As we all know, The definition of the Combination product is " a product comprised of
any combination of a drug and a device; a device and a biological product; a biological product
and a drug; or a drug, a device, and a biological product. Under § 3.2(e), a combination product
includes:
1. A product comprised of two or more regulated components, i.e., drug/device,
biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or
otherwise combined or mixed and produced as a single entity (single-entity combination
products);
2. Two or more separate products packaged together in a single package or as a unit and
comprised of drug and device products, device and biological products, or biological and drug
products (co-packaged combination products);
3. A drug, device, or biological product packaged separately that according to its
investigational plan or proposed labeling is intended for use only with an approved individually
specified drug, device, or biological product where both are required to achieve the intended use,
indication, or effect and where upon approval of the proposed product the labeling of the
approved product would need to be changed, e.g., to reflect a change in intended use, dosage
form, strength, route of administration, or significant change in dose (a type of cross-labeled
combination product); or
4. Any investigational drug, device, or biological product packaged separately that
according to its proposed labeling is for use only with another individually specified
investigational drug, device, or biological product where both are required to achieve the
intended use, indication, or effect (another type of cross-labeled combination product). "
The US FDA requires the manufacturer of a combination product to determine the Primary mode of action (PMOA) of the combination device so that it can be properly directed to the appropriate review center within the FDA.
One of the main issues manufacturers face is defining the PMOA. In many instances, the combination device does not have a single primary mode of action. This becomes even more difficult with implantable devices.
Do you have experiences with defining PMOA for a combination Device? if not, what do you think is the best way to identify the PMOA.
I personally have no experience working with PMOA for combination devices. But the best way to understand what is the PMOA is by seeign the two possible designation. And then evaluate if it were to go through the FDA process with the two possible designations individually, which one will match the intended therapeutic effect or action. This helps to make the determination because if it the portion that needs to be evaluated by the FDA through the end to end process.
Hello Fady,
I have a small amount of experience in working with PMOA’s for combination products. In my experience, I have worked with drug/device PMOA’s and the separation of two drugs until consumer use (for example: two active vitamins are separated until the granulate is poured from the package, which contains 2, independent chambers.)
In most cases, we found that it was fairly straightforward to determine the PMOA but in the instance that we did not, we would meet with and discuss with the regulatory affairs department to determine what PMOA was most suitable for the product.
-Michelle
Outlined by the FDA if it is difficult or unclear on determining the primary mode of action for the combination product, you can file a Request For Designation (RFD), which is outlined in 21 CFR Part 3, and the specific information to be included in the RFD is described in detail in 21 CFR 3.7. With this the FDA determines the 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.
https://www.linkedin.com/pulse/how-determine-combination-products-primary-mode-action-travaglio
I do not have any experience with working with PMOA for a combination device. After doing research on this topic, I have come to the conclusion that if a company cannot identify a PMOA, a Request for Designation can be submitted to the FDA to determine the classification of a combination device. Additionally, before submitting the request, a meeting with the Office of Combination Products (OCP) can be set up if you are uncertain about the type of information to include or about the need to submit an RFD. A meeting with OCP would be helpful in providing the FDA with a better understanding of how the product works and guidance can be developed.
I have not had an experience working with PMOA for a combination device yet. Upon some researching, I have found out that PMOA is very critical when establishing a product's regulatory and product development framework. Technically speaking when we need to identify the function of a product, we look at what the product does and where is the greatest impact. In other words, if we have to determine the primary mode of action of a combination device, then we need to determine what the most important therapeutic action. Basically, what action of the device makes the greatest contribution in overall effect of the device.
In a device, list out all the components and their intended use in comparison with the overall intended use of the device. Then, identify one component without which the device would not reach its intended use.
As we have learned from Dr.Simon MDD1 (Medical Device Development 1) on WEEK 4 about combination product:
Definition of Combination Product
Primary mode of action = the single mode of action of a combination product that provides the most important therapeutic action of the combination product.
Includes two or more separate products packaged together
Includes products sold separately but intended for use with another type of product.
Dr.Simon mentioned that if you don't know the product is a device or a drug, you will need to submit Request for Designation (RFD)
Companies may submit RFD outlining the rationale of the product as being a device, biologic, or drug
FDA responds to designate which center has lead responsibility based on primary mode of action
Decisions can be appealed to Ombudsman
Also, FDA,the Office of Combination Products (OCP), help to o classify medical products as drugs, devices, biological products or combination products and assign them to an FDA center for premarket review and regulation, where their classification or assignment is unclear or in dispute.
https://www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm101496.htm#roles
I have not had any experience in defining the Primary Mode of Action (PMOA) for a combination device. The best way to define the device is by analyzing the two components involved in the product. Based on this, it will narrow down the type of designation the device will be given. In addition, the FDA has Request for Designation that can be filled as someone has previously mentioned. With this form, it allows for a request to identify the designation of the product. This would be the most effective way to identify the PMOA. This would then ensure that the product follows the regulations presented by the FDA.
https://www.fda.gov/RegulatoryInformation/Guidances/ucm126053.htm#IIB
I do not have experience working with combination devices, but several of the posts above mentioned the option of submitting an RFD, so I did some research on this topic to see if it is as easy as it sounds. In one article I found, the author mentioned that between 2009-2014, 67 RFDs were submitted to FDA, and 69% of them were found to have insufficient information provided by the sponsor. The biggest deficiency found was that companies failed to distinguish between the primary mode of action and multiple modes of action with reasonable certainty. So although it sounds relatively easy to submit an RFD and just let the FDA decide what regulatory center is responsible for the device, it appears that many companies fail to provide adequate information for FDA to make that decision.
I tried to post the link to the article but I kept getting an error. Below is the title of the article for your reference.
Title: COMBINATION PRODUCTS - 6 Guidelines to Follow When Developing Combination Products
The PMOA for a combination device determines the lead agency center .The component that contributes the most to the combination device’s intended therapeutic effects determines lead agency center. If PMOA is unclear ,a request for RFD can be filled.This will help to established lead center of combination device.After receiving RFD ,FDA will assign device to agency center that regulates other similar product,if no similar product exists,FDA will assign to agency center with most expertise to evaluate safety and effectiveness of combination device.
Beyond identifying a combination, I wanted to touch upon some of the challenges that surface when understanding the classification, and jurisdiction of these products. Common challenges include legal issues, marketing, premarket, post market, and cross labeling. Legal issues arise because there currently statutory or regulatory standards for combination products are not well defined. Additionally, marketing strategies are not the same in different markets (eg. biological products and device industries). Premarket and post market challenges are typically due to different data requirements, review timelines, factors such as promotion and advertising, and regulatory requirements in the different markets. Labeling challenges include labeling consistency, proprietary data reliance, coordination of changes, coordination of marketing review, and authorization.
