In the previous two posts (Part One and Part Two), I have considered implications of what it means to have exosomes present in donor-derived amniotic fluid used for therapy. The conclusion I reached is that there is a huge void in what we know about exosomes found in amniotic fluid, so it puzzles me why everyone seems to think they are a great therapeutic agent, based apparently on nothing but hope. And then there are the potential and serious issues with exosomes being able to carry cargo that includes prions (the causative agent for neurodegenerative diseases) and viral particles.
Just so you don’t think I am making too much of the possibility that bad things can happen with donor-derived tissue, I call your attention to the recent report that four recipients of organs from a donor who had undiagnosed breast cancer, went on to develop metastatic cancer, from which three of the recipients died. I don’t want to slam the door on using exosomes found in donor tissue, but without a demonstrated benefit I am not sure the juice is worth the squeeze of exposure to viruses and prions, no matter how unlikely.
In addition to the aforementioned issues with the donor-derived nature of amniotic fluid, there is potentially another issue with amniotic fluid used for therapy, based on the presence of exosomes. I began to contemplate this issue when I reviewed the Minimal Manipulation and Homologous Use (MM/HU) Guidance the FDA issued last November concerning the regulatory status of amniotic fluid. As I mentioned previously (Post dated 91118), the FDA considers amniotic fluid to be a secretion, as indicated in this excerpt from their MM/HU Guidance:
Secreted body fluids (e.g., amniotic fluid) are generally not considered HCT/Ps.18 Cells from secreted body fluids are generally considered HCT/Ps, and the definition of minimal manipulation for cells or nonstructural tissues would apply.
To save you the trouble of looking up what Footnote 18 says:
18 21 CFR 1271.3(d) states, “…The following articles are not considered HCT/Ps:…(3) secreted or extracted human products such as milk, collagen, and cell factors, except that semen is considered an HCT/P”.
So, amniotic fluid without cells (and no micronized tissue, either) is not considered to be an HCT/P, because the FDA calls it a secretion. However, the cells found in amniotic fluid are “…generally considered HCT/Ps…”. Seems straight forward, huh? Not really, so I will explore several aspects of the current regulatory approach to amniotic fluid used for therapy, and how exosomes might change the situation.
Current Regulatory Approach to Amniotic Fluid
Although the FDA clearly states that amniotic fluid without cells is not an HCT/P, I am pretty sure you can’t harvest amniotic fluid without recovering any cells that are present, along with secretions like “cell factors” and my favorite, meconium. So, is raw amniotic fluid an HCT/P to begin with, but reverts to being a non-HCT/P when the manufacturer removes the cells? It isn’t obvious if that is how the FDA treats raw amniotic fluid and a final product of amniotic fluid without cells. However, I suspect the FDA will continue to require testing of all donor-derived materials, including amniotic fluid used for therapy. Subsequently, if the amniotic fluid is filtered to remove cells prior to sale, it might qualify as a secretion, thereby avoiding a designation as a biological drug.
Do Exosomes in Amniotic Fluid Alter Its Regulatory Status?
While the raw amniotic fluid probably will be tested as currently mandated for HCT/Ps, what about the exosomes that we know are present in products composed of amniotic fluid? One could argue that exosomes are just “cell factors”, since like a protein secreted from a cell, exosomes are released by cells. But, whereas the protein is itself the functional factor, we know from published reports that exosomes contain biologically-active materials, including proteins, but also mRNA and miRNA, among other bio-active components. I described the major components found as “cargo” in exosomes in Part One of this series.
Thus, I am left wondering if it is appropriate to deal with exosomes as a simple fluid secretion. I would argue that because they carry genetic material that has been shown to be active in recipient cells (see Part One and Part Two for links to articles), exosomes aren’t `361 category material, but rather are biological drugs.
The FDA has stated in 21 CFR 1271.10(a)(4) that HCT/Ps need to satisfy the following in order to be considered a `361 HCT/P:
(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.
Obviously, if the HCT/P is used in an autologous manner, there is no issue. However, commercially-available amniotic fluid used as therapy isn’t autologous, and since it most likely contains exosomes, I contend it isn’t just a secretion. There are several relevant elements to keep in mind:
- The FDA has indicated that the primary function of an HCT/P implant can be linked to the metabolism of viable cells.
- The Agency made the following statement in the comments discussion for 21 CFR 1271 when it was first promulgated back on January 19, 2001:
“…an HCT/P that either has systemic effect or depends upon the metabolic activity of living cells for its primary function would not be appropriately regulated solely under section 361 of the PHS Act, and therefore will be regulated as a drug, device, and/or biological product.” (FR 66(13): 5459)
- An example of an HCT/P with a systemic effect is an implant of pancreatic islet cells, which the FDA says influences organs and tissues throughout the body by the secretion of insulin (FR 66(13): 5459).
Thus, there are a couple of issues that need to be considered to try to sort out if exosomes transform a secretion like amniotic fluid used for therapy into a biological drug. Can amniotic therapy used in humans be considered as a strictly local therapy, or is there a potential for a systemic effect? The other question concerns the meaning of the phrase “metabolic activity of living cells”, and does this require the presence of the viable cells in the HCT/P, or can a biologically active material like exosomes serve as a proxy for the cells?
These two questions will be examined in the next post.