Combination Product - clearing a device as a standalone product before submission

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December 2016

Combination Product – clearing a device as a standalone product before submission

2 min reading time

We are working with a pharmaceutical company who, in the past, developed a combination product (drug/device). Because the device was included in the drug submission, it led to many questions, specifically about the device, by the agency because both CDER and CDRH were involved. The process dragged on, mostly related to the device questions and left a bad taste in the pharmaceutical company’s mouth. The client is now working on a new drug which will be kitted with a medical device and they are considering their submission options.

For this second case, the medical device, if classified on its own, would be a Class I, 510(k) exempt product. I understand that kitting it or making it combination product would throw it into a different regulatory category. However, the client is wondering if there is a way to “submit” the medical device separately (ahead of the combination submission) to receive FDA clearance for the medical device as a standalone product, and then just reference the clearance (510(k) number) in the drug application. Specifically, the client would like FDA to view documentation and data about the device ahead of the drug submission because they do not want the same thing to happen as before where questions about the device cause issues. The challenge in this case is the device being a 510(k) exempt product code as a standalone device.

Because this device would be 510(k) exempt, I have the following questions.
1. Would FDA accept a 510(k) submission for a product code that doesn’t require a 510(k), or would they just reject it because it goes beyond what is required?
2. I’ve been told that if you submit a Device Master File to FDA, they will not review it until it is reference in a submission. Is this true? This could be another path; but if FDA would not review it head of the drug submission, it does not meet the client’s desires.
3. Are there any other regulatory options that you are aware of for this case?

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Posted by Kristin Benokraitis

Asked on December 19, 2016 12:00 am

301 views

	Private answer Kristin Benokraitis, we are in the same boat with one of our new inventions. Please keep me in the loop. I'd be happy to share our notes with you confidentially. Marked as spam Report spam
	Private answer Kristin Benokraitis, may I ask if the first device which gave them such a bad taste in the mouth would also have been a Class I, 510(k) exempt? It seems surprising that CDER (probably the ones who had the most questions about the device) would have so many time-consuming questions re. such a low risk -and thus low complexity device. If it was not, maybe your client should worry a bit less. If it was, then I would suggest they revisit all the questions asked last time, and have answers to them ready in the initial submission. As far as submitting a 510(k) for a Class 1 510(k) exempt device, you will almost certainly get a RFA (refuse to accept) letter back (after some delay, of course...). Another option would be if said device was part of a previous, already cleared, combination device (different drug). Keep us posted on what your client deciced to do. Good luck Marked as spam Report spam
	Private answer Kristin Benokraitis The previous device (submitted as a part of the NDA) was a Class II, 510(k) non exempt. We plan on calling FDA's DICE division after the holidays to see if they would be willing to answer some questions. But yes, I am worried about a refusal to accept. I also don't know what we would reference for a predicate 510(k) number since there isn't one. Appreciate the commentary and the reality that others are in a similar situation. I will try to keep the comment chain updated with our experience. Marked as spam Report spam
	Private answer Kristin Benokraitis - I tend to agree with Jacques Ginestet about the likelihood of RFA. Not sure why the device garnered so many questions previously, but perhaps knowing what they were or why they were asked would inform a separate brief that could explain/inoculate against such a delay. Likewise, I'm interested to learn how your project progresses. Reaching out to DICE is a good idea. Marked as spam Report spam
	Private answer Kristin Benokraitis - Companies tend to make mistakes with their first drug-device combination products. I would encourage your client to learn from the experience and be better prepared for the second combination product. Trying to file the device earlier and separately may appear to be a good approach. However, for combination product, the key is to demonstrate that the combination product as a system works as intended. Thus, having the device (pre-)cleared by the FDA does not necessarily reduce the effort nor risks on the combination product, but it will definitely increase the upfront regulatory and technical effort and costs. So, your client should carefully consider the options based on their expertise, risk attitude (real and preceptive), timeline, financial strength, and other factors. Marked as spam Report spam
	Private answer I guess ecen if this device is 510k exempt you need to demonstrate a Minimum design control. It is even more true if this device is packed with the DP becoming a CP. Marked as spam Report spam
	Private answer Mark Proulx, CQA, cSSBB Kristin Benokraitis First of all, you should be contacting the OCP, Office of Combination Products because they will work with you to determine the exact route to take, what to submit, when, etc. I worked with them on prior products and it saved a huge amount of frustration down the road. Start with them, prepare a presentation to let them know the MOA (mode of action), is n other words which is more important to the action - the drug or device. They will instruct you as to who has oversight and will be making the final decisions. Marked as spam Report spam
	Private answer Is there an on-label use for the device as a stand-alone product? If not, and it can only be used with your drug, it may be a non-starter. Marked as spam Report spam
	Private answer Our medical device is 510k cleared for "controlling pain from injections" despite the components both being class 1 exempt. This obviates drug device pk Issues since the FDA cleared the device for ANY injection. That said, the device is not in direct contact with the drug administration system, so it may not be applicable for your situation. Marked as spam Report spam
	Private answer Yong Cho I worked on implantable pump containing peptide DP which was packaged with insertion kits made up of mostly Class I marketed/cleared devices and complied with Part 4 including HF for NDA submission. We deemed it better to comply than to raise few unnecessary eye brows at FDA. Also worked on adding a new vibration mesh nebulizer to IFU of an existing biologic DP as part of PAS. Seemingly simple addition of 510k cleared nebulizer to IFU with reference to DMF however took more efforts even though the drug in ampule and nebulizer were not "co-packed". It triggered Combination Product Development process including design control, risk management and HF (only formative as FDA said no need to do summative based on formative report and draft IFU which they took the liberty to revise). Add to this Phase IV clinical and extensive in-vitro study. Marked as spam Report spam
	Private answer Yong Cho Your client should consult with CDER via Type C meeting on the submission requirements/expectations rather than repeat the past mistakes or try to skirt around. Co-packed product is considered as drug-device combination product. Per FDA: Examples of combination products where the components are packaged together (21 CFR 3.2(e)(2)): Drug or biological product packaged with a delivery device Surgical tray with surgical instruments, drapes, and lidocaine or alcohol swabs Marked as spam Report spam
	Private answer Type C meeting is the best route for combination products. The responses are legally binding, with defined timeframes. Plus, multiple divisions can respond, not just CDRH -if you submit it as a device through 510K. Email and calls are not binding if they are not through a formal communication. The other device route suggestions don't solve the issue since CDER was asking the questions with the first device, not CDRH. With device only submission, CDRH will have their questions addressed, but CDER might come back with more questions during NDA/BLA submission. I wouldn't recommend anything but a formal, legally binding meeting to address and lower risk from CDER side (Type C or Type B - if you already have one planned and can add device questions). Also, keep in mind that there is a big difference in responses between CDER groups and even between reviewers. Keep this in mind when asking questions under an IND and planning to submit a BLA/NDA later - you would need to adjust your approach accordingly. Marked as spam Report spam
	Private answer Kristin Benokraitis Tat Tsui: I have some knowledge of the previous submission, even though I (or the company I work for) was not involved in it. I've written/submitted enough 510(k)s myself to know that they did miss a key element on the device side and the same mistake would not happen this time (I can't share more due to confidentiality reasons). This may have prompted more scrutiny than normal from FDA, but it really is hard to say. Jonathan Mahoney: New device, but there are others available on the market which are not used with a drug. Ultimately, they could sell the device as a standalone product if they wanted to (I don't expect it). Amy Baxter MD: Good to know that you did not receive a RFA for your Class I exempt device. Ultimately, this is what I am most interested in - how often FDA just flat out rejects 510(k) submissions for Class I, non-exempt devices. Did you happen to have meetings with FDA ahead of your submission, or you just let the submission fly on it's own? Thanks everyone! Marked as spam Report spam
	Private answer Kristin, I work almost exclusively with drug delivery combination products. Getting a significant number of questions regarding the device on an NDA or BLA submission is not unusual. Some of the advice that you have received in previous posts are helpful, some are not, and some are just wrong. I would advise that if your class one device is to be used exclusively for your drug, and the drug cannot be used without the device, it will be very difficult if not impossible for this not to be reviewed by CDER as a combination product. I would be glad to take a few minutes to discuss this with you if you desire. My contact information is on LinkedIn. Marked as spam Report spam
	Private answer I agree with Lee. There is little chance of piggy backing on a Class 1 or 2 device in the circumstances you describe. Marked as spam Report spam
	Private answer Hi, I'd just like to highlight a couple of things from my experience: 1 I think you've identified that in the past, there may have been a naive mistake, leaving something out that resulted in more questions and scrutiny - something to learn from! 2 Delays have been recognised as an issue for sure, but the OCP are doing a lot to address this now, with support from higher management, see: http://blogs.fda.gov/fdavoice/index.php/2016/08/piloting-an-improved-intercenter-consult-process/ Very worthwhile to contact them for advice, prior to arranging more formal meetings. They are definitely open to helping out and improving processes in the future - they have been vocal about this at recent regulatory meetings both in US and EU. Good luck! Marked as spam Report spam
	Private answer Adam F. Atherton, PE Hi Kristin, Agree with Lee Leichter. Additionally, I have seen mfrs stumble again and again in their submissions due to two things: One, mfr not doing enough work to prove their CP is ready for prime time; Two, mfr not being an expert on their own system. The former indicates a lack of insight into the burden inherent in developing quality CPs. The latter is an outcome of much outsourcing, but also a lack of diligence on the mfr part. Hope it helps. Marked as spam Report spam
	Private answer How would FDA view such devices from the "companion diagnostics" perspective? For example, is there an underlying diagnostic that would be treated as a companion diagnostic vs the device itself? Marked as spam Report spam
	Private answer Acacia Parks I'm wondering whether a Class I 510k exempt device can even be part of a combination product? I see from the comments that it would be submitted along with the drug and evaluated together (fine!) but what would the evidence requirements be, if any (since 510k exempt has no evidence requirement)? Marked as spam Report spam

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