Navigating the arena of clinical use of a biologic such as stem cells or differentiated cells made from stem cells can be challenging.
There are many important issues including what defines “minimal manipulation” of biologics such as cells.
One particular issue that is critically important and has drawn less attention than it deserves is “homologous use”. It also happens to be one of the more confusing issues in the stem cell field.
An official definition of homologous use as it pertains to HCT/Ps is found in 21 CFR 1271.3(c):
“Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.”
In regular Engilsh, what the heck does “homologous use” mean?
“Homologous use” means that a human cellular or tissue product (HCT/P) is used clinically in a manner that is essentially the same as the natural endogenous function that it performed.
For example for use of stem cells to qualify as “homologous use” they must be used clinically to do what they do naturally in an endogenous setting rather than some other job that nature never intended them to do. This is important from a safety perspective. It also poses big challenges as of course us scientists come up with nifty innovative ways to use stem cells to potentially treat patients, but it seems to me that innovation predisposes to a non-homologous use definition.
Homologous use can be confusing and this is not just a case of stem cell semantics. There are huge real world implications of ‘homologous use’.
Operationally, “homologous use” as a definition is vitally important for stem cell clinical practitioners to understand because non-homologous use of stem cells by definition makes those stem cells a biological drug (351) rather than simply an HCT/P (361).
As you can see, “homologous use” is a very challenging definition at times to clearly understand and evaluate in the real world for various stem cell-based products.
If the FDA would more clearly define homologous use in layman’s terms it would be very helpful for the field in an operational sense and providing more real world type of examples for the stem cell field would go a long way to helping avoid confusion.
It is nonetheless extremely helpful to look at the FDA record in this regard as actions speak louder than words. Although admittedly in this case the FDA’s actions consist of words.
At the bottom of this post, I’ve listed some very specific, relevant FDA definitions of non-homologous use organized by date. Here are some take home messages/predictions from that FDA list:
- The standard for homologous use is very strict and in general the FDA most likely will not define even modestly different uses as homologous.
- Using adipose MSCs, for example, to treat conditions such as MS or for most cosmetic procedures is almost certainly non-homologous.
- There is unlikely to be any way to ever use stromal vascular fraction (SVF) in a homologous fashion. (Note, in addition, that the FDA already has defined SVF as a drug in at least two cases, and to my knowledge has never defined its use as homologous use).
- The use of bone marrow MSCs for treatment of neurological conditions is almost certainly non-homologous.
A significant number of point-of-care stem cell businesses are using stem cells in what the FDA is almost certain to define as a non-homologous fashion, but claim homologous use and 361 status for their stem cell products. You folks had better talk to the FDA stat.
Here’s the abbreviated list (emphasis mine) of FDA recommendation on homologous use. For whatever reason many examples relate to bone. My list is gleaned from the material on this issue from Tissue Reference Group (TRG) at the FDA (if you click on the link you can see the full list):
- Adipose-derived mesenchymal stem cells product used as a bone graft substitute for the repair, replacement, or reconstruction of musculoskeletal defects is not a 361 HCT/P because it is dependent upon the metabolic activity of living cells for its primary function and is not intended for autologous use or allogeneic use in a first or second degree blood relative.
- A human amniotic membrane product used for bone tissue replacement to support bone regeneration following surgery to repair or replace bone defects is non-homologous use and therefore is not a 361 HCT/P.
- Allogeneic, processed acellular dermis, rolled or folded to serve as a structural support and placed in defects following breast conservation treatment, is non-homologous use and therefore is not a 361 HCT/P.
- Allogeneic adipose-derived stem cells seeded onto a bone scaffold for filling, augmenting or repair of pathologically or surgically created bony voids is considered a biological product, and not a 361 HCT/P, because the product is dependent upon the metabolic activity of living, unrelated allogeneic cells for its primary function.
- Allogeneic placental-derived extracellular matrix and hematopoietic progenitor cells contained in the placental vasculature of the same donor used for repair, replacement and/or reconstruction of bone defects is considered a biological product, and not a 361 HCT/P because of the non-homologous use, combination with another article and a systemic effect.
- Umbilical cord stem cells treated with enzyme to increase engraftment are considered biological products and are subject to INDs and BLAs because this processing constitutes more than minimal manipulation.
- Allogeneic processed acellular dermis advertised for glenoid coverage, protection or cushioning would not be considered a 361 HCT/P because these would be non-homologous uses.
- Hematopoietic stem cells from first and second degree blood relatives for induction of tumor regression in cancer patients are considered to be biological products because this intended use is considered a non-homologous use.