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2018 Orthobiologics Surgical Skills Online
3 - Regulations by Ken Vaslav, MD
3 - Regulations by Ken Vaslav, MD
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Video Transcription
dry topic today. So pardon me, these are mostly going to be word slides. There's going to be a lot of abbreviations that you don't understand, and I'm going to spend most of this time just defining everything for you. Because it's important, as the practitioners, that we have an ability to understand, as well as industry, what are the rules of the road, what needs to be regulated, what doesn't fit into regulatory pathway, and if there is a regulatory pathway, what is that, and how do we approach it to get these products out safely to our patients? I also want to thank the Owen Foundation. Kay has been really great at helping us get scientist fellowships. It's very easy to get clinical fellowships from lots of companies, but the Owen Foundation has been great in helping us stimulate scientists in this area. And I'm also excited to say that the AOSSM, the ICRS, the ANNA group, and the Academy have worked together now to form a biologic alliance. Jason, who's here today, and Burt Mandelbaum are the chairs of that process, and we're excited that the orthopedic community is now going to speak as a single voice regarding orthobiologics and regenerative medicine. So far, this has really been taken over by the physiatrists, pain specialists, and primary care physicians in the U.S. and the lay press, and in the Internet, and it's time for us to take this back. And I'm excited. This is one of the first steps is this course. These are my disclosures. So, as we've seen from Rachel's talk, both physicians, patients, and the FDA have seen an explosion of advertising and patient recruitment for untested orthobiologic treatments throughout the U.S., and this is just a smattering of the types of things you'll see on the Internet. And when the FDA saw this, they realized that in response to this, both the CBER division and the CDRH division decided we have to put out some kind of guidance and start to regulate these products to protect the safety of U.S. patients. So, first of all, for those of you who don't know, CBER is the biologics group at the FDA. It's the Center for Biologics, Education, and Research. CDRH is the device group. You'll hear a lot of these mnemonics over this talk, and it's good for you guys to get a sense of who they are. There's also an office of combination products when you mix a pharmaceutical or a biologic with a device. And this group together put out the regulatory considerations for human cells and cell-based tissue products, and this was written in December of 2017, so it's been around for about a year. And what does this regulatory document do and what does it not do? So, first of all, it defines what is and what is not a human cellular and tissue-based product, or what we will call the rest of this talk HCTPs. And it defines and gives examples for certain words that are key here. What does it mean to have minimal manipulation and what is homologous use? So, remember, this is a guidance document. It's not actually a legally enforceable responsibility, but the FDA puts these out so that practitioners and industry understand what should be regulated when you bring a new product out and what might not need to be in their own thought process. But there are legal instruments that are the basis for why the FDA can regulate these, and those are the Food and Drug Cosmetics Act, or the FAD&C Act, and the Public Health Service Act, which is the PHS Act. So, they can do this, and they legally will be doing it over the next 26 months. So, first some definitions, for those of you not involved with new product research. An IND is an investigational new drug. It's really true about devices, drugs, or biologics. An IND allows the manufacturer to ship product to legally approved investigational sites only while doing a study to get a BLA or an NDA. What's a BLA? What's an NDA? The NDA is a new drug application. So, any new pharmaceutical, a BLA is the same thing for a biologic, and the 510k product pathway is what we use for devices, just so we're all on the same page. So, if a manufacturer's – according to this guideline, if a manufacturer's product does not meet one of the following criterias or exemptions that are described in this document, 1271, and you can forget all these numbers, but for your handout, I wanted you to know where you can find these. If they do not meet these specific exceptions or criteria, they have 36 months as of December 17 to get an NDA or a BLA approval, or their product will be enforced by the FDA and pulled off the market. So, what are these criterion that allow you to stay out of this process? The first is a criterion of minimum manipulation, which we'll define in the coming slides, a criterion of homologous use, and then there's a same surgical exception, which actually was written just before this document and supersedes all the documents being written on adipose that were prior written. This now supersedes that and has been put into this document. So, the FDA will regulate all products unless they meet these criteria. So, first of all, what counts and what does not count as an HCTP? What is a cellular tissue anything with bone, ligament, skin, dura, heart valve, cornea, any hematopoietic progenitor stem cells from peripheral cord or cord blood, manipulated chondrocytes or epithelial cells, whether they're on or off a matrix, semen, or any other reproductive product. These all fit into HCTPs. What is not included, and this is very important for one of the big products we'll use during this weekend, not included are any fully vasculite organ transplants. So, everything that UNOS controls in the United States is not included. Whole blood or its components are not included. Secreted milk from women and collagen or other cell factors except for semen. All those others are not included. So, therefore, PRP is not regulated under these ordinances. PRP is a blood product, and as long as it's used autologously from you to you, there is no regulation. So, the HCTP or the cellular tissue product can be regulated solely under Section 361 of the Public Health Service Act if it meets all of these criteria. So, if it meets these, no BLA or NDA is needed. So, it's minimally manipulated. It is for homologous use both on the labeling of the product and the way the manufacturer intends to market it. It has to not be combined with any product or article except for water, crystalloids, or a sterilizing preserving agent. Those are allowed. Most importantly, number four in this particular group of rules is that the HCT can have no systemic effect, just a local effect on the joint or the tendon, and it is not dependent on the metabolic activity of a living cell for its primary function. And if it is systemic or it is reliant on a metabolic activity, it can only be used for autologous or first, second-degree relatives or for reproductive use. Obviously, people do egg donors. So, let's first define what is minimal manipulation. So, before you can define minimal manipulation, you need to know is the tissue structural or is it cellular? So, if it's structural, the processing to that structure cannot alter the original relevant characteristics of this cell relating to what it's used for in the body. So, it still has to be used for repair, replacement, or reconstruction after you do whatever you do to it. If it's cellular, the processing that you do cannot alter any of the relevant biologic characteristics. So, it's a little confusing. How do you know whether what you're using is structural or cellular? Most of us believe everything we take from structure has cells. So, this is the definition according to the FDA. So, when you determine minimum manipulation criteria, first you have to determine is it structural or cellular. So, if in the natural state in the donor, this tissue you're taking either supports or serves as a barrier or a conduit, or it connects any tissues or cushions the donor, it is structural. Anything that doesn't fit that is cellular. So, the examples would be that bone, skin, amniotic membrane, umbilical cord, adipose tissue itself, articular cartilage, meniscus, tendon, ligament, these are all structural. Secreted fluids such as amniotic fluid itself, if it had no cells in it or has no cells, are not involved here. But if you have live cells from these fluids, now they need to be minimally manipulated and the criterion come back into play. For structural tissues, we are allowed to mill it, shape it, clean it, and cut it. So, those are still considered minimal manipulation. I know this is very exciting stuff, but trust me, it really matters. It took me about 10 hours to understand all of this. Homologous use. Okay, so what does homologous use mean? At first, I thought when I heard this, when the FDA was talking about it, that it meant you had to put it back in the same place in your body, but that's not the case. When you take a tissue and you put it into someone else's body, that HGTP has to perform the same function in the recipient that it did in the donor. So, it does not have to go into the same anatomic area, but when it gets to whatever area you're putting it in, it must do the same thing there that it did. So, if it cushioned, it needs to cushion. If it filled, so it's okay to take fat and stick it under your lips to make them bigger or to put it in your, you know, to take away wrinkles because it's cushioning the thing, and if you decide that maybe what fat's doing is giving you a good source of progenitor cells, you might say, well, that's what it's going to do where I'm putting it to. There's a lot of gray area here, but that's the definition. It has to be doing the same job. Now, what about the same surgical exception? This is really in a very important addition, especially for the adipose tissues. This states that if you are doing a procedure in an establishment, like your office or an operating room, and you remove this tissue from an individual and you implant it back into that same individual during the same surgical procedure, you are exempt from being a 351 product. So, we'll talk about what that means in a second. So, meaning you don't need a BLA, you don't need an NDA. So, the agency is not going to control what you take from a person and put right back into that person in that OR as long as this caveat exists. It's minimal manipulation and that the HCTP remains in its original form. Now, you are allowed to rinse it, cleanse it, size it, and shape it. So, we'll have to have discussions over this weekend about what counts as those four things and, therefore, still count as minimal manipulation. So, basically, the FDA feels if you're taking a tissue from you and you're putting it back in and you're not taking it out to a lab in between and you're not coming back another day, that you're really not potentially harming the patient. So, they're not going to get very involved and that there's no increased risk of infection over that of the normal surgery. So, let's put that into a flow chart. You have something you want to do for a patient. How do you think about it? The first thing is, does your product fit into the HCTP? Is it an HCTP? And, as we said, if it's blood, it's not. You're free. You can do what you want to do with that blood on the same patient. If yes, though, you have to go on to step two and you say, is this fit in the same surgical exemption? If it fits in the exemption, you're not required to comply. If it doesn't fit, you now have to meet one of the four criteria we listed earlier. Minimum manipulation, homologous use, I mean all four of these, I'm sorry. Minimum manipulation, homologous use, not a combined product except with water or sterilizing agent, no systemic effect or metabolic activity. If you meet those four requirements, again, you are not going to be regulated. You can go right ahead. If you do not meet those four, you then need to register with the FDA, and we'll talk about that in a minute. So, in summary, you have 361 products, which means they are regulated by the Public Health Service Act 361, which means you don't need a BLA or an IND. You don't need to be regulated. You just need to register this product so the FDA notice exists, and that's it. If you're a 351 product because you do not meet one of these exemptions or one of these criteria, then you will be regulated as of 26 months from now. So, what's next? From 36 months, from December 2017, the FDA is giving manufacturers and practitioners an ability to think, does this thing we're doing already on the market, even though it's not paid for insurance, but we're doing it, does it need to be regulated? If the product meets the criterion, then you don't have to worry about it. You just register, and if it's not, you must begin this IND-BLA process. What about enforcement in the meantime for the next 26 months? The FDA has pledged basically to try to just keep the public safe, so they're going to look at what things are really dangerous, and when they define something that's high risk, they do it either because it's non-homologous use, so anything homologous is not considered high risk, and or how it's administered. So, if it goes in IV, intraocular, intrathecal, CNS, inhalation, all of these are considered potentially dangerous, but we do where we inject it into a tendon, bone, or joint is not considered high risk, so they're really not going to be going after these in the next few months before the regulatory process begins. All right, so what happens, though? We still want to move this forward, and we would like to see the future of regenerative medicine orthopedics, so what if you don't fall in the simple minimal manipulation, and you want to move this product forward, what do you have to do? Well, luckily, based on the last Congress, actually my former Representative Eric Cantor, who was the House Majority Leader, pushed through this new Cures Act, and as part of the Cures Act, they have listed that there are regenerative med therapies that address serious conditions or unmet needs, and if they fit into this category, the FDA is going to help you streamline the process to get through and push these things through to protect the safety of the population, but not at the rate that it normally takes for a new product, so a serious condition is not something that just kills you. Any disease or condition associated with morbidity that has a significant impact on day-to-day function counts as a serious condition, and I think we would believe that osteoarthritis fits that bill, and then, of course, there are unmet needs for diseases that are not treated with any disease-modifying agents at all today, and that's usually not so orthopedic, so what do you get from the FDA if you're considered in this expedited program? You may get an accelerated approval process. First of all, they will meet with you right away, and they have been really accommodating in my experience now in the last two years. They're meeting with people, they're talking with you, they're helping you think through these product developments and think on how you need to regulate them. They also may allow you to use early data to get approval, as we did many, many years ago for Genzyme's cortisol, so there were no regulations at the time, so they gave an accelerated approval, and then they allowed them to do post-marketing studies that many of us here in this room were involved with, so you may be able to do that, or you may be able to use a surrogate endpoint. Rather than true clinical benefit based on function and pain, you may be able to pick some other surrogate endpoint that they believe accurately predicts the future endpoint, or there can be an intermediate relevant endpoint that they say is safe enough and important enough to show efficacy that they'll move you on to a legal status with an application that's a license to sell, and then you'll have to do some post-marketing studies. If you don't have this process, those of us who are in the science field and do clinical research know this is a very long, normal process to get through, from beginning to talk to them about an IND, going through phase one, two, and three studies that could cost millions of dollars in a long period of time, and I'm happy to say that I know at least about one. Gloria will be speaking to us in a moment, but her company, I do believe, has been granted the first of these RMT exemptions to move forward with a chorionamnion product, and we've started those studies in multiple centers in the U.S. on this, so they've already agreed that osteoarthritis counts, so that's good news for us. So, in conclusion, I know it's a little boring, but we're entering a new phase, a new world of tissue and cellular biologic repair. There are very different parameters. You know, it's very easy for them to start thinking of everything as a drug, but dosing is very important in drugs, and as my friend Arnie Kaplan keeps drumming into my head, dosing is irrelevant, maybe, with biologic. We don't know that more cells is better than few cells. We don't know which cells are better yet, so there's a whole lot for the FDA to be considering, and it's a different thought process, and they're just trying to catch up and maintain safety for the U.S. population at the same time as they help us encourage new product development. We're in a 26-month holding pattern now where lots of things are available. Some will be regulated, some won't be, but at the end of that period, fewer options certainly will be available to us 25 to 6 months from now, and they'll be, however, a very straightforward, clear routine to bring new products onto the market. Thank you very much for your attention.
Video Summary
The speaker in the video discusses the regulations and guidelines surrounding the use of orthobiologics and regenerative medicine in the United States. The FDA has recognized the need to regulate these products due to the increase in advertising and patient recruitment for untested treatments. The FDA has put out a regulatory considerations document, which defines what is considered a human cellular and tissue-based product (HCTP) and what is not included. The document also outlines the criteria that HCTPs must meet to be exempt from regulation, such as minimal manipulation and homologous use. There is also a same surgical exception, which exempts products that are removed from and implanted back into the same individual during the same surgery. The FDA will regulate all products that do not meet the exemption criteria. The speaker explains the definitions of minimal manipulation and homologous use, as well as the steps practitioners must take to determine whether their product falls under the exemption criteria or requires regulation. In summary, the speaker emphasizes that we are entering a new phase of tissue and cellular biologic repair, and while regulations are necessary to ensure safety, they can also hinder product development.
Keywords
orthobiologics
regenerative medicine
FDA regulations
human cellular and tissue-based product
exemption criteria
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