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Should your medical device company address biocompatibility? The short answer is, yes. Every single medical device should conduct some level of biocompatibility testing. What’s important is that you understand to what extent.In this episode of the Global Medical Device Podcast, Jon Speer talks to Mike Drues of Vascular Sciences about medical device biocompatibility, the applicable FDA and ISO guidelines companies need to follow and the possible ramifications of what happens if you don’t.

 

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Some highlights of this episode include:

  • Select Updates for Biocompatibility of Certain Devices in Contact with Intact Skin: FDA Draft Guidance is new, but doesn’t cover any new content. FDA’s intent is to clarify the types of biocompatibility information in submissions for certain devices made from common polymers and fabrics that come in contact with intact skin.

  • What is biocompatibility testing? If you don’t know, that’s why regulation and guidance is necessary. Nobody knows everything, recognize what you don’t.

  • ISO 10993 Evaluation and Testing: Review guidance, educate yourself, and engage experts because objective evidence is needed to corroborate the case for biocompatibility. 

  • FDA’s Recommendations for Biocompatibility:

    • List device materials with direct/indirect skin contact and statement comparing/confirming safe use of those materials.

    • Provide history and clinical study reports of adverse effects/events of skin contact materials, such as redness, swelling, irritation, allergic responses.

    • Documenting sponsorship determining where biocompatibility risk and testing is not necessary, such as purchasing controls.

    • Using labeling to mitigate risk of possible skin reactions.

  • Technical Considerations for Non-Clinical Assessment of Medical Devices Containing Nitinol: FDA Final Guidance raises special considerations for thermomechanical behavior and processing sensitivity of nitinol when compared to conventional metals.

 

Links:

FDA Draft Guidance - Select Updates for Biocompatibility of Certain Devices in Contact with Intact Skin

FDA Final Guidance - Technical Considerations for Non-Clinical Assessment of Medical Devices Containing Nitinol

FDA Final Guidance - Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"

FDA Special Considerations: Biocompatibility

ISO 10993

ISO 14971

FDA - 510(k) Premarket Notification

Mike Drues on LinkedIn

Vascular Sciences

Greenlight Guru YouTube Channel

MedTech True Quality Stories Podcast

Greenlight Guru

 

Memorable quotes from this episode:

“Every single medical device needs to address biocompatibility.” Jon Speer

“Unfortunately, there are some people out there—I don’t want to stereotype—some people really know what they’re doing. Regrettably, there are other people out there that really don’t.” Mike Drues

“You have to have prior art, so to speak, or prior knowledge, or prior evidence.” Jon Speer

“Labeling is the least effective means of mitigating risk.” Jon Speer

 

Transcript:

Announcer: Welcome to the Global Medical Device Podcast, where today's brightest minds in the medical device industry go to get their most useful and actionable insider knowledge direct from some of the world's leading medical device experts and companies.

Jon Speer: There are a few topics that are ubiquitous and need to be addressed by every single medical device, and one of those topics is biocompatibility. I don't care if your product is non- patient- contacting and is only software- based, there's still something you need to address from a biocompatibility standpoint. I know it seems silly in those non- patient- contacting type products, but you still need to deal with it and address it in some form or fashion. Keep in mind that patient- contacting devices, there's a huge ramification with respect to biocompatibility. And FDA has recently come out with some new guidance documents. Of course, there is the long- standing ISO 10993 series of standards on the topic as well. Well, on this episode of the Global Medical Device Podcast, Mike Drues and I dive into some of the details on the topic of biocompatibility. So enjoy this episode of the Global Medical Device Podcast. Hello, and welcome to the Global Medical Device Podcast. This is your host and founder at Greenlight Guru, Jon Speer. And folks, kind of an interesting topic to talk about today. I'm just thinking about it. Have we ever talked about this on the Global Medical Device Podcast? And I don't think so. And the topic today is biocompatibility. And some of you may be wondering about why we're diving into biocompatibility today. Well, short story, and we'll get into the details, of course, is there are some relatively new guidances that have come from FDA addressing the topic of biocompatibility, and I want to dive into some of the details. Now, I'll give you the caveat or disclaimer at the beginning anyway, that the intent of this episode is not to dive into the super- depth details and get into prescriptive practices on biocompatibility, but more about sort of big picture things as it relates to the topic. And joining me on this episode of the Global Medical Device Podcast is Mike Drues with Vascular Sciences. So, Mike, welcome.

Mike Drues: Thank you, Jon. Always a pleasure to speak with you and your audience.

Jon Speer: Absolutely. So as I mentioned, there has been some recent movement or activity from FDA with respect to biocompatibility. It might be a good place to sort of set the stage for folks on some of the newer guidances that are out there on the topic. So do you mind diving into that portion first, and then we'll get into some of the details?

Mike Drues: Yeah, absolutely, Jon. And as always, thanks very much for the opportunity to have this discussion today about a very, very important topic, and that is biocompatibility in medical device development. So specifically, there were three either new or updated guidances that FDA has put out literally within the last month. And let me just tick them off very quickly, and then we can talk about them individually. The first one and really the only new one is titled Select Updates for Biocompatibility of Certain Devices in Contact With Intact Skin, and that was a draft guidance that just came out literally a week or two ago. The other two guidances are finalized guidances. And keep in mind, Jon, as we've talked about before, there's really no such thing as a final guidance, but that's what FDA calls it. The first one is Technical Considerations for Non- Clinical Assessment of Medical Devices Containing Nitinol. That originally came out as a draft about a year- and- a- half ago, and now FDA has just now finalized it. And then the third guidance that was finalized last month, Use of International Standard ISO 10993- 1, Biological Evaluation of Medical Devices Part One for Evaluation and Testing Within a Risk Management Process. That's sort of the bible, if you will, on biocompatibility. That one was finalized just last month. So those are the three guidances, and we can provide links to those after this part of the podcast, but that's what we're going to drill into a little bit today.

Jon Speer: Yeah, absolutely. We'll definitely provide links, folks, so be sure to check those out in the text that accompanies the podcast on Greenlight. All right. So I guess a good place to start, let's start with the biocompatibility guidance. What is this all about? What is this regarding?

Mike Drues: It's a great question, Jon. So first of all, this is a new guidance, and I'm putting the word new in air quotes because the guidance just came out. This is a draft guidance. But in terms of subject matter, in terms of content, there's really nothing new here. And basically, the intent of FDA is to try to clarify the types of biocompatibility information that they're looking for in submissions, specifically with regard to devices mostly made of polymers that come in contact with the skin. So this is a fairly focused guidance. It deals with primarily medical devices that come in contact with the skin. And as you probably know, Jon, when it comes to biocompatibility, and this is all spelled out in the ISO 10993 as well, so you can kind of think of this biocomp guidance as really nothing more than a subset of the ISO 10993 standard. But they basically, in part, break this down by exposure. So, for example, if it comes in contact with intact skin for less than a day, that would be limited exposure. Between one day and one month, that would be prolonged. Or finally, long- term contact, which would be more than a month. But I always find it interesting, Jon, working in the gray area. So, for example, I've had situations where a device is in contact with a patient for some period of time, and then it's not, and then it comes in contact with the patient again for a period of time, and then it's not. So those kinds of things, those kinds of situations, they don't fit easily into one of those buckets. And that's up to us to figure out how to apply it. So it's those gray areas. That's one gray area. Another gray area, as well, what if the person is wearing clothing, or what if they have hair or sweat? How can that interfere? So again, that's all part of the calculus here. But here's the concern that I have about this particular guidance, Jon, and I would be curious as to hearing your thoughts on this, if you agree or perhaps disagree. FDA outlines some of the criteria for certain medical devices that are made of these materials that have what they call, these are FDA's words, Jon, not mine, very low biocompatibility risk and a long history of safe use in medical devices. And in those cases, FDA goes on to say that you may be able to bypass biocompatibility testing. As a matter of fact, let me read to you one sentence from the guidance, and I would love to hear your thoughts on this, Jon. They say, " This select update describes a least burdensome approach for these devices that recommends specific material testing in a pre- market submission," and this is the concerning part to me, Jon, " in lieu of biocompatibility testing." In lieu of biocompatibility testing. And let me explain why this is a concern to me, Jon, and then, again, you can tell us if you agree or not. What I'm afraid is that some folks, especially people who are not real knowledgeable about biocompatibility in particular or medical device development in general, they're going to interpret that in perhaps a not appropriate way. In other words, they're going to look at that as an excuse to say, " Oh gee, FDA says I don't have to do biocompatibility testing." And I don't know about you, Jon. I'm not naïve. I didn't fall off the turnip truck yesterday. That's a big fear that I have, that some people may easily misinterpret what FDA is meaning her. Do you have a similar concern, Jon, or maybe you think I'm just overreacting in my old age?

Jon Speer: No. Yes, I have a similar concern, and no, I don't think you're overreacting. I mean, and I guess a little bit of context and background. Hopefully, the topic of biocompatibility is not new or novel to folks listening, especially if you have patient- contacting products. I mean, the 10993 standard, gosh, I don't even remember the first version of that standard, but it's been around a long, long, long time. And over my career anyway, I know it's sometimes a debatable topic. I remember some projects that I worked on in the past and devices I've worked on where we were using a material where we already had a history of biocompatibility and/or there was already industry history of that. And we were always trying to leverage or justify the previous or prior art, if you will, with respect to that. And I think that's a key point, that some people, to your point, might be misinterpreting. I mean, you have to have prior art, so to speak, or prior knowledge or prior evidence to support that. But read the wrong way, someone could easily formulate a different point of view. And so yeah, I do see that statement as problematic.

Mike Drues: Well, Jon, let me give you a quick example. So you mentioned that biocompatibility is not new or novel, and listen, as a biomedical engineer, I would agree with you more than 100%. And for the benefit of our audience, some people may already know that I am a subject matter expert for FDA in a few different areas, one of them being biomaterials and biocompatibility. So this is something that I do a little something about. But to your point about this is not new or novel, I wonder if, for some people, it is, and here is what I mean. A while ago, I got a call from, at the time, one of my new customers, and they were getting ready to go to the FDA with a presub. And I was going through my laundry list of questions. Have you done this? Have you done that? And so on. And we got to the topic of biocompatibility, and I said, " Where are you on your biocomp testing?" And I guess I should say, Jon, that this is a medical device that was going to be going inside of a patient, an implant for the rest of their life. So I asked them, " Where are you on your biocomp testing?" And they said, " What's that?"

Jon Speer: Oh, no.

Mike Drues: And I wish I could tell you that I was making this story up, Jon. I can't. I mean, obviously I'm not going to name the people or the company or anything, but that is a true story. And regrettably, Jon, this helps to explain why we have so much regulation and so much guidance. Because, unfortunately, there are some people out there, I don't want to stereotype. Some people really know what they're doing, but regrettably, there are other people out there that really don't. And if you don't, that's not necessarily a bad thing. Just recognize that you don't and get somebody on your team, either internally or perhaps an external consultant like me or somebody else, to help you. Because nobody can know everything, but you're got to be able to recognize, obviously, what you don't know. So is biocompatibility new or novel? Absolutely not, at least not to some of us. But to others, perhaps so.

Jon Speer: Yeah. And I'm going to make a statement that I think is universal, and we can peel it apart if necessary. But folks, every single medical device needs to address biocompatibility. Now, I know some of you might be saying, " But my device is software. It's not patient- contacting." Okay, valid. You still need to address it from the eyes of the regulatory perspective and from your own perspective. If it's not applicable, then you need to explain why it is not applicable, but this is not a topic that you can ignore. I mean, it's table stakes, in my opinion, for every single medical device. You have to address biocompatibility.

Mike Drues: I definitely agree with you, Jon, and I would just like to make one other point, and then I have some recommendations based on this guidance. To me, what I just said and then what you just said, there is nothing new here. This has always been my approach. One of the problems that I have with the way that the 10993 standard is laid out, and as I said earlier, this is sort of the gold standard for biocompatibility, they have these tables, depending on whether this is a skin contact or an implant or whatever it is. And okay, if you're doing this kind of a device, this is the kind of testing that you need to do. That kind of device, this is the kind of testing. I think that's okay as a starting point, but I never take that as gospel. I never take that as coming down from upon high because, in some cases, some of the testing that they recommend, in my opinion as a professional biomedical engineer, is not necessary. And in other cases, what they're recommending might not be enough, and we need to do more. So I believe those quote, unquote standards, and I'm putting the word standards again in air quote, is just a starting point. It's not gospel. So should we go on and talk about some of the suggestions and recommendations from this guidance?

Jon Speer: In one moment. I just want to build upon that. Folks, the 10993 series of standards, there's a lot of parts to it. It is a somewhat complicated series of standards with respect to biocompatibility, and it's, for the layperson or even for an experienced medical device professional, interpreting all of the nuances and the details of these standards, you're going to have to consult somebody that has expertise in this, chances are. Somebody like Mike Drues, for example, who has expertise with biomaterials and application of biocompatibility. So this is not a trivial thing. Don't just assume that you can review the guidance or review the standards, check some boxes and be done. And there is a good chance, especially if your product is contacting the patient in any sort of way, you're going to have to corroborate the biocompatibility of your product with objective evidence. So actual testing has to be done to corroborate your case for biocompatibility. So this is a big deal, and don't make the mistake that Mike shared, where you're somewhat midstream in your product development, you're pursuing a presubmission or maybe even further down the road and you've got an implant or any sort of patient- contacting product, if you haven't addressed biocompatibility, put the brakes on right now and educate yourself and learn about what's important with respect to your product and engage experts to help you navigate this process. But yes, Mike, let's dive into some of the more specifics. What is FDA suggesting and recommending in this guidance?

Mike Drues: So I have just three or four specific comments and suggestions based on what I thought was important in the guides. The first one is FDA is asking manufacturers to include a list of all of the materials that we use in our device that, in this case, have either direct or indirect contact with the skin and a statement concerning that the list of those materials has a documented history of safe use in a legally- marketed medical device in the United States. Those are very easy words to say, Jon, but what do they mean in reality? In other words, how do we show that? One problem that I run into in working with a number of companies is they treat a number of materials in sort of a generic or ubiquitous sense. They say, " Well, we're using polyurethane. Somebody else used polyurethane. Therefore, it's the same." Well, there are hundreds, maybe thousands, of different versions of polyurethanes that have different catalysts, different cross linkers, different maybe mechanical properties and chemical properties and so on. So we can't overgeneralize. We have to be able to do an apples- to- apples comparison. Even in one of the companies that I'm working with right now, we're putting together a presub, they are using silicone in their particular medical device, and they're trying to make an argument that people have been using silicone for a long time for different things. But the problem is there's different kinds of silicone, and they don't always act the same way. And the challenge for us as manufacturers is the material suppliers that we're getting our materials from, they are usually not going to be keen on telling us, " Oh yeah, this exact formulation of this material is something that we sell to your competitor to make some other medical device." And one of the ideas that I have suggested, Jon, maybe this is a topic of a different discussion, is maybe we need a biomaterial approval pathway, something like a 510( k) or De Novo for materials, because right now, Jon, there is no way to get FDA to approve a material. The only way to do that is they approve a device, and if the device is made of a new material, then they kind of approve it. But that, I think, would help a lot.

Jon Speer: Can I chime in on that?

Mike Drues: Yeah, please, absolutely.

Jon Speer: And I'll bring in an example from my, I guess, now somewhat distant past on a project that I was working on. And I don't want to give too many details away but enough to where people can kind of wrap their head around this. So I was working on a project that involved some wound therapy, and it involved this polyurethane foam material. And the particular polyurethane foam material was already in use for this exact application, exactly the same formulation. I mean, there's three suppliers in the world that make this particular foam, and we were trying to assess and evaluate the biocompatibility impact and what we needed to do and that sort of thing. And the supplier had shared with us that there was, I don't remember the exact term, but a master file that they had with FDA on that particular material. But it was hidden from us, right? We didn't have access to this, and we basically had to get a letter from the supplier to authorize FDA to consult that particular file. And I thought that that was going to be helpful, and I'm not sure if it was or was not, quite frankly, because even after we did that, we ended up still having to go through the whole battery of tests. And that was a head scratcher for me, to be quite honest. Granted, it was maybe a different era, maybe not, or maybe things are different today, but there was a ton... I mean, this is a commodity, a material, that had been used for decades, and there was a long history of use. And reportedly, there was a whole master file with FDA from this particular supplier with respect to biocompatibility, but we still had to go back to the drawing board. So that was a little bit of a head scratcher to me.

Mike Drues: That's a great example, Jon. Thank you for sharing that. So here's my next suggestion/ concern from the guidance. Another thing that FDA asks for is a history of adverse events that have been experienced from this material. Remember, we're talking skin contact applications here, Jon, so we're talking about things like redness and swelling and irritation and sensitization and allergic or other immune responses, and so on. They're asking specifically for these adverse events being reported in clinical studies. Well, first of all, are we talking about pre- or post- market, right? Keep in mind, Jon, the vast majority of medical devices don't undergo clinical trials. So is that suggesting that we need to do a clinical trial for a Band- aid, for example, right? And I'll leave that as a rhetorical question, Jon, but that's a concern that I have about this guidance.

Jon Speer: Well, I was going to say, if I could chime in there, too.

Mike Drues: Please.

Jon Speer: In my entire history of working in the medical device industry, I mean, I appreciate the context of identifying any sort of adverse events that are quote, biocompatibility related. But that's not always an obvious adverse event, right? So how does one do that?

Mike Drues: Well, now you're getting, I think, Jon, to the question of what defines an adverse event or a significant adverse event. That would be a topic of a different discussion, but it's not an easy question.

Jon Speer: For sure. Okay.

Mike Drues: All right. Just one or two other suggestions about the guidance. FDA says that sponsors should document how they determine the biocompatibility risks and where biocompatibility testing is not necessary. And again, to me, this is a no- brainer. This is something that I've been doing for the nearly 30 years I've been playing this game. However, they go on to give some examples and again, I quote. " Identifying biocompatibility testing where it's not necessary such as through purchasing controls, production and process controls, medical device reporting or MDRs" and so on. And as you might guess, Jon, it's the first one. It's the purchasing controls that concerns me the most here. In other words, they're advocating using purchasing controls as a form of risk mitigation. Now, in some cases, that might be appropriate, but here is the concern that I have. It seems that some of my friends at FDA have seemed to forget about the recent and not- too- small gynecological mesh problem that we had, which is basically a very common surgical implant that led to the largest litigation in history since asbestos. And one manufacturer, in particular, is facing 48, 000 lawsuits over this, and they used purchasing controls as one of their principal forms of risk mitigation. Well, suffice it to say, Jon, and I have to be a little careful what I say here because I am acting as an expert witness in that product liability case involving this area. But that was not an effective way of risk management in this particular case. Just pause, Jon, because obviously I know you have a lot of experience and expertise in the area of risk and quality. Any thoughts on that one?

Jon Speer: Well, yeah, it is...

Mike Drues: Didn't mean to put you on the spot.

Jon Speer: No, no, that's okay.

Mike Drues: Well, maybe I did.

Jon Speer: Well, you probably did. I know you well enough that I think you take pleasure in that sometimes. But no, I think it's... Folks, Mike and I have a good time on these things. But anyway, yeah, I don't know. It's a little bit complicated because, like the purchasing controls, what does that mean? So I'm buying something. How do I mitigate and manage those risks when it comes to biocompatibility? I mean, and hopefully what I'm about to share helps address this in some respects. But again, going back to the way- back machine a little bit in my brain. But I remember trying, in the past, purchasing materials and trying to identify material providers that were providing materials to a med device. Maybe that's a form of risk mitigation sort of. But then I would inquire, " Hey do you have biocompatibility data on this particular material?" And once upon a time anyway, I don't know if this is still valid, but you probably remember that the USP Class VI stuff?

Mike Drues: Yeah.

Jon Speer: Yeah. So sometimes suppliers would provide USP Class VI information about the material, and then that was kind of a head scratcher. This isn't really what I need from a biocompatibility standpoint. Forget the fact that the raw material that I'm going to be purchasing I'm probably going to process further, whether it's pellets for extrusion or injection molding or whatever the case may be. I'm going to do something else to that material that arguably could somehow change its physical characteristics in some ways. So that is a little bit of a head scratcher to me. I don't know how much value one gets from that perspective.

Mike Drues: Well, let me just say this, Jon. When it comes to biocompatibility and risk mitigation via a variety of methods including purchasing controls, this is obviously a complicated topic, and we can probably have a discussion just on that in the future if you wanted to.

Jon Speer: Yeah, we could.

Mike Drues: But let me be clear. I'm not suggesting that we should not use purchasing controls as a form of risk mitigation here for biocomp. We can. We just have to be careful in, as you just alluded to, Jon, the details of how we do it. And it should also not be, in my opinion, the principal or certainly not the only way that we mitigate risk in this case. Which brings us to my last comment and suggestion about this particular, Jon, and thank you for sharing your thoughts on this because it's a good discussion that we're having here. FDA goes on to suggest that labeling be used to mitigate risk of possible skin reactions. And again, I find that particular curious for a couple of reasons. First of all, because as you know very well, Jon, ISO 14971 says quite clearly, it's one of the things that I agree with them on, that labeling should not be a primary risk mitigation measure. In other words, we should always do everything else that we can based on design, based on training, yada, yada, and labeling should be a last resort. And also, from a product liability perspective, Jon, a lot of people don't know in advance if they're hypersensitive or allergic to a particular material. So even if we were to label it that way, how is the person supposed to know? Comments on that one, Jon?

Jon Speer: Yeah, a couple of comments. And absolutely, not just because 14971 says so, but just pragmatically speaking, labeling is the least effective means of mitigating risk, period, full stop.

Mike Drues: Are you suggesting, Jon, that not everybody reads and follows the labels that we put on our products?

Jon Speer: Well, sorry I snorted on that one.

Mike Drues: I think that's what ISO is saying.

Jon Speer: Well, you and I both know very well that if you're counting on labeling to be your CYA, and folks, if you don't know what CYA means, look it up, I'm sure you'll find it on Google. But if you're relying on labeling to be your CYA, I mean, come on, man, that's not a good idea. But then, I'm a little conflicted sort of, because there are certain materials where there is, you mentioned asbestos a moment ago, but there are certain materials that are more, I guess, commonplace in that device. The first example that comes to mind is latex. That's a material that is very well- known, and I'm picturing a box of latex exam gloves and seeing right on the box the labeling that says, " This product contains latex." And I suppose those glove manufacturers have mitigated that by making gloves out of different materials. Yeah, so I just think labeling, if you're counting on that, it's just a poor practice in general, especially considering most folks aren't even going to read it.

Mike Drues: Well, once again, I don't want the audience to misunderstand what we're saying or let me not speak for you, Jon, what I am saying. I'm not suggesting that we should not use labeling as a form of risk mitigation. We certainly can, but it's only one piece, and it shouldn't be the only piece. As I said before, ISO recommends, and I strongly agree, that it should be the risk mitigation of last resort. We should do everything else that we can short of labeling to mitigate risk. And I'll give you a perfect example, Jon, and I think this is going to lead us right into the discussion of the second guidance, and that is on nitinol. I'm involved in some devices right now from a product liability perspective where these were permanent implants containing nitinol that went into patients, and some of these patients experienced adverse event reactions because of the nickel in these. And regrettably, the company did not even suggest that the patients were pretested before the surgery to see if they were sensitive to nickel. What a lot of surgeons will do is they'll ask the patient, " When wearing jewelry, for example, have you ever had any reaction?" And that's okay, but that's often not enough, especially when it comes to a permanent implant. And so basically what I was able to do is I was able to flag this. And actually, it's interesting. I have to be really, really careful what I say here, Jon, but in the depositions of the companies involved here, when they were asked, " Why didn't you do this?" which is technologically feasible, we could easily pretest these patients, they basically said, not quite in these words, but they basically said that, " Well, our device is a 510( k), and there are people that did the 510( k) s before us, i. e. our predicates. They did not make that recommendation in their labeling, therefore, we did not make it in ours." This is regrettably, Jon, and I take no pleasure in saying this, something that you and I have talked about many times. Just because a company gets a 510( k) clearance, a PMA approval, a ISO certification, a CE mark, that's the academic equivalent of being a C student. And that regrettably, what I just said, I think, Jon, maybe you disagree, that's a regrettable example of that.

Jon Speer: Yeah. Well, and keep in mind, folks, that if you reference a predicate that has any, we'll just say, age to it, which all predicates have some age to them as far as 510( k) s are concerned, you have to keep up with the times and the state of the art. And what we know today might be entirely different than what we knew back then. And just because somebody else didn't do it doesn't mean that you don't have to do it as well. You have to keep up with what's expected state of the art, and we know today that there have been some issues with nitinol material and some adverse reactions that patients have with nitinol devices.

Mike Drues: So shall we move onto that, to the guidance dealing with nitinol- containing devices?

Jon Speer: Yeah, let's do it. Yeah, let's do it.

Mike Drues: Okay. So I just wanted to start with a short personal story on this. When FDA originally came out with this guidance about a year- and- a- half ago and now, as I said earlier, was just finalized literally about a week or so ago. As I said before, I'm an SME for biocomp for FDA, and before they came out with the draft guidance, one of my FDA friends sent me a copy of the guidance, not just me but a few other people, just to kind of solicit our thoughts. And I basically said to them, " Look, what you have in the guidance is fine, but let me ask you a stupid question. There's nothing in this guidance that..." It came out in 2019 and finalized in 2020. " There's nothing in this guidance that isn't in my biomaterials textbook from when I was a graduate student 30 years ago." And they basically said, " Yes, Mike, we agree with you, but regrettably, there are people out there that don't know that." And that's a problem.

Jon Speer: Well, this might be a crazy thought or idea and probably, well, not quite impossible or not entirely impossible but very difficult to manage. Maybe it's a rhetorical question. Shouldn't a medical device professional designing a developing product, shouldn't they have some sort of, not necessarily advanced degree, but certainly some sort of training or certification with respect to biomaterials? Like I said, maybe that's a rhetorical question.

Mike Drues: Well, Jon, I'm going to leave it as rhetorical because I think you and probably many in our audience know how I feel already about that one. But let me tick through just a couple, two, maybe three specific recommendations about what's in this guidance. The first one is basically the guidance addresses devices that contain nitinol that come in contact with a patient, not just in terms of biocompatibility but mechanical testing, corrosion, labeling and so on. But again, just like we talked about with the previous guidance, Jon, what I find interesting is when we're working in the gray areas. So, for example, what if you have nitinol that you've done some sort of a surface modification to it, which is very common to do with devices today? Or you've applied a coating to it or a litany of other technological possibilities. How does that affect what's in this guidance? Another concern that I have, or maybe concern is too strong, but observation. Like we talked about earlier with polymers, where there's lot of different forms of polyurethanes and Dacrons and Teflons and so on and so on, we have to be careful about overgeneralizing. There are a number of different types or formulations of metal, like stainless steel and nitinol. Granted, not as many different formulations as polymers, but still there are some differences, and these differences do have different properties that can influence biocompatibility, especially if they're used in different parts of the body. It's one thing to say, " My device is going to be used in contact with the skin." It's another thing to talk about, say, a subcutaneous implant, maybe something in contact with the bone. It's a third thing to say a cardiovascular implant, maybe a stent that's going to be in contact with the blood. We can't treat all of those similarly. And again, I'll give you an example from my world, Jon. I had a company come to me sometime ago. They said, " We're using this particular material. It has a history of use in other medical devices in the body." I said, " Okay, fine, tell me more." It turned out that they were doing a blood contact application, and they were trying to make comparisons to similar materials that are put in the abdominal cavity. In other words, in contact with the visceral organs. Well, it shouldn't take a PhD in biomaterials or really immunology, Jon, because when we talk about biocompatibility, that's nothing more than a synonym for immunology. It shouldn't take an advanced degree or, as you said a moment ago, a certification in biocompatibility to appreciate that gee, maybe the same material might be viewed differently by the body in the abdominal cavity versus in contact with the skin or in contact with the blood and so on. I don't know, Jon. Is it me, or is that an unreasonable expectation to have?

Jon Speer: I don't think it's unreasonable at all, and let me elaborate a bit and maybe provide some examples. I mean, polyurethane, stainless steel, nitinol, all great materials and all with terrific history of use in a lot of different applications for medical devices, along with many, many, many other materials. Like polyurethane, yeah, you get a formulation that has been used on other products, but let's talk about a catheter application. A common additive to polyurethane is some radiopaque material so that it can be visible under x- ray or CT and that sort of thing. Well, the moment you start to add something to that, it now changes that urethane. Or another common thing that happens with some urethane, especially catheter type applications, is that you might put some sort of coating on the outside to make it more lubricious, and that now changes it as well. Same thing with an implant. There's lots of work being done on putting some sort of surface coating on hip implants and knee implants and that sort of thing. Well, that arguably has an impact on the material characteristics, especially from a biocompatibility standpoint. Stents is another example. I mean, your nitinol or other stent material may be all fine and good, but what if you want to apply a drug coating to that? And what happens over time? These are all significant factors that you must consider on this particular topic.

Mike Drues: Very good. Very well said, Jon. Maybe we can talk about perhaps one more question, and then we can wrap this up.

Jon Speer: Sure. That'd be great. So, so-

Mike Drues: Go ahead.

Jon Speer: Yeah. We're already hit on a lot of key points. I can imagine a lot of folks are like, " Okay, great. Mike, Jon, so what? What does this mean to my preregulatory pathway? What do I do next?"

Mike Drues: Well, all right. So if we want to jump to some takeaways from this discussion, here's what I think are some of my most important thoughts on this, Jon. And if I miss anything, by all means feel free to add them. First and foremost, as you alluded to a couple of times now, do your homework. If you are not an expert when it comes to biocompatibility, and there's nothing wrong with that. None of us can be experts in everything. And recognize that that's not your strength, and make sure that you have somebody on your team, again, whether it's an internal resource or an external, somebody like me or somebody else, who understands biocompatibility. And remember, as I said, biocompatibility is nothing more than a synonym for immunology. Understand not just what's in those guidances, including the ISO standard, because that's just the beginning. That's just the starting point. But really understand the intent of those guidances and how to use them in reality. Don't just follow the guidance. Do what makes sense. I mentioned earlier, I've been in many, many situations, Jon, where in particular the ISO standard 10993, in some cases, is suggesting too much. And I will go to the FDA, usually in the form of a presubmission meeting or a presub, and say, " Hey, this is what 10993 says, and this is why we're not going to do it, and here are the following reasons." And in other cases, what 10993 or these other guidance says, in my opinion as a professional biomedical engineer, is not enough. And I go to the FDA and say, " This is not enough, and here's what we're going to do instead." So don't just follow the guidance like a mindless automaton. Do what makes sense. And I know, Jon, we've talked about these kinds of things before, maybe not precisely in the context of biocompatibility, maybe in the form of other examples. But sometimes I wonder, Jon, I know we have an awful lot of people that listen to our discussions, but is anyone really listening? Because these problems, regrettably they seem to happen over and over. So those are just some of the high points that I would offer. I'm sure there's others that I haven't mentioned, Jon. What would you add to that list?

Jon Speer: Just to reiterate that, folks, this is a topic that you need to address for any and all medical devices. Now, again, to be redundant from what I've said earlier, I get it. You may be developing a software as a medical device. Is biocompatibility, is it applicable there? Probably not, and you can't just assume that you don't have to do anything. You still need to provide rationale, justification and explanation as to why. I know it seems silly, but this is the expectation. I mean, I note the requirements of a 510( k) submission as an example. Biocompatibility has its own section in a 510( k). You can't leave that blank, for example. And this is a deep topic that is not a trivial thing. Do your homework. Again, I know we've stressed this a few times on the conversation today. And start it early because I'll wrap up my side of things today with a short story. Many, many years ago, I was designing and developing my first product as a biomedical engineer, product development engineer, and I was excited because we were about a week or so away from preparing and submitting our 510( k) submission. This was going to be my first in my career. And I started to go through the traceability matrix from our design control and from a risk standpoint, and I realized that we had omitted or forgotten or something had fallen through the cracks on a particular biocompatibility test. And that's not something you want to forget about, especially if you're about to submit a 510( k) to the FDA. That's certainly going to be a question, if not a reason for rejection from FDA. And then when I peeled it back further, that particular item that I had forgotten about was about an eight- week test, and it was going to cost about$ 15,000. So do your homework and do it early. Don't get to the point where you're about a few weeks away from a 510( k) or any other sort of regulatory submission to start thinking about it, because it's way too late.

Mike Drues: Well, if I may, Jon, I know we're trying to wrap this up. But I thought the example that you mentioned a moment ago about biocomp testing for software as a medical device, SAMD, was an interesting one. I want our audience to remember that one of the most common reasons why submissions, including 510( k) s, are rejected on RTA, on administrative review, is because a section is omitted. And that, to me, is such an amateur mistake. Put yourself in the shoes of the reviewer. If there's a section that's blank or omitted, FDA has no idea why that section is not there. Is it not there because it's not applicable? Or is it not there because you just simply forgot about it and didn't know about it? So even in a case where biocompatibility for software, that would be kind of a stupid thing for somebody to talk about, but you say in there, " not applicable." And I usually take it one step further, Jon. I usually will go on to say, " It's not applicable, and here is why." Now, not all companies do that. Some companies only want to tell FDA exactly what they have to and nothing more, and the logic to support that is, " We don't want to create a problem where no problem exists." But on the other hand, other companies, and this is usually my approach, we try to prevent problems or questions from occurring. So I'll offer, not a lot but maybe a one- or two- sentence justification as to why it's not applicable and just a brief explanation. And I always do mentally sort of a risk benefit analysis in just a mental, two- minute exercise. What is the benefit of providing that additional one- or two- sentence explanation as to why this is not applicable versus the risk of that, in and of itself, generating another question or a problem? So this is a strategy that it's amazing to me how few people do it.

Jon Speer: I agree, and it's so simple to do. If you find yourself writing an explanation or a justification and it ends up being some sort of dissertation or report, you might want to rethink that. If you can't simply state it in a sentence or two, then chances are it probably is applicable. So just keep that in mind, folks. Mike, anything else?

Mike Drues: Or perhaps put it a slightly different way. If it takes you more time and effort to justify why you're not doing something than what it would take to do it, maybe that's indicative of another problem.

Jon Speer: Exactly. Mike, this has been terrific. And, folks, I hope you have enjoyed a little bit of a deep dive into the topic of biocompatibility. Lots of nuggets of information.

Mike Drues: Well, I hate to say it, Jon. As a biomaterial guy, I'm not sure I would consider this to be a deep dive, but it was a good dive.

Jon Speer: A deeper dive, a little bit below the surface.

Mike Drues: A deeper dive. A deeper dive.

Jon Speer: We're dipping our toe in the water.

Mike Drues: There you go. There you go.

Jon Speer: And, folks, remember Mike Drues, Vascular Sciences, has a ton of expertise on all things regulatory, and specifically as it relates to this particular topic, biomaterials and biocompatibility, he is an expert. So if you have some questions, reach out to him. He is available. He is happy to help you and figure out actions and paths and ways to particularly navigate this topic. So Mike Drues, Vascular Sciences, as always, I appreciate the opportunity to chat with you on the Global Medical Device Podcast. And folks, a little bit about Greenlight Guru. Hopefully you know about the Greenlight Guru Medical Device Quality` Management Systems software platform that we have. It's the only medical device quality management systems software platform that exists that's been designed specifically for the medical device industry by actual medical device professionals. I encourage you to go to www. greenlightguru to learn a lot more about the platform. And if you're interested in getting a demo, click the button, request it. We'd be happy to chat with you. We're rolling out some exciting new functionality. We have this new thing called visualize that is pretty new in the platform. And think of a mind map, if you will, a picture. And this visualize component is a picture of your quality management system and all of the documents and records that you're maintaining as a medical device company and the connective tissue and how one thing may relate to another. And on the topic of biocompatibility, if I need to change a material, I can instantly click a button, see how that material is impacted throughout my entire business. That's pretty freaking awesome, if you ask me. So go to www. greenlightguru to learn more about visualize and the entire medical device quality management system. And as always, thank you so much for being a loyal listener of the Global Medical Device Podcast. You are keeping us as the number one podcast in the medical device industry, so continue to spread the word and share this with your friends and colleagues. As always, this is the host and founder at Greenlight Guru, Jon Speer. You have been listening to the Global Medical Device Podcast.


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