PRP & FDA

Here's a summary of the FDA regulations concerning PRP...

Here's a nice summary article with wonderful references...
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Here's an abstract summary of the above article...
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Here's where the FDA plainly says that PRP is not under consideration for regulation..
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New England Journal Article about Stem Cells...
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Training for physicians...
Urogynecological (click) <--
Men-Urological (click) <--
Facial Aesthetics (click) <--

Transcript

Charles Runels: To clear up some of the confusion concerning stem cells and their regulation by the FDA, I thought I would go through some things that have been published both by the FDA and others.

First of all, this is a really informative editorial-type article in the New England Journal of Medicine talking about the FDA regulation of stem-cell-based therapies. What it says is that, "Any stem-cell-based product that contains cells or tissues that are highly processed," this is a quotation, "are used for other than their normal function, are combined with non-tissue components, or are used for metabolic purposes would be subject to the Public Health Safety Act, Section 351." This appeared in October of 2006. Other articles have appeared since then with more and more strict-type warnings that, outside the regulation of IRB, stem cells will be relabeled as a drug-type product rather than just tissue, so let's look at more about what that means.

This is a really nice article that talks about the definitions, current use, and the FDA stance on platelet-rich plasma, and so let's go through this. There's a link to this here below the video. There's a link to this article. First of all, it's nice to look at what exactly is regulated. Is it the platelet-rich plasma or the device? Here this author say the first point of confusion is that in there are many pathways in which a drug or a medical device can be brought to market. Most of the FDA-approved kits came through a 510(k) where a device is given clearance because it's equivalent to a previous device, and these devices were approved to prepare platelet-rich plasma for use in bone, for mixing with bone transplants, and they've been shown to help, so if you're a bone graft. There are numerous PRP preparation systems on the market with FDA clearance. Nearly all of them are cleared for producing platelet-rich plasma mixed with bone graft materials to enhance the take of that.

A PRP system with clearance indicates a device is safe in that it does not create a preparation that's hazardous or dangerous, which could happen if you used a lab kit that's made to isolate platelets, because the level of sterilization is different, and a different method is used that is pyrogenic, and a different level of sterility is used, so these FDA-approved devices are made to prepare the plasma in a way that it is safe. Number two, that its performance is substantially equivalent to a predicate PRP device, meaning that it's demonstrated the capability to actually isolate the platelets from the whole blood, but the clearance applies to producing PRP for use with bone graft materials. Now, if you want approval for a specific indication other than that, then it requires a BLA or a PMA application, which is more rigorous and much more expensive but, by definition, platelet-rich plasma is a biologic.

Now, what does the FDA do? The FDA is responsible for protecting the public health by regulating human and animal drugs, biologics, that's vaccines, cellular and gene therapies, medical devices, food and animal feed, cosmetics, and products that emit radiation. Where does PRP fall into this category? Under that idea, then PRP would be considered a biologic. How is a biologic regulated? For clinicians using PRP, it's important to understand how they regulate this.

The first is whether it's being used as intended. If the devices are intended for use with bone grafting, then off-label, which sounds scary to lay people, would mean that it's used in a different area, but it just means that you're still using materials that have proven to be safe just with a different indication. For office injections to be on-label and approved, then you would have to submit animal studies and clinical trials, which is very time consuming and very, very costly. The problem is, because it's not a drug, who pays for the very costly process? Which is where our group is coming into play to at least give the ideas that, just the idea ... To do a pilot study will cost six figures, so to do one of these type studies would be in the millions, and there's no pharmaceutical company or other, even, device company that's yet stepped to the plate to do that. The reason the device companies have not is because they know, if they fund this research, there's 30 other kits out there that you could use other than the kit that funded the research.

This is key. The FDA does not regulate the practice of medicine. Clinicians are free to use a product off-label, and we do this all the time because we know that, if there is research to support the idea, then waiting for the pharmaceutical company to pay the money or something like blood where no one's going to pay the money, most likely, then we do the research, and the FDA lets the doctor decide. Over half the drugs that are prescribed by oncologists are off-label. In some studies, 20 to 30% of the prescriptions written by a family practitioner are off-label, meaning that we take the evidence ... We don't just think of these ideas out of the blue. We take really good research and evidence-based ideas and see how they apply, so exactly how that's done. These guys give a really nice idea of how that goes.

Clinicians have the responsibility to be well-informed about the product to base its use on scientific rationale and sound medical evidence and to maintain records of the use and the effect, so keep good medical records and base it on research. They do not require the submission of IND, or IDE, or oversight from Institution Review Board. If you're going back, the scenario they're using here is using it in a joint, injecting it in a joint, a young patient with glenohumeral arthritis, a review of the literature is performed, and it shows that it's a reasonable idea, and so the PRP is used, and they keep a record of what happens like any good medical practice.

Conversely, if you intended to use investigational manner, as in do a formal study versus treating a patient, then you need an IRB, which is what we did with our lichen sclerosus study, and it's what we will do with our blinded study that's coming up and other studies that we are funding with our provider group. That's what the money goes to. A huge portion of that goes to funding our research, and the other bulk of it goes to legal so that others who are not basing their ideas on our group's collective efforts of thousands of procedures with comparing notes and comparing outcomes, then that would be misleading to let patients think that their doctor was plugged into that conversation when they may not even be using an FDA-approved kit. If you do a formal study, then you need an IRB. If you're treating an individual patient based on clinical rationale and using an FDA-approved kit, then that does not require an IRB, or you'd have 30% of the prescriptions being written, between 20 and 30%, or more if you're an oncologist, not ... us not being able to help people.

If you look at the Code of Regulations, there's this tiered approach, and it gets more specific. The FDA had a ruling, 2005, that any procedure in which human cells are manipulated is subject to clinical oversight. More than minimally manipulated was the exact phrase. If they're more than minimally manipulated, then it must be treated like a drug. Then that sparked this debate about does the FDA really have the power to regulate the practice of medicine with the respect to biologics? Back to our PRP example, PRP obtained from a 510(k)-cleared device is unregulated because it's just blood. It's, basically, you've isolated the platelets but you've done very little to them, but people became concerned is that more than minimally manipulated? To date, the FDA has not attempted to regulate PRP or even activated PRP where you add a few drops of calcium chloride.

Here's the approach of the authors of this article who are using PRP off-label. They discuss it with the patient. They review the research. They have a consent form that people sign where they promise them no guarantee, that their options include not treating the condition at all, that they encourage the person to talk to their primary care physician, which I always do. I'll even make phone calls to the primary care physician so other physicians are involved in the conversation. Then, in the days following the injection, you follow up with phone calls and records. This is what we will be doing with some of the surveys that'll be sent out so we can collectively pool our data. They say, "To date, we've not observed any serious adverse events or unanticipated effects that fall outside the scope of what you would expect from an injection."

In summary, there are several systems for obtaining PRP that have received 510(k) clearance, which indicates that a given preparation system is substantially equivalent to a predicate device and that it's safe and capable of producing PRP. Any doctor not using an FDA-approved device, in my opinion, is practicing substandard medicine, unless, unless, I will qualify that, the doctor's gone through the very expensive $100,000 process of creating a lab that's up to standards, then that would be an exception, and that requires a whole different conversation and approval by the powers that be.

Second point, per the FDA, PRP's intended uses in an operative setting to mix with bone graft materials to enhance bone graft handling properties. Outside setting is considered to be off-label use, which means that you're using research. Clinicians using PRP off-label as injections is part of good medical practice in the best interest of the patient have the responsibility to be informed on the product and to keep records of it use. However, they do not require oversight from the FDA. The language in 21 CFR 1271 regarding the manipulation of cells has impacted the use of cultured stem cells, causing concern for some over-activated PRP.

To date, the FDA has not attempted to regulate activated PRP, so even adding a few drops of calcium. Calcium's in the blood already, so it makes sense that adding extra calcium ... so you're taking blood from a patient, taking part of that and putting it back into the same person, and you're putting calcium, which would be in that person anyway, in there with it, or thrombin, which the body would make anyway. You would be making that thrombin, again, from the person's own blood, so either calcium, which is in the blood already, or thrombin, which the person would make already, is used. Clinicians using activated PRP should be mindful of these concerns and stay informed, so let's stay informed.

The FDA has a meeting scheduled September 12, 2016 where they will have an open discussion about the use of stem cells, regulation of human cells, tissue, or cellular-tissue-based products, but notice this. The FDA welcomes comments that will enhance the usefulness and clarity of these documents. They're getting ready to shut people down is what this amounts to. By the way, I am not anti-FDA. The FDA may not be a perfect institution. Any time you have people in a large institution, there's always the possibility of imperfect people doing imperfect things, but the FDA serves a very important function, and having a device that I'm sure is giving me a sterile liquid that actually has platelets in it is extremely important, and it's reproducible so that I know it's going to be about the same concentration no matter which one of the doctors in our group uses it. Without that, we can't have a meaningful conversation, and we have less degree of safety.

Notice this next sentence. The FDA recommends that comments exclude discussion of products that do not meet the definition of a HCT/P, go back up here, human cells, tissues, and tissue-based products such as platelet-rich plasma and other products. The FDA is telling you right there that the platelet-rich plasma does not meet the definition of HCT/P. The FDA will consider information obtained through the public hearing in the finalization of the four draft guidance documents, so they're creating their new regulations, and people are signing up. If you are using stem cells, I would recommend that you keep up with this. As PRP providers, we will keep up with this but, as of now, there it is in black and white. The FDA does not consider platelet-rich plasma, which makes sense. They shouldn't regulate, and they realize this, putting a person's body back, regulating, say, for an example, a tissue or a skin graft or regulating transfusion of blood. That's the purpose of this.

As providers in our O-Shot, and Priapus Shot, and Vampire Facelift provider groups, we insist that people follow these guidelines where we're keeping records, we're gathering data on our patients, but any formal studies that we do outside this area of just individual medical records that we're keeping track of and keeping track of what we're noticing, then we can actually be smarter about designing the IRB-approved formal studies where we perceive prospectively like we did with our lichen sclerosus study. Hopefully, that helps. I'll put links to these documents below the video. I hope you find this helpful.