Rebutting Misinformation in Orthopedic Journals: Ittleman and Shapiro

fda regulation vangsness

Orthobiologic treatments represent a disruptive technology that I have blogged on dozens of times. Given that many patients who used to get invasive orthopedic surgery are now skipping those procedures and instead using interventional orthobiologics, orthopedic surgeons have varied reactions to this new playing field. We’ll explore those issues today in the context of an explosion in published misinformation in orthopedic journals. The key piece of misinformation I’ll focus on today is an article published by an orthopedic surgeon and a medical student and the published rebuttal of that article. Let’s jump in.

Orthopedic Surgery Rates Are Dropping

If orthobiologics like PRP are a disruptive technology, then applying those substances without the need for arthroscopic or open surgery is even more disruptive. That’s the concept behind interventional orthobiologics and that new field is slowly putting a dent in the number of invasive orthopedic surgeries, which creates a dilemma for surgeons. A good chunk of them at this point have decided to begin to embrace orthobiologics. However, some have gone the other direction and are still screaming at the rain. That last response has launched a good number of editorials and opinion pieces steeped in obvious misinformation that get published in orthopedic journals.

Today we’ll review one published article that’s frankly dangerous as it created a false narrative that went unchallenged or questioned by reviewers for a major orthopedic journal. Why the concern? Because this review butchers regulatory law in an attempt to make physicians think twice before using common autologous orthobiologics. As a result, I’ll also review the published rebuttal by an actual regulatory attorney.

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The Vangsness Et Al Regulatory Review

The American Journal of Sports Medicine(AJSM) is a vaunted orthopedic surgery publication that first appeared in 1972 and has the highest impact factor of the 72 journals that publish in the field of orthopedics. In fact, our science team has had the honor of publishing one of our recent works here (9). In other words, what gets published in AJSM gets read by lots of orthopedic surgeons and other related specialists

Last year, an article written by Fang and Vangsness was published in AJSM that reviewed the regulations behind orthobiologics. Given that this is a big deal journal, that review would generally be considered authoritative by more than twenty thousand US orthopedic surgeons (3). And that folks, is the problem because what was asserted was a mish-mash of misinformation about the regulations behind using common orthobiologic therapies.

To review this Vangsness et al paper I’ll be quoting the rebuttal written and recently published by Andrew Ittleman (an actual regulatory attorney) and Shane Shapiro, M.D. (a physician who actually practices interventional orthobiologics) (7). I’ll keep the original Ittleman et al rebuttal citation numbers and add those to the references below.

Blood Products

Vangsness et al Claim: Physicians MUST use 510K cleared, purpose-built devices to be able to make platelet-rich plasma. 

Ittleman et al Response: “Nevertheless, the article concludes ‘‘that either a BLA [biologics license application] or PMA [premarket approval] approval
or de novo 510(k) clearance is needed for PRP to be ‘approved’ for use in a clinical injection setting.’(3) These two points are clearly irreconcilable, and there is no mandate that practitioners use cleared medical devices when processing PRP. The conclusion that a BLA, PMA, or 510(k) is required is also contradicted by FDA’s blood product regulations, which exempt licensed practitioners from FDA’s registration and listing requirements when they manufacture PRP solely for use in their own practices. (4,8) Thus, although centralized manufacturers and distributors of blood and blood products are subject to extensive federal regulation, licensed practitioners using autologous PRP in orthopedic and sports medicine procedures are generally left to regulation by the individual states in which they practice rather than by FDA as product manufacturers.”

My comments: This seems to be an attempt to go after physicians who use labs to process autologous biologics. As you can see, there is no regulatory basis for this assertion.

Bone Marrow

Vangsness et al Claim: To use bone marrow concentrate for orthopedic use, full FDA approval must be obtained. 

Ittleman et al response: “First, although FDA guidance on the minimal manipulation of bone marrow is somewhat lacking, FDA has made clear that when ‘‘a manufacturer performs cell selection on a mobilized peripheral blood apheresis product to obtain a higher concentration of . . . cells for transplantation,’ (5) the process is generally considered minimal manipulation, assuming, of course, that the practitioner does not culture expand the resulting cell population. FDA’s guidance regarding the concentration of blood would likely be applicable to bone marrow as well.
Second, regarding homologous use, FDA has not directly commented on whether BMAC is homologous when used in an orthopedics or sports medicine setting, but the available guidance does make clear that bone marrow is homologous when used to form, replenish, and/or reconstitute the hematopoietic system.(5) Peer-reviewed position papers of professional medical societies have generally supported this conclusion with reference to intraarticular microfracture procedures that expose the bone marrow cavity and release bone marrow cells for subchondral bone and cartilage repair. (12) A similar relationship exists between bone marrow and the intervertebral disk, tendon, and ligaments, with studies showing that tendon health in the rotator cuff is directly related to the number of progenitors in the bone marrow area where the tendon attaches to bone. (13)”

Ittleman et al go on, as Vangness et al completely missed the CFR 1271.15(b) same surgical procedure exemption: “As it relates to practitioners, one of the most important regulations in Part 1271 is 21 C.F.R. 1271.15, which provides the following regulatory safe harbor: ‘‘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.’’ According to FDA, it created this exemption because when the same HCT/P is used in the same patient in the same surgical procedure, it raises ‘‘no additional risks of contamination and communicable disease transmission beyond that typically associated with surgery.’’6 In the article, however, the authors did not discuss this final guidance as it pertains to PRP or BMAC, thus contributing to incorrect conclusions.
In short, even if autologous BMAC and PRP were HCT/Ps, when used in orthopedics and sports medicine settings, they would still be considered ‘‘the same surgical procedure’’ because they involve the same patient, the
same surgical setting, and the same HCT/P. To the extent that practitioners process autologous blood and bone marrow ex vivo before administration, they stay within this regulatory safe harbor because the HCT/P ‘‘remains in its
original form’’ and the only additional processing involves ‘‘rinsing, cleansing, sizing, and shaping, whether manually or through centrifugation or filtration to remove debris.(6)”

My comments: Vangness et al are attacking physicians that use bone marrow concentrate in orthopedics, a mainstay of interventional orthobiologics. However, they completely missed the actual regulations that allow a physician to use autologous bone marrow concentrate (BMC) for orthopedic use.

Off-Label Use

Vangsness et al Claim: Physicians that use PRP and BMC are engaging in off-label use. 

Ittleman et al rebuttal: “Under US 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 FDA. Subject to limited exceptions, FDA does not prohibit physicians from prescribing or administering approved drugs and devices offlabel, and 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.’’ (2) Today, practitioners enjoy wide leeway when using products off-label, and in some cases, doing so can be treated as standard of care. (1) As 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 products liability-law.’’ (14) Manufacturers of approved products, however, do not enjoy the same leeway to the extent they market their products off-label. (15) 
In any event, in order for a product to be used off-label, there must first be an on-label, that is, an approved product with approved labeling. Consequently, in most instances, the term off-label is inapplicable to autologous PRP and BMAC because they are not required to be approved in the first place and therefore have no approved labeling.”

My comments: This last part seems to be an attempt to shame physicians using PRP and BMC by claiming that they’re engaged in some sort of clandestine off-label use. However, to be “off-label”, something must first be “on-label”, the latter being a term that only applies to prescription drugs.

Final Ittleman et al Conclusions

This is a powerful statement: “Respectfully, there are real-world consequences of the authors’ misinterpretation of the law. As orthobiologic procedures become more prevalent and approach the standard of care, they are also becoming the subject of media attention and court cases. It is therefore critical that we accurately describe the relevant rules so as to avoid creating misinformation.”

Celebrating Setting the Record Straight

From interviewing one of the authors of the rebuttal, I know that this work took many months to get published as AJSM and/or the authors of the review were not responsive. I know this uphill battle very well as many of us, have published rebuttals to misinformation or worked on these critical pieces. So I want to say a big “Thank You” to both Ittleman and Shapiro for taking the time to rebut misinformation.

The upshot? Rebutting the misinformation machine in orthobiologics is a full-time job. So here’s a big thank you to the dozens of unsung heroes who have taken the time to publish rebuttals to pieces published in big-name journals. Hopefully, many people get a chance to read this excellent rebuttal published by Ittleman and Shapiro!

_______________________________________________________

(1) 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.

(2) 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.’’)

(3) Fang WH, Vangsness CT Jr. Food and Drug Administration’s Position on Commonly Injected Biologic Materials in Orthopaedic Surgery. Am J Sports Med. 2021 Oct;49(12):3414-3421. doi: 10.1177/0363546521990900. Epub 2021 Mar 26. PMID: 33769895.

(4) FDA. Questions and Answers Regarding the End of the Compliance
and Enforcement Policy for Certain Human Cells, Tissues, or Cellular
or Tissue-based Products (HCT/Ps), July 2021. https://www.fda.gov/
vaccines-blood-biologics/cellular-gene-therapy-products/questionsand-answers-regarding-end-compliance-and-enforcement-policycertain-human-cells-tissues-or

(5) FDA. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use, July 2020. https://www.fda.gov/media/109176/download

(6) FDA. Same Surgical Procedure Exception Under 21 C.F.R.
1271.15(b): Questions and Answers Regarding the Scope of the
Exception, November 2017, at p. 3. https://www.fda.gov/media/
89920/download

(7) Ittleman AS, Shapiro SA. Food and Drug Administration’s Position on Commonly Injected Biologic Materials in Orthopaedic Surgery: Letter to the Editor. Am J Sports Med. 2022 Aug 4:3635465221116119. doi: 10.1177/03635465221116119. Epub ahead of print. PMID: 35925639.

(8) FDA. United States Code of Federal Regulations, 21 CFR § 607.65(b) –
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSear
ch.cfm?fr=607.65

(9) Berger DR, Centeno CJ, Kisiday JD, McIlwraith CW, Steinmetz NJ. Colony Forming Potential and Protein Composition of Commercial Umbilical Cord Allograft Products in Comparison With Autologous Orthobiologics. Am J Sports Med. 2021 Oct;49(12):3404-3413. doi: 10.1177/03635465211031275. Epub 2021 Aug 16. PMID: 34398643.

(12) Manchikanti L, Centeno CJ, Atluri S, et al. Bone marrow concentrate
(BMC) therapy in musculoskeletal disorders: evidence-based policy
position statement of American Society of Interventional Pain Physicians (ASIPP). Pain Physician. 2020;23(2):E85-E131.

(13) Mazzocca AD, McCarthy MBR, Chowaniec DM, Cote MP, Arciero
RA, Drissi H. Rapid isolation of human stem cells (connective tissue
progenitor cells) from the proximal humerus during arthroscopic rotator cuff surgery. Am J Sports Med. 2010;38:1438-1447

(14) New Drug, Antibiotic, and Biologic Drug Product Regulations; Final
Rule, 52 Fed. Reg. 8798, 8803 (March 19, 1987).

(15) U.S. v. Caronia, 703 F.3d 149, 155 (2nd Cir. 2012); citing U.S. Food
and Drug Administration, Guidance for Industry, Responding to
Unsolicited Requests for Off–Label Information About Prescription
Drugs and Medical Devices (2011), at 2-3.

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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

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NOTE: This blog post provides general information to help the reader better understand regenerative medicine, musculoskeletal health, and related subjects. All content provided in this blog, website, or any linked materials, including text, graphics, images, patient profiles, outcomes, and information, are not intended and should not be considered or used as a substitute for medical advice, diagnosis, or treatment. Please always consult with a professional and certified healthcare provider to discuss if a treatment is right for you.

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