Regulatory Considerations

Have you ever wondered who wields the power when it comes to Orthobiologics regulation? We reveal the key players and decision-makers who shape the industry's destiny and other substantial information under it!

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Intro

Hey, I'm Dr. Ariana De Mers. I'm an orthopedic sports medicine surgeon, and I have successfully integrated orthobiologics into my busy practice so that I can provide a continuum of care and treat patients who are in the gap. The gap is this gray area in orthopedics where standard conservative treatments have not been effective, but surgery may not be warranted. And we usually tell our patients, come back when it's worse. What? These are your patients coming to you for help. Orthobiologics is that solution that can fill the gap and help you treat your patients who are in your office looking to you for help. Orthobiologics can also be an excellent treatment for frustrating problems without good surgical outcomes. This podcast will help you create the orthobiologics business that will make you love your job again. We will focus on value of orthobiologics, patient selection, how to talk to your patients about money, office setup, and other logistics. If this is something you've always wanted but don't know where to start, join me in "The Business of Orthobiologics" podcast.

Dr. Ariana

Hey, welcome. I am going to be talking to you today about regulatory considerations. So here's what we'll cover. Who is in charge of regulatory guidance? What is HTP/C? What is the difference of 351 versus 361? What is actually under FDA regulation? Can we talk about PRP, BMA, adipose, amniotic, and exosomes? And then what about the FTC? So here's a little primer on FDA regulation. Who is in charge? The FDA. Yes. So is the FDA, Federal Drug Administration, in charge of regulating PRP? Well, this is what they had to say. While PRP is considered a medical procedure rather than a drug, the FDA has specific guidelines to ensure patient safety. These guidelines focus on intended use, manufacturing processes, labeling, and claims made about PRP products. It is important for orthopedic practices offering these services to comply with these guidelines to ensure patient safety and regulatory compliance. So what is this HCT/P? This stands for human cells, tissues, and cellular and tissue-based products. The FDA classifies HCT/Ps into two main categories, 351 and 361. So the FDA regulates biologics, including orthobiologics under different pathways based on their intended use and complexity. The key distinction is that 351 products require pre-market approval, a BLA, while 361 products can be marketed without pre-market approval if they meet certain criteria, including minimal manipulation and homologous use. Things to consider about the 351, 361. HCT/P 351, these are more regulated human cell and tissue products. They undergo a more rigorous review by the FDA, and they require an approved biologics license application or a BLA before they can even be marketed. Examples of these products include certain stem cell therapies or genetically modified cellular therapies, such as things that you would use with rheumatology or rheumatologic diseases. HCT/P 361, these are human cell and tissue products that are subject to less stringent regulation by the FDA. They are typically considered minimally manipulated and used for homologous purposes, meaning they perform the same basic function in the recipient as the donor. Examples of these 361 products include PRP, bone marrow aspirate, adipose tissue, amniotic products, and exosomes that are derived from these tissues. However, the bottom line is when you're using human cells or tissue, you need to use an approved product or procedure that is a 361. Otherwise, it is considered a drug and it requires 351 approval. I'm going to share with you the FDA guidance documents that are nonbinding regulations from November 2017. The HCT/P is minimally manipulated. It is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent. The manufacturer of the HCT/P does not involve the combination of the cells or tissues with any other article except water, crystalloids, or sterilizing or preserving a storage agent, provided that the addition of the water crystalloids or sterilizing or preserving agents does not raise new clinical safety concerns with respect to the HCT/P. Either the HCT/P does not have systemic effects and is not dependent on the metabolic activity of the living cells for its primary function, or it does have a systemic effect or is dependent on the metabolic activity of the living cells for its primary function. And it is for autologous use or allogeneic use in a first-degree or secondary blood relative, or it is for reproductive use. That is straight off of the FDA website from the guidance document. This was updated in July 2020 regarding minimum manipulation. There was a lot of discussion about what was or was not minimally manipulated. Part 1271 is that defined as minimally manipulated, showing for structural tissue processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement. For cells or non-structural tissues, the processing that's defined as minimal manipulation does not alter the relevant biologic characteristics of the cells or tissues. Number three, there are criteria for HCT/P to be regulated solely under the 361 of the PHS Act, as well as regulations in the Part 1271 that say HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications by the manufacturer's objective intent. So, homologous use means the repair, reconstruction, replacement, or supplementation of the recipient's cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as a donor. To clarify Section 1271.3 provides two definitions of minimal manipulation: one that applies to structural tissues and then one that applies to non-structural tissues. For structural tissues, minimal manipulation means that the processing of the HCT/P does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement. For cell or non-structural tissues, minimal manipulation means that the processing of the HCT/P does not alter the relevant biologic characteristics of the cells or tissues. So to be clear, platelet-rich plasma and bone marrow concentrate are not actually even considered regulated under HCT/P. So in their own words, platelet-rich plasma is a blood-derived product that is typically regulated by the FDA as a human cell tissue-based product under certain conditions. Whether PRP falls under regulations depends on how it's processed and used. Bone marrow is a source of a hematopoietic stem or progenitor cell. And minimally manipulated bone marrow for homologous use and not combined with any other article is not considered an HCT/P under Section 1271. However, if bone marrow is more than minimally manipulated, intended by the manufacturer for non-homologous use, or combined with any other article with limited exceptions, it then does meet the definition of an HCT/P and is subject to the regulations in part 1271. If you want to be off the FDA radar, PRP for homologous use and BMC are really the safest way to go. Now, if you're a little bit more interested in cellular therapy, including adipose and MFA, go ahead and keep listening. So back in the 2020 update on minimal manipulation on structural versus nonstructural, here's their definition. So HCT/Ps that physically support or serve as a barrier or conduit or connect cover or cushion are generally considered structural tissues for the purpose of applying the HCT/P regulatory framework. Examples of these structural tissues are included in tendons, bone, and adipose, those types of structural tissues. HCT/Ps that serve metabolic or other biochemical roles such as hematopoietic, immune, and endocrine functions are usually considered cellular and non-structural tissues for the purpose of applying the HCT/P. Structural tissues are bone, skin, amniotic membrane and umbilical cord, blood vessels, adipose tissue, articular cartilage, non-articular cartilage, tendon, or ligament. Examples of non-structural tissues include reproductive cells or tissue such as oocytes, hematopoietic stems, or progenitor cells like cord blood, lymph nodes and thymus, parathyroid glands, peripheral nerve, pancreatic tissue, and secreted body fluids. Amniotic fluids are not generally considered HCT/Ps, but the cells secreted from bodily fluids are generally considered HCT/Ps. Then the minimal manipulation for cells or nonstructural tissues would apply. They gave an example regarding adipose, which is what I get a lot of questions about. Example 19-6, the basic function of adipose tissue includes providing cushioning and support for other tissues, including skin, and internal organs, storing of energy in the form of lipids, and insulating the body. One idea or one application, adipose tissue is used to fill voids in the face or hands for cosmetic reasons. This is considered homologous use because it provides cushioning and support as its basic function. Example number two, an HCT/P from adipose tissue used to treat musculoskeletal conditions like arthritis or tendonitis by regenerating or promoting regeneration of articular cartilage or tendon is not generally considered a homologous use because regenerating or promoting regeneration of cartilage and tendon is not the basic function of adipose. However, if you are using it for cushioning and support within a tendon or a bursa, or a meniscus, this could be reasonably considered to be homologous use. Example number three: HCT/P from adipose tissue used to treat neurologic disorders like multiple sclerosis by limiting autoimmune reactions or promoting re-myelinization. This is generally not considered a homologous use because limiting immune reaction and promoting re-myelinization are not basic adipose functions of the adipose tissue. Example number four, adipose tissue used for transplantation into the subcutaneous areas of the breast for reconstruction or augmentation procedures is considered homologous use because providing cushioning and support is a basic function of adipose tissue. Hopefully, that cleared up the use of adipose, and we'll get into the use of adipose a little bit later as well because this has been a topic that's near and dear to my heart and has been a little concerning for me. I've dove in both feet as to is it under the FDA purview and is it reasonable to be using or am I going to be finding myself in stripes or in jumpsuits. The next part of this discussion is what about 510(k) cleared devices? 510(k) clearance means that the FDA has determined that the device to be substantially equivalent to a legally marketed device that does not require pre-market approval application. You can use a 510(k) cleared device in your clinic when providing orthobiologics as long as the device is intended for the specific use that you have in mind and is appropriate for your patient's needs. What about off-label use? So off-label use refers to using a medical device or medication in a way that it wasn't specifically approved for by the FDA in the device's labeling or drug prescribing information. Off-label uses often occur when a physician believes that using a device for a different indication or in a different patient population may provide benefit. So when can physicians use devices off-label? This has to do with the practice of medicine, so medical judgment, where physicians can use an approved device off-label if they believe based on their own medical judgment and expertise, that is the best course of treatment for a particular patient's condition. Additionally, if you have lack of approved alternatives, off-label use may be considered when there are no other approved alternatives available for a specific condition or patient population. And then emergency situations, you can also choose to use off-label devices as a physician, save a patient's life, or prevent serious harm. With that comes physician responsibility of off-label use. Please remember, if you're going to use something off-label, you need to obtain consent from the patient explaining the off-label use, potential risks, potential benefits, and available alternatives. The patient should also have a clear understanding of the treatment and give their informed consent willingly. Additionally, physicians need to document the rationale for off-label use in the patient's medical record, including the reason for choosing this approach and the discussion with the patients. Next, you need to be monitoring your patient's response for the off-label treatment and adjusting the treatment plan as necessary. And then obviously, physicians should stay current and informed about the latest clinical evidence and guidelines related to any off-label use to ensure that their decisions are based on the most up-to-date information. So, how do you educate your patients on off-label use? You need to provide a clear, concise, thorough explanation to the patient as to why you're recommending an off-label use of the device. This should include what their potential risks and benefits are, what the alternative treatment options are, including those that are FDA-approved, and then explain why the off-label use is being considered the best course of action. Then we need to get informed consent. We need to ensure that the patient understands the treatment, acknowledges the off-label use, and provides informed consent in writing. Why go all through the 510(k) clear device information as well as the off-label use? Well, I have had good discussions on the fact that there are FDA-cleared and approved devices to process adipose tissue. Additionally, this indication has been used for orthopedic uses. And so there are devices that are out there that you can use. If you are going to be using it in a manner for which it is not labeled, then you can use it off-label, provided that you have consented the patient, discussed it, and documented in their medical record why this is the best course of action and that there's good scientific evidence to be able to use this. So what about these birth tissue and exosome products? Currently, there are no FDA-approved exosome products. Now, it doesn't mean that these aren't effective. And I've had lots of conversations with doctors like, well, but this works so good. And that is not at the discussion point. The question is, is it legal? Just because it's effective doesn't mean that it's approved. It's just not legal for use. So this is from the FDA website. This is a consumer alert on regenerative medicine products including stem cells and exosomes. Exosomes are products that are regulated by the FDA. As a general matter, exosome products intended to treat diseases or conditions in humans require FDA approval. There are currently no FDA-approved exosome products. Anyone considering the use of anything purported to be a regenerative medicine product, including stem cell products, exosome products, or other widely promoted products, such as products derived from adipose tissues, this product is also known as a stromal vascular fraction, or human umbilical cord blood, or Wharton's jelly or amniotic fluid should know these are not approved by the FDA from the FDA website. A word about amniotic or birth tissues. Amniotic tissues are defined as having original, relevant characteristics of amniotic membrane relating to its utility to serve as a barrier, generally included the tissue's physical integrity, tensile strength, and elasticity. These are examples. A manufacturer processes an amniotic membrane to preserve it and package it in sheets. The HCT/P generally is considered minimally manipulated because the processing did not alter the original relevant characteristics relating to its utility to serve as a barrier. Next example. A manufacturer grinds up and lyophilizes the amniotic membrane and packages it in particles. The HCT/P generally is considered more than minimally manipulated because processing alters the original relevant characteristics of the HCT/P relating to its utility to serve as a barrier. Just look on the FDA website to see what happens if you don't comply. The FDA sends a warning letter to the companies for offering unapproved umbilical cord blood products that may put patients at risk, and then goes forward and names Liveyon Labs and warns that their products pose a potential risk to the public. People ask me all the time, including my patients, well, if they're not legal, why are people marketing and how are they still available? And it comes down to a couple of reasons: money and consequences. So here's the question. What else is available but not legal? Heroin, speeding, drunk driving, not reporting on your taxes? But it all depends on the consequences. And I tell people all the time, you know when's the last time you were going over the speed limit? Well, a lot. But people will say, what's the consequence? How likely is it that you're going to get caught? And what's the downside of this? Now, if you apply that same rationale to drunk driving, people take a much larger pause and say, yeah. Then if you're a physician talking about drunk driving, where if you are arrested and have a DUI, there's a risk you lose your license, well, then it starts to become not worth it. For companies that make these products, what's the risk? What's the consequence? They get a slap on the wrist, they get a letter, and you know they continue making millions. And if they get shut down, well, they get shut down and they open up business somewhere else. Now, for doctors, if they get these same problems, you know, you can lose your license, you cannot practice, you may get jail time. You may owe Medicare millions of dollars for fraudulent billing. You get the picture. So we are the perfect patsies with a lot to lose as compared to these companies. This is why I want to share all of this with you so you can stay out of trouble. I hope this has helped to clarify what the FDA is recommending and trying to keep us safe. This next topic is pretty short, but we want to talk about who else has purview over what we do in orthobiologics? Well, the FTC does. The Federal Trade Commission. And specifically, this is true in advertising. What they care about is what you put out there in the world, on your websites, on your brochures, and in your advertising. How do you stay safe from the FTC? It's pretty simple. Avoid misleading claims. Don't mislead the public. Don't mislead your patients. Clearly state the limitations of your treatments. Use evidence-based information. Disclose any potential risks. Provide clear contact information on how your patients can get a hold of you. Place disclaimers in terms of use on your website. And then if you need to, please consult legal professionals. This is important. This is your livelihood. Don't put yourself at risk. Remember, this is our responsibility. Maintaining compliance with the FTC guidelines and providing accurate, responsible information is crucial to protect the patients and maintain ethical practice. It's essential to stay updated on regulatory changes and consult with legal professionals when needed to ensure ongoing compliance with the rules and regulations that have been governing the ever-changing field of orthobiologic therapies. Please remember, it's not the fault of the IT guys, the advertiser, your office manager. This all comes back to you and your practice. Please make sure to review all of the written things that are going out for your practice and on your website. This has been a lot to review. It's pretty simple to stay out of trouble. Number one, use FDA-compliant autologous products. Number two, use FDA-approved 510(k) cleared devices and use clear and honest communication. "Where there's great power, there's great responsibility", says Winston Churchill. Thanks so much for listening and stay tuned for our next topic, near and dear to my heart, data collection. Take care.

Outro

This has been "The Business of Orthobiologics" podcast. Thank you so much for joining us today. If you want to know more, please join us on the website, "PRP-Now.com", and click on the FREE masterclass. Also, don't forget to "SUBSCRIBE" to this podcast to get more guidance on integrating PRP in your busy practice. Bye for now.