As response to accumulating complains about lack of clarity on regulation of human cell tissue products (HCT/P), derived from adipose tissue, FDA just released a guidance document, which clarifies regulatory considerations. I’d like highlight some important points from this guidance and highly encourage you to read it.
- General criteria for all HCT/P to be regulated solely as “tissue for transplantation” ( section 361 of the PHS Act) or as a “drug” (section 351 of the PHS Act) defined in 21 CFR 1271.10.
- FDA sees fat tissue as “structural tissue” (“its utility to cushion and support the other tissues in the subcutaneous layer”). Of course, fat tissue have some other functions, such as metabolic, but for purpose of regulation FDA (quote) “generally consider adipose tissue to be a structural tissue”. Therefore, definition of “minimal manipulation” should be applied as it is for “structural tissue”.
- The structural components of adipose tissue are (1) adipocytes and (2) extracellular matrix. Notably, according to FDA, decellularized fat tissue-derived extracellualr matrix considered as more than minimally manipulated, because such processing alter ability tissue to provide “structural” function. Therefore, the only way to fit fat-derived product in HCT/P as not a drug (361) is to derive adipocytes for homologous use (ex: liposculpture).
- Isolation of any “non-structural” component cells (such as SVF, pericytes, vascular cells, hematopoietic and blood cells…) from adipose tissue by any means (enzymatic or mechanical dissociation) considered as “more than minimal manipulation”.
Processing to isolate non-adipocyte or non-structural components from adipose tissue (with or without subsequent cell culture or expansion) is generally considered more than minimal manipulation. This is because the connective tissue and structural components of the adipose tissue are entirely removed from the non-adipocyte or non-structural isolates, thereby altering the original relevant characteristics relating to the tissue’s utility for reconstruction, repair, or replacement.
- Examples of minimal manipulation, cited in guidance: aliquoting, rinsing, removal of macroscopic debris, and freezing. Enzymatic or mechanical dissociation for cell isolation considered as more than minimal manipulation. Guidance use “cell isolation” term in regard to “more than minimal manipulation”. Any cell culture considered as “more than minimal manipulation” and should comply with 351 (drug) regulatory pathway.
- FDA defines homologous use of adipose tissue-derived HCT/P only if it “was is the only for the repair, reconstruction, replacement, or supplementation of a subcutaneous adipose tissue defect”. Read: injecting fragments of fat tissue subcutaneously for cosmetic purposes. Notably, even if adipose tissue used for breast plastic and augmentation by subcutaneous injection for re-shaping (structure), it is not considered as “homologous use”, since primary function of breast tissue is producing a milk.
- Adipose tissue-derived product could be exempted from “drug pathway” only if processing of autologous tissue done as “the same surgical procedure”. You can look at definition of “same surgical procedure” here. Notably, only 3 types of processing, cited by FDA would allow exemption under “same surgical procedure” – rinsing, cleansing, or sizing. The question about centrifugation seem to be resolved – apparently it could be considered as sizing. But only if whole fat tissue was centrifuged at low speed and tissue was not digested or “stem cells were not isolated” before. The question remain – couldn’t SVF be isolated by simple centrifugation (without enzymatic digestion)?
In regard to HCT/Ps from adipose tissue, we generally consider the exception in 21 CFR 1271.15(b) to apply only if the HCT/P from adipose tissue is for autologous use, is removed and implanted within a single operation or in a limited number of predetermined operations in order to achieve the intended effect, and does not undergo processing steps beyond rinsing, cleansing, or sizing.
Overall, the document provides very good clarification on some unclear issues. The guidance pretty much closes all holes, which would make you think that stromal vascular fraction (SVF) is 361 HCT/P. FDA says “it will be regulated as a drug” and there is no way around it!
My biggest concern here is the following: FDA says that (quote) “regulates HCT/Ps with a tiered, risk-based approach”. But I don’t understand how (1) auto- adipocytes for re-shaping of breast or auto- SVF to assist liposculpture within one procedure could be the same risk tier as (2) allo- SVF for stroke into the brain artery or auto- adipose MSC expanded for 3 weeks in culture for liver failure into hepatic artery. Does it look like (1) and (2) have exactly the same risks to you?
I’d like to remind you that this document is a draft and you have 90 days to submit your comments to FDA. But I don’t think by March 31, they will change their minds dramatically and it will be declared officially – autologous adipose SVF is a drug in United States!
This post is a part of series Breaking Down Fat. In this series we will talk about identification, characterization and clinical processing of potentially therapeutic cell populations from adipose tissue. We started this series in response to the growing trend of wide (mostly uncontrolled) clinical use adipose-derived cells and some controversies/ misconceptions in the field.If you would like to contribute to this series or become a sponsor, please contact us!