Kari Miller, Regulatory and Product Management Leader, Pilgrim Quality Solutions
In Part 1 of this series, Combination Products: Past, Present, and Future, we focused on the past, a necessary step in understanding just how far we’ve come in this space. We also reviewed the definition of a combination product before strolling down origins lane, to ensure proper focus. As witnessed through the lens of history, the road to regulatory and quality compliance for combination products was and is a complex one, and in many ways, the regulatory path for these products is still under construction.
As discussed, Combination Product companies find themselves in a unique position in the United States. Not only do they need to comply with the cGMP for combination products (21 CFR Part 4), they need to be concerned with the compliance and quality of the constituent parts of the combination product, which means compliance to either 21 CFR Part 210/211 (drug), 21 CFR Part 820 (device), or both cGMPs. The Primary Mode of Action (PMOA) dictates which cGMPs need to be followed for a given Combination Product. Therefore, we will transition briefly to how the PMOA is determined.
Primary Mode of Action
As defined by 21 CFR 3.2 (m), the PMOA is the single mode of action of a combination product that provides the most important therapeutic action. It is through this definition that the lead center at the FDA is assigned, and while one might think it would be the Office of Combination Products (OCP), it is not. One of the three below centers will be assigned based on the PMOA:
- Center for Drug Evaluation and Research (CDER)
- Center for Devices and Radiological Health (CDRH)
- Center for Biologics Evaluation and Research (CBER)
Simple examples of PMOA, and therefore Center assignment, will be used here to explain or define PMOA. For the first example, let us look at a Drug-eluting stent. A stent is a small mesh tube (device) used to keep arteries open. There are Bare-metal stents and Drug-eluting stents. While the Drug-eluting stents assist in prolonging artery blockage, the stent is the primary constituent component keeping the artery open. This type of combination product would be assigned to the CDRH as the device provides the PMOA. In the case of an asthma inhaler, it is the drug that provides the medical benefit by opening the airways, while the device (the inhaler mechanism) is the delivery mechanism for the drug. Due to the drug providing the PMOA, this combination product would be assigned to CDER.
The PMOA is not always readily apparent. This can certainly be the case during early development, but that is not the only occasion in which identification of the PMOA is unclear. When two or more constituent parts provide different modes of action and neither is subordinate to the other, classification of the combination product and assignment to a center can be difficult. Assisting with this classification and assignment to a center is one of the primary duties of the Office of Combination Products (OCP). In cases where PMOA is unclear, it is recommended to work with OCP early in the development cycle, submitting both a Pre-Request for Designation (Pre-RFD) and a Request for Designation (RFD).
Role of the Office of Combination Products
The U.S. Office of Combination Products is a statutorily mandated office, and the role of the OCP includes not only the combination product classification and agency assignment, it serves as the coordinator and overseer of the regulations regarding combination products. It also resolves disputes between agencies and/or Sponsors. Per 21 CFR 312.3(a), “Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.” The OCP also reports to Congress annually and it serves as a resource for industry. The goal of the Office is to provide consistent, predictable, transparent regulation of combination products, which includes adherence to the appropriate cGMPs for the combination product in question.
CGMPs in Combination Products
While the assorted cGMPs clearly have much in common, they also differ because each has been designed to address the characteristics of the products to which they pertain. Consider the Corrective and Preventive Action (CAPA) process. In the device quality system regulation (QSR), CAPA requirements are quite specific, however, CAPA principles are included in multiple parts of the pharmaceutical cGMP. Therefore, organizations whose core competency is Pharmaceutical are likely to find themselves struggling with design controls, purchasing controls, installation, service, and CAPA. While organizations with a core competency in Medical Devices are likely to struggle with yield calculations, packing, testing for release into distribution, stability testing, and expiration dating. The below chart indicates the areas where your organization may have cGMP weaknesses based on your organization’s primary competence, and therefore, the basis for your current quality management system.
Other Influences on Combination Products
One major influencer of the current improved status of combination products was the 21st Century Cures Act Section 3038. It served to improve the regulation of combination products through faster assignment of the products to a primary agency center (CDRH, CDER or CBER), quick assignment of PMOA, and defining the process for resolving disputes about those assignments.
The Combination Products category can be quite complex, and because it is one of the major innovation categories for Life Sciences, it is not surprising that disputes may arise regarding the PMOA. In Section 3038 of the Cures Act, Sponsors are allowed to request a substantive rationale for their PMOA determination and the agency is required to provide the scientific evidence relied upon for the that determination. Additionally, the Sponsor may propose one or more studies to establish the relevance of a PMOA. Collaboration on studies is to occur between the Secretary and the Sponsor, with a goal to reach agreement in 90 days or less.
Finally, after the PMOA determination is established, the Sponsor may request in writing a meeting to establish clarity and certainty on that determination. The Secretary must respond to these written requests in 75 days or less. Meeting topics may include:
- Standards and Requirements for market approval or clearance of the combination product
- Requirements for post-market modifications
- cGMP practices applicable to the combination product
All final agreements, as a result of the meeting, are to be made in writing as well.
How it all Works Together
Combination product organizations have more clarity on how combination products will be regulated than ever before, and that includes definitions of how the OCP works with the CBER, CDER, CDRH, and other agency components as appropriate to establish and clarify regulatory approaches and the way forward. This includes inter-center coordination of reviewer tools and training, inter-center work groups, internal memorandums of understanding and standard operating procedures, as well as the creation and update of guidances and regulations regarding combination products.
The three key concepts the FDA uses in the regulation of combination products are as follows:
- Constituent Parts retain independent regulatory status and duties.
- Combination Products are a distinct regulatory class; a combination product is not a combination device, or a combination drug — it is a combination product regulated by PMOA.
- Use due diligence in ensuring comprehensive, effective oversight of combination products without undue redundancy.
As mentioned in Part 1 of this series, the regulation of combination products has come a long way, but there is still much to do. The OCP has its work cut out. The classification of a combination product is not clear cut in many cases, and bringing clarity to this space will require the continued care and due diligence we’ve witnessed thus far from the OCP.
The Life Sciences industry finds itself in an interesting place today. Innovation is occurring in combination products, and the category is a major growth segment of the industry. Staying abreast of the regulatory and quality compliance requirements of combination products can be quite a challenge as the FDA’s management activities have demonstrated. Likewise, whether you are located in, Australia (TGA), Europe (EMA), the UK (MHRA), or the rest of the world (ROW), you are witnessing that we are all focused on promoting and protecting public health through management of combination products.
In the final installment of this 3-part blog series, Combination Products: Past, Present, and Future, we’ll review what analysts are saying about this market, and what future activities and enforcement actions are planned by the OCP. Finally, we’ll take a look into the crystal ball to examine just what the category’s future might hold.
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