How To Determine A Combination Product's Primary Mode of Action (PMOA)
By David Amor, MSBE, CQA, Medgineering
PMOA is the most critical element in determining regulatory strategy for combo product submissions, including FDA review center.
When the antiproliferative drugs sirolimus and Paclitaxel were first added to bare metal stents in the early 2000s, in the hope of combatting restenosis events, they were viewed as “premium add-ons” to an existing device platform that did most of the work in treating artery disease and atherosclerosis. Defined as “combination products” per 21 CFR 3.2(e) – a combination of a drug and a device, in this case – drug-eluting stents (DES) are reviewed and approved by FDA’s Center for Devices and Radiological Health (CDRH), otherwise known as FDA’s device arm.
Drug-eluting stent (DES) submissions usually take the form of a premarket approval (PMA), which is clearly a device submission pathway. The product is assigned a medical device product code – NIU – and the reviewers are from the Office of Device Evaluation (ODE). The drug-eluting stent is, in a nutshell, treated as a medical device.
Why?
The Significance Of Primary Mode Of Action
A combination product’s primary mode of action (PMOA) establishes its regulatory and product development framework, including how it is viewed in the eyes of a regulator. The PMOA is such an important concept that the FDA published a docket in August 2005 entitled Definition of Primary Mode of Action of a Combination Product. In this guidance, the FDA lays out a process — which we’ll review in this article — for defining and then using the PMOA to make regulatory decisions. So what is the PMOA?
A mode of action (MOA) is defined as the means by which a product achieves its intended therapeutic effect or action. If you think back to the basic definition of a medical device, its means of therapy — per 201(h) — are achieved in ways that don’t include chemical actions or being metabolized; otherwise, it is classified as a drug. So when you have a product that is literally a combination of a drug and a device, what is it considered?
The PMOA helps us come to a determination. PMOA, as defined in the 2005 FDA guidance is the “single mode of action of a combination product that provides the most important therapeutic action of the product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.” In plain English, PMOA is the constituent part of the combo product that is most responsible for treating/curing/mitigating whatever the intended use indicates.
How To Make The PMOA Determination
Returning to the DES example, we would start the analysis of PMOA with, “what is the product’s intended use and indication?” From the approval letter of Cook Medical’s Zilver PTX Drug-Eluting Stent: “[The product] is indicated for improving luminal diameter for the treatment of de novo or restenotic symptomatic lesions in native vascular disease…” We then ask:
- What is the device’s MOA? The stent’s primary function is to provide apposition force to the walls of the vessel, essentially moving the plaque or lesion out of the way to restore patency to the vessel. The device features an inflatable balloon and strong mesh of alloy wire that is deployed to remove the blockage, thus increasing the luminal diameter.
- What is the drug’s MOA? Antiproliferative agents, like the drugs coated onto DES stents, are known to prevent or slow neointimal tissue growth. The MOA for the drug is chemical action that helps blocks the re-proliferation of the neointima and thus prevents the lumen from becoming occluded again.
When determining PMOA in this scenario, ask yourself, without one constituent part of the drug/device combo, would the product still achieve its intended use? In this case, the device alone (the stent) would still open the luminal diameter with its action. The drug provides the secondary effect of making sure that lumen doesn’t restenose as quickly, or at all. Thus, although the drug’s MOA is important, it’s not as critical to performing to its indication when compared to the device.
Agency Assignment And Request For Designation (RFD)
Determining the PMOA allows a company to formulate its regulatory approach.
- PMOA = device --> lead agency = CDRH
- PMOA = drug --> lead agency = CDER
- PMOA = biologic --> lead agency = CBER
The agencies will usually outsource other constituent submission parts to other agencies for review, but the lead is responsible for the premarket review.
If the PMOA is unclear or there are multiple MOAs that are competing or equally important, there are other ways to determine which agency a company should submit to:
- Consider precedence — Are there similar products on the market? If so, how were they submitted? If the predicates were commercialized post-2005 (when the final rule for PMOA came out), ensure that the predicate’s PMOA assignment would not have changed with the new rules.
- Consider the concerns around each constituent part — Which constituent causes the most safety or efficacy concerns? For example: if the combination product leverages a brand new drug on a well-known device platform, the drug may have less history to support its safety. In these cases, the lead agency may be assigned by the manufacturer according to which constituent has the most “questions” that need to be addressed, so that the proper expertise is in place during pre-market review.
If a company cannot come to a conclusion on PMOA, a mechanism called request for designation (RFD) allows a sponsor to submit a petition for FDA to determine a combination product’s classification and lead agency assignment. However, the FDA’s designation response is binding and will dictate the regulatory path for the sponsor. I always encourage clients to reach out to OCP early to request a meeting to discuss their product’s actions, prior to submitting an RFD.
If an RFD is deemed necessary, the FDA’s guidance on the subject, How to write a Request for Designation, aids the process. One of the most common errors that sponsors make with RFDs is not providing sufficient product information to help FDA make a determination. In fact, only about 50 to 60 percent of RFD submissions ever result in a designation. Often, the sponsor will withdraw the request, or FDA will cite incomplete information.
Example: PMOA determination
- Combination Product: Epinephrine auto-injector (injection pen)
- Intended Use/ Indication for Use: Epipen example - EpiPen and EpiPen Jr Auto-Injectors are for the emergency treatment of life-threatening allergic reactions (anaphylaxis) caused by allergens, exercise, or unknown triggers; and for people who are at increased risk for these reactions.
- MOA Assessment:
- Device (Injector Pen): houses drug (container), helps provide access to patient anatomy (needle).
- Drug (Epinephrine): Epinephrine is a drug that can help stem, stop, or prevent anaphylaxis caused by allergens, exercise, or other triggers.
- PMOA Determination: The PMOA in this case is the drug Epinephrine because it provides the most critical therapeutic action that addresses the indications. Furthermore, by reviewing the FDA Guidance Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products, it can be determined that most pen injectors used with drugs are classified as “Drugs” where the main submission pathway is a New Drug Application (NDA) – or a derivative such as a 505(b)(d) – and the lead agency is CDER.
Conclusion
Determination of the PMOA is one of the most critical elements of a company’s regulatory strategy for combination products.
Inputs to the PMOA decision include identification of the intended use and indications, assessment of the product’s various modes of action, and research of predicates and comparable products for previous assignment history. PMOA decision outputs include its regulatory pathway, lead FDA agency reviewers, and the quality management system and submission focus.
If the PMOA remains elusive, consider the RFD process after initial meetings with the OCP.
About The Author
David Amor, MSBE, CQA is a medtech/ biotech consultant and mobile health entrepreneur who founded Medgineering, a company focused on remote compliance, regulatory & quality systems consulting for larger companies and start-ups alike. A graduate of the prestigious Innovation Fellows program at the University of Minnesota’s Medical Device Center, Amor was named a Top 40 Under 40 Medical Device Innovator in 2012 and a 35 Under 35 Entrepreneur in 2015 by MN Biz Magazine. He co-founded and helped launch Remind Technologies, a Texas-based mobile health company developing a smartphone-based remote medication management system. He is also co-inventor on several issued utility patents and co-pioneered a disruptive e-consulting platform for the medtech and pharma industries called QuickConsult. Amor serves as an adjunct professor at St. Cloud State University (Maple Grove, MN) where he teaches courses on risk management and design control. The current focal points of his consulting practice are specializing in risk management, design controls, combination products and mHealth. He can be reached at david@medgineering.com or at 786-546-1806.