to provide a comprehensive summary and overall perspective of the combination product regulatory landscape. We hope that our listeners will gain an understanding of the complexities revolving around the regulatory pathway of combination products through post-marketing requirements, as well as the impact of the 21st Century Cures Act.
For more information on how the 21st Century Cures Act is changing regulatory requirements for combination products, register for Cardinal Health’s webinar on the topic.