I worked on a combination product a few years ago for Pfizer. it was Xyntha a drug for Hemophilia A patients. The key to the product was to make a simplified dosage for home use with a dual chamber syringe. The marketing differentiator was to eliminate the patient manipulation of a syringe and vial. The dual chamber syringe had a design where two chambers: one for the freeze dried drug product and the other for the WFI diluent. The patient would need to remove the syringe from the freezer and connect the syringe (luer lock) to a cathether, press the syringe to allow for WFI to enter the other chamber, reconstitute and control the infusion into the arm.
The product was filed through CDER with NDA regulatory process. The interesting observation was the FDA wanted to have human factors study on the syringe and that is where I came in. I was responsible to conduct a risk analysis including marketing/patient, manufacturing and quality. It included a FMEA on patient usage, manufacturing and supply chain due to the drug product characteristics.
An example of a combination product currently on the market is an antibiotic-loaded bone cement. Antibiotic-loaded bone cements are used in orthopedic surgery for implant fixation, holding the implant against the bone, while reducing the chances of infection. The antibiotics are in powder-form to prevent alteration of the mechanical properties of the bone cement. The primary mode of action is the fixation of the bone to the implant, so the device should be under CDRH, since it is an implant which does not achieve its primary purpose through chemical action on or within the body, nor is it dependent on being metabolized. More specifically, antibiotic-loaded bone cements are Class 2 devices. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm?id=mbb
Since this is a Class 2 medical device, a Premarket Notification, 510(k), is needed, in which evidence must be given that it is substantially equivalent to a predicate device.
Here are some examples of antibiotic-loaded bone cements:
https://www.zimmerbiomet.com/medical-professionals/cement/refobacin-bone-cement-r.html
Sirolimus Eluting Coronary Stent. This device is indicated for improving coronary luminal in patients.The mode of Action for this device is a drug elutingballoon- expandable stent that is pre-mounted on PTCA catheter delivery system. It falls under CDRH and considered as Class 3 device, so it needs PMA.
Combination Product: Promus Element Stent
This stent is coated with a drug that helps reduce the chances of arteries becoming blocked. The stent is designed to fit in the arteries and prevents blockage. I believe it falls under the Center for devices and Radiological Health (CDRH) because the actual device, the stent, has the primary purpose to fit into arteries to prevent blockage, and the drug aids in the process as it is released into the coronary arterial wall. The drug helps the implantation process to have better effects and to cover up the metal with a coating so it does not harm the body.
Insulin Pump is a tool that helps inject the patient with insulin based on the patient's blood glucose level. The device monitors the glucose level in the patient's blood periodically and adjusts the amount of insulin injected based on the patient's needs. The main purpose of the device is to deliver the drug "insulin" which is why CDER is the lead agency. Finally, the submission pathway most applicable for this combination device would be a New Drug Application (NDA) or an appropriate filling of a 505(b)2.
https://www.medtronicdiabetes.com/treatments/insulin-pump-therapy
An example of a combination product is antibiotic-impregnatedbone cement (also referred to as antibiotic-loaded bone cement)releases the antibiotic agent(s) into the surrounding tissue. The innovators claim that the antibiotics in the bone cement give added protection against infection over conventional antibiotic regimens. There is some controversy as to the most effective use of antibiotic-loaded bone cement. However, it is a medical device that releases drugs. Therefore, it is a class III device that also needs to get approval from CDER. However, the main purpose of the device is, it's bone cement. Therefore, the company should apply for NDA(New drug application).
Combination Product: Trulicity
Trulicity is a once-weekly injectable glucagon-like peptide-1 (GLP-1) receptor agonist that has been approved for use as a supplement to diet and exercise in persons with type 2 diabetes to enhance glycemic control. It helps patients' bodies release their own insulin when they eat by acting like the hormone GLP-1. Trulicity is available as a pen, so the patient does not have to mix, measure, or touch the needle. It can be injected subcutaneously into the abdomen, thigh, or upper arm at any time of day, with or without food.
Since Trulicity is now considered a biological medicine, it would fall under FDA's Center for Biologics Evaluation and Research (CBER). Since Trulicity is a Part 3 combination product (21 CFR 3.2(e)); therefore, it must also comply with postmarketing safety reporting requirements for an approved combination product (21 CFR 4, Subpart B).
An example of a combination product is an auto-injector. An auto-injector contains a pre-filled syringe and the device releases a plunger that contains a spring when activated to inject the drug product into the patient. Auto-injectors can be used to administer different types of drug products. This product should be submitted to the Center for Devices and Radiological Health (CDRH) since the drug itself likely would have been submitted to the Center for Drug Evaluation and Research (CDER) to be administered via a syringe and needle system. Since the mechanism is more focused on pushing the stopper within the syringe using an activation force to ensure that the patient is able to administer the drug, it would make sense to submit this as a device. Additionally, most of the parameters within the auto-injector such as injection time and exposed needle length are more dependent on device-related parameters rather than drug-related parameters.
