What does homologous use mean?
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):
“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):
2012
- 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.
2010
- 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.
2008
- 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.
2006
- 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.
2002
- 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.
Very helpful and informative discussion. Thank you.
Interesting discussions.
From a clinical perspective, the use of the word “Homologous” is relatively inert in today’s practice. Inert is defined as devoid of purpose.
Just from the perspective utilizing non-manipulated SVF cells for multiple clinical uses, these cells are vascular derived cells. They reside in every blood vessel and organ of the body and are activated upon injury. FDA has not in any meaningful way addressed the characterization of this cell population and other components located within this regenerative population. They have consistently deployed a simple ‘cut and paste” standard response to industry participants that is sadly lacking any scientific validity. Deer in headlights is the position they are currently in.
Homologous and autologous use are two separate considerations in the US regulations. 21CFR1271.10(a) says:
“An HCT/P is regulated solely under section 361 of the PHS Act and the regulations in this part if it meets all of the following criteria:
(1) The HCT/P is minimally manipulated;
(2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;
(3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and
(4) Either: (i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or (ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and: (a) Is for autologous use; (b) Is for allogeneic use in a first-degree or second-degree blood relative; or (c) Is for reproductive use.”
In other words, only cell-based products that meet ALL of (1)-(4) are exempt from the FDA approval process. Each factor is a separate consideration, with homologous use being only one factor.
Thus, the first bullet under 2012 in the blog post doesn’t say anything about whether that product is for homologous use. Instead, it says it’s not autologous or from a 1st or 2nd degree relative (and obviously not for reproductive use), so FDA considers it a biological drug.
Please note that I’m not defending FDA’s (really Congress’) rules here. Just trying to clarify what they actually say (insofar as I understand them, anyway).
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It seems strange that the FDA says a stem cell product cannot be a 361 HCT/P if it is dependent upon the metabolic activity of living cells for its primary function, even though one would assume that in its homologous state in vivo it must and can only function due to the metabolic activity of its living cells. That is, dead stem cells really do not do any good.
It is also somewhat difficult to follow how MSC isolated from different sources (bone marrow, fat, etc.) are not considered equivalent in nature even though most phenotypic and functional data would say it is. There are slight differences but no more than expected with MSC isolated from the same source but from different individuals.
Great Summary of FDA’s learning curve.
Pericytes from adipose tissue are vascular supporting cells. If used in fat grafting for cell enhanced fat transfer (CEFT) for example, how is that not homologous use? Seems to me the literature supports such use, not only in CEFT procedures but in many others when inosculation of transplanted tissues is desired. Further, it could be argued that those same cells can be used in areas where vascularity is desired. Critical limb ischemia is only one example there are many others.
The definition of “homologous” came from the issue of safety upon donation from donor to recipient (read citation from 21 CFR 1271.3(c) at the top of the post). It can not be applied to autologous applications, unless FDA implies the authority over the body of the each and every living individual.
Nathan, you raise a singularly important point. I had hoped (against the odds) that the FDA would consider the issue of “homologous vs nonhomologous” to be outside of the set of “autologous”. (Excuse the mathematics, I know of no other way to be precise.)
But, going to the “Tissue Reference Group (TRG) at the FDA” link above, we find:
“A solubilized collagen product prepared from autologous tissue would not be considered an HCT/P because secreted or extracted human products, including collagen, is not an HCT/P, as defined under 21 CFR 1271.3(d).”
So, I fear that the FDA does presume to have “the authority over the body of the each and every living individual.”
The FDA has shown that it does not filter the homologous vs non-homologous definitions depending on autologous vs allogeneic status.
To me, from a common sense perspective, homologous use is indeed independent of whether a product is autologous or not. For example, it’s easy to see how even in an autologous context a product could be used in very non-homologous manners (e.g. fat stem cells from person A for treating MS in person A is both autologous and non-homologous).
Finally, I don’t see why this active model of FDA regulation via the “homologous use” definition including autologous products necessitates that the FDA have authority over all of us as you suggest. That seems like a scare tactic. Once stem cells are removed from our bodies and especially if they are manipulated in a lab setting, they are not “us” anymore. They are a biologics product.
Now it sounds even more absurdic. If I spill on the finger cut, my saliva is considered a drug. Should I ask for permission?
It’s not a scare tactic, it’s common sense and a history of the FDA authorisation to regulate recipient-donor relationships, that what HCT/P is for.
Could you define the bological purpose of mononuclear cells, including MSC, from bone marrow or other tissue? Could you bring evidence that these cells, being relocated into another “non homologous” tissue, change its original functions? Unless there are clear answers, entire discussion is purely speculative and baseless.
But the FDA does make “homologous” a function of whether or not the biological material is “autologous” — as can be seen by the many references to “allogenic” and “blood relatives” and so forth in examples that you yourself cite.
If my recollection of history is correct, homology is definitely about comparison between species. Richard Dawkins discusses homology in “The Greatest Show on Earth”. FDA is distorting the word in ways that I don’t understand (I bet no one else does either). In it’s original form, homology is Heaviside but once a determination of being homologous is made the resulting relationship between species definitely involves a transformation (eg D’Arcy Thompson 1917) that could be well approximated as being mathematically continuous.
The FDA version of “homologous” is sounding more and more like governmental “doublespeak”.
I’m not engaging in “scare tactics”, I’m point out the fundamental errors, the FDA is creating arbitrary switches based upon a metric that they neither quantify nor properly define.
I did a little searching. It seems that others (presumably specialists in their field) are calling for some of the issues I raise to be addressed:
http://onlinelibrary.wiley.com/doi/10.1002/bies.200900175/abstract;jsessionid=5C9CFC85D340599A984376090F3F53B1.d03t02
The bottom line is that the FDA has NOT defined homologous. Instead, the FDA prefers to, from time to time, make rulings about that which it considers to be non-homologous…. This method of doing business is at best arbitrary and at worst it destroys scientific reasoning with extreme prejudice.
If homologous is a scientifically meaningful metric, then first we should at least examine whether or not it is really of a Heaviside step function form. Different cells under different circumstances might be homologous to various degrees.
Regulators certainly like to create arbitrary switches (think about +/- a day making the difference the difference between consenting sex and statutory rape). But scientists are NOT supposed to think a certain way just because regulators find it convenient.
Thanks, Paul. This is the best, clearest, most succinct discussion of the question (with respect to stem cells) I’ve seen anywhere, ever. And it leads to the (I think) important question of whether one can even think of a realistic therapeutic use of stem cells – embryonic, adult, or IPS – that actually could qualify as homologous.
It sounds to me like the only stem cell therapies that might qualify as “homologous” would involve putting autologous cells back into the same tissue they were taken from — i.e. expanding bone marrow MSCs and then injecting them back into the bone, or maybe using adipose MSCs to reconstruct the breast after mastectomy? It seems very hard to prove that the cells are only going to serve the same function they would normally serve in vivo, especially when the extent of their normal in vivo functions is still unclear!
Thanks for the comment, Bonnie.
It’s a seemingly strict standard indeed, but less strict than I first imagined before I did more research on it recently.
Administration of the product to the same tissue from which it was derived is not required.
For example, some people make the argument that using adipose or marrow MSCs for joint repair is homologous use since the joint normally contains MSC-like cells/MSCs and they are very important for cartilage homeostasis.
I appreciate that, Bill. It’s a very important issue, but still seems nebulous and confusing. This could be helped by more clear guidance from the FDA as well as more discussion on this issue amongst all of us in the stem cell field.
As to your question, it’s a good one. Many are arguing homologous use, but it’s hard to know what the FDA will decide in each case.