In the previous two posts (Part One and Part Two), I have examined comments made by Gassman, et al. in which they erroneously stated that bone marrow aspiration is painful and that it is associated with increased aspiration site morbidity. Their comments were directed at an article by Xing, et al. published together in the same journal issue. Briefly, Xing, et al. determined that bone marrow aspirate (BMA) and bone marrow concentrate (BMC) both contributed to the viability of fat grafts in a rabbit model, with some advantages demonstrated in BMC-laced grafts. I reviewed the details of the study in a series of posts. The one main difference between the Xing, et al. study and fat grafting in humans is that lipofilling in humans occurs in subcutaneous tissues (e.g., the back of your hand or the face), while the Xing, et al. fat grafts were implanted into the ears of rabbits. This was done for a variety of quite valid reasons. Consequently, I believe the observations from the study have some bearing on studies in the human literature involving fat-derived therapies, as examined in Part Three of the Combination Cell-Based Therapies series.
I will move on in this post to explore and correct some of the statements Gassman, et al. made concerning regulatory aspects associated with a hypothetical physician who combines an autologous fat graft with a material like bone marrow concentrate, as was studied in Xing, et al. Needless to say, I am puzzled by some of the statements made by Gassman, et al.
Consider the following:
“The authors’ technique for fat grafts supplemented with bone marrow aspirate or concentrate [reported in Xing, et al.] would be considered restricted from human application by the U.S. Food and Drug Administration. The U.S. Food and Drug Administration is clear that the application of nonsimilar, autologous cell transfer is forbidden.”
Yeah, I also am left scratching my head at what charitably I will label as rubbish. I have read a lot of documents written by the FDA and I haven’t a clue what Gassman, et al. are referring to when they state that the FDA “…is clear that the application of nonsimilar, autologous cell transfer is forbidden.” I assume the authors think the FDA has a problem with physicians who want to mix and match autologous therapies. They could be right, but I have never seen such a statement in any FDA document.
They compound their sins, in my opinion, by explaining:
“…the [FDA] published [a] draft guidance for working with [HCT/Ps] from adipose tissue…[which] must meet the following requirements for clinical use:
…4. Adipose tissue cannot:
Have a systemic effect.
Be dependent on the metabolic activity of living cells for its primary function.
Have allogeneic use in a first-degree or second-degree blood relative. …”
It is hard for me to know where to begin to unwind such a tortured interpretation of 21 CFR 1271. The short answer is that a patient receives their own fat in a fat graft, which makes it an autologous procedure. In which case, their comment in Item 4 is way off the mark. In particular, if fat is being used on an autologous basis, then it can be as metabolically active as possible and not trigger the wrath of the FDA. In fact, the Holy Grail in fat grafting is to ensure viability of all adipocytes in a graft so that graft volume is maintained over time. Furthermore, the FDA considers fat grafts to have a basic function of cushioning and supporting structures in subcutaneous tissue, which is dependent on having viable adipocytes. If you don’t have happy adipocytes in a graft it will shrink up and not do a good job of cushioning and supporting. So, Gassman, et al. completely missed the mark with this criticism.
While there is some ambiguity as to just what the FDA means by “systemic” effect, the real hot button of the FDA when working with a structural tissue like fat is that it is not overly processed (i.e., meets minimal manipulation standards) and is placed in a location that normally has fat tissue present, which is why the procedure is referred to by the FDA as lipofilling.
While I have offered several rebuttals to the authors’ crazy statement about not being able to use fat grafts, as indicated above, I will provide an example from a final Guidance the FDA issued last year covering the acceptable uses of fat grafts, and will complete my review of the Gassman, et al. regulatory craziness in the next post.