Who Benefits From Doctors Misconstruing Orthobiologic Regulations?

“I’m not an attorney, but I play one on TV,” is something you might hear in a cheeky TV ad. You don’t, however, expect to see it in a vaunted orthopedic journal. Let’s dive in.

Orthobiologics Are a Game Changer for Most, But a Real Problem for Some

The great news is that platelet-rich plasma (PRP) and bone marrow concentrate (BMC) treatments now have dozens of high-level randomized controlled trials supporting their use for orthopedic conditions (13-55). Bone marrow concentrate has three RCTs supporting its use in knee arthritis. In addition, two more midterm analyses of BMC use have recently been published, and the full RCTs are expected to be published this year on ACL and shoulder rotator cuff tears. If you’re interested in reducing surgery rates, this research is fantastic news. However, if you’re interested in creating FDA-approved drugs to accomplish the same things or trying to keep orthopedic surgical rates high, these studies are a problem. While you can produce studies that are designed to counter this evidence, like the recent Bennell et al study in JAMA, these studies are resource-intensive and take years to design, fund, recruit, write, and publish.

If creating an opposing study is difficult, is there some other way to put the brakes on this trend toward less invasive orthobiologic injections that replace surgeries? Sure, you can just try to convince everyone that procedures that the FDA has stated are fine are, in fact, illegal. Let’s dive into a letter that appeared last year in the American Journal of Sports Medicine (AJSM).

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The AJSM Article

An article entitled “Food and Drug Administration’s Position on Commonly Injected Biologic Materials in Orthopaedic Surgery” looks very authoritative. It seems to make its case by reviewing a bunch of complex FDA regulations. In the end, it concludes that commonly used orthobiologics like PRP and bone marrow concentrate are actually FDA-regulated drugs and are illegal to use to treat orthopedic problems. However, in reading the article it becomes all too evident that Fang and Vangsness need to take a course on the FDA regulations on orthobiologics instead of pretending to teach one. Or, as I would say, “I’m not an attorney, but I play one on TV.”

To make sure I’m right about this one and not just playing an attorney myself, I reviewed this paper with an experienced FDA regulatory attorney whom I know the FDA respects. Meaning that when he sends them [the FDA] a letter, they know he knows the law in this area and has objective evidence of the results.

The main issue with the AJSM article concerns four exempted areas of orthobiologics that the FDA has clarified many times:

1. Blood Products

The article tried to convince the reader that to use PRP, FDA approval is first required, either in the form of a biologic drug license or an FDA 510(k) clearance for a device. There’s just one issue with that conclusion: It’s not actually supported by FDA’s own regulation and statements. Why? First, blood products, such as PRP, are not considered HCT/Ps and are exempt from regulation so that practitioners do not need FDA approval when administering PRP to patients (1). In addition, if a provider is creating PRP in their office, that provider is exempt from the FDA’s registration and listing requirements when they “manufacture” PRP solely for use in their own practice (2).

Where are Fang and Vangsness getting confused? Centralized manufacturers and distributors of blood and blood products (like a blood bank) are subject to extensive federal regulation, but licensed practitioners using autologous PRP (i.e., orthobiologics from a patient’s own body) in orthopedic and sports medicine procedures are left to regulation by the individual states as practitioners rather than as product manufacturers.

2. Bone Marrow

Fang and Vangsness also fail to fully comprehend the regulations surrounding the use of bone marrow concentrate (BMC or BMAC) by providers. On the one hand, they correctly state that “minimally manipulated bone marrow for homologous use” is not an HCT/P under Part 1271, but then they randomly conclude that BMC needs FDA approval before use. Huh?

First, making a bone marrow concentrate requires simple cell selection via centrifugation. Although the FDA’s guidance on the minimal manipulation of bone marrow is vague, FDA has made it abundantly clear that when “a manufacturer performs cell selection on a mobilized peripheral blood apheresis product to obtain a higher concentration of…cells for transplantation,” the process is generally considered minimal manipulation (3). Meaning cell selection meets the standard of minimal manipulation.

The term “homologous use” means that the orthobiologic serves the same function in the body as it does in the treatment. In this regard, the FDA has not directly commented on whether BMC is homologous when used in an orthopedics or sports medicine setting. However, peer-reviewed professional medical society position papers have scientifically supported that bone marrow is homologous to joints, the intervertebral discs, tendons, and ligaments (4). In other words, the body uses bone marrow cells in the maintenance and repair of these tissues naturally, meeting the FDA’s definition of homologous.

3. Same Surgical Procedure Exception

Fang and Vangsness also ignore 21 CFR 1271.15(b), otherwise known as the Same Surgical Procedure Exception (5). This FDA regulatory “safe harbor” states: “You are not required to comply with the requirements of this part if you are an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure.” Note that the terms “same HCT/P,” “same individual,” and “same surgical procedure” are used.

So what happens when a doctor uses the same platelets or bone marrow nucleated cells in the same patient and in the same procedure? Because the treatment raises “no additional risks of contamination and communicable disease transmission beyond that typically associated with surgery,” FDA regulation is not needed (6).

Why ignore this critical safe harbor in a narrative review on the regulation of orthobiologics? That’s like ignoring the possibility of addiction in a narrative review of opioids to treat chronic pain. Oh, wait, that has actually happened already.

4. Off-Label Use

Fang and Vangsness also contend that using PRP or BMC for orthopedic purposes qualifies as “off-label” use. However, without an FDA regulation classifying these items as drugs when used as described above, applying the moniker of “off-label” makes no common nor regulatory sense.

Under U.S. law, “off-label” simply refers to a physician’s use of a cleared or approved product for purposes other than those cleared or approved by the FDA. The Supreme Court has described this approach as “an accepted and necessary corollary of the FDA’s mission to regulate in this area without directly interfering with the practice of medicine.” (7) As the FDA has explained, “Once a drug product has been approved for marketing, a physician may, in treating patients, prescribe the drug for uses not included in the drug’s approved labeling. Control of the practice of medicine in these cases is primarily exercised through State laws affecting medical licensing and practice and through product liability-law.” (8)

Fang and Vangsness use this same argument to suggest that physicians using general-purpose lab equipment to create PRP and BMC for their own use are violating the law. However, these devices typically do not require FDA approval or clearance and feature broad, “tool type” indications in FDA regulations (9). The FDA has also 510(k)-cleared other devices that automatically process PRP or BMAC with similarly broad indications, such as “piston syringes,” “automated cell separators,” and “general purpose laboratory equipment labeled or promoted for a specific medical use.” (10-12)

The Negative Consequences of Pretending to Be an FDA Regulatory Attorney

First, because of these errors, the AJSM never should have accepted this paper for publication. It should also never have been sent to physician reviewers, but instead directly to qualified FDA regulatory counsel for review if they had wanted to publish something like this. The problem? The AJSM likely has few expert reviewers focused on regulatory law. That same problem is likely why we don’t see legal journals publishing clinical trials.

What’s the harm of printing this type of misinformation? The biggest issue is that physicians and others will read it and believe that the AJSM did its due diligence before publishing it and that it must be accurate information. They won’t take the time to meet with qualified legal counsel and vet this opinion piece.

Who Are Fang and Vangsness?

William Fang, near as I can tell, is a grad or medical student at Western University of Health Sciences in Pomona California. I didn’t actually find too much about him. The big question is, “What would a grad student in the sciences know about the complex legal regulation of orthobiologics?” Your guess is as good as mine.

Thomas Vangsness, MD, is an orthopedic surgeon at USC. Given the clear inaccuracy of the information he has published, it’s certainly fair game looking into his conflicts of interest with autologous orthobiologics. By searching other COI statements, I know he’s a shareholder in an arthritis drug company called CarthroniX (56). We also know that he was paid by Osiris Therapeutics (now Mesoblast) to conduct an early-stage study on the use of allogeneic MSCs in knee meniscus surgery (57). Other COIs exist online.

The upshot? When you play an attorney but aren’t one, all sorts of misinformation can be spread. Let’s hope Fang and Vangsness take the time to actually read and understand the FDA regulations and stop claiming to be experts in matters of regulatory law.

__________________________________________

References:

1. 21 C.F.R. § 1271.3(d)
2. 21 CFR § 607.65(b)
3. See, FDA Guidance, “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use,” July 2020, at p. 19; Example 19-1
4. Manchikanti L, Centeno CJ, Atluri S, Albers SL, Shapiro S, Malanga GA, Abd-Elsayed A, Jerome M, Hirsch JA, Kaye AD, Aydin SM, Beall D, Buford D, Borg-Stein J, Buenaventura RM, Cabaret JA, Calodney AK, Candido KD, Cartier C, Latchaw R, Diwan S, Dodson E, Fausel Z, Fredericson M, Gharibo CG, Gupta M, Kaye AM, Knezevic NN, Kosanovic R, Lucas M, Manchikanti MV, Mason RA, Mautner K, Murala S, Navani A, Pampati V, Pastoriza S, Pasupuleti R, Philip C, Sanapati MR, Sand T, Shah RV, Soin A, Stemper I, Wargo BW, Hernigou P. Bone Marrow Concentrate (BMC) Therapy in Musculoskeletal Disorders: Evidence-Based Policy Position Statement of American Society of Interventional Pain Physicians (ASIPP). Pain Physician. 2020 Mar;23(2):E85-E131. PMID: 32214287.
5. 21 C.F.R. § 1271.15(b)
6. FDA, Same Surgical Procedure Exception under 21 C.F.R. 171.15(b): Questions and Answrs Regarding the Scope of the Exception, November 2017, at p. 4; available at https://www.fda.gov/media/89920/download.
7. Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341, 349-350 (2001); citing 21 U.S.C. § 396 (“Nothing in this chapter shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship.”)
8. See e.g. Alexander v. Smith & Nephew, 98 F.Supp. 2d 1299 (N.D. Ok. 2000) (holding that FDA regulations do not impose a standard of care on practitioners).
9. FDA, The 510(k) Program: Evaluating Substnatial Equivalence in Premarket Notifications, July 2014, at p. 16; available at https://www.fda.gov/media/82395/download.
10. 21 CFR 880.5860
11. 21 C.F.R. 864.9245
12. 21 C.F.R. 862.2050
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Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. View Profile