In my last post, I continued my discussion about Dr. Paul Knoepfler’s “out there” heavily biased blog post on the alleged evils of stem cell clinic’s patient treatments with “…non-FDA approved offerings.” Today, I am going to discuss the importance of two recently issued FDA Guidances.
For some of us, November 16, 2017 will be remembered as the day the hammer came down on all of the “…manufacturers, healthcare providers, and other interested persons…” who have been making money off of non-compliant regenerative therapies, either donor-derived or autologous. What made that day so important? The FDA issued two Guidances relating to 21 CFR 1271:
“Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-based Products: Minimal Manipulation and Homologous Use”
“Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception”
These Guidances have been a long time coming, since the FDA originally issued three draft guidances in 2014 (one in October and the other two late in December) and the remaining one in 2015. So, why are there only two final Guidances out of four draft Guidances? It seems like the FDA wanted to make it easier on us, so they cut out the draft Guidance on adipose tissue, by transferring most of its key examples into the guidance on minimal manipulation and homologous use. They also combined the separate draft guidances on minimal manipulation and homologous use into a single guidance. Only the original draft guidance on the same surgical procedure exception made it from draft to final, more or less intact.
I will expand on the good, the bad and the puzzling elements from my point-of-view in the next few posts, but I would like to summarize what I think the regenerative landscape looks like in terms of winners and losers.
Physicians who use compliant regenerative therapies:
- Amniotic fluid without cells
- Blood-derived preparations (e.g., PRP, PPP)
- Bone marrow aspirate
Physicians who use non-compliant regenerative therapies:
- Adipose tissue-derived materials obtained by enzymatic digestion
- Adipose tissue-derived materials obtained by mechanical disruption
- Amniotic fluid with cells
- Cord blood derived materials (non-autologous treatments)
- Micronized tissues, including placental-derived, cartilage-derived, etc.
- Cultured cells obtained from any tissue
While I will go into more detail in subsequent posts, I would like to cover a few points that I gleaned from my quick read of the two guidances.
A recurring impression I picked up from the Guidances was that the FDA appears to have decided to leave nothing to the imagination of those among us who previously had contributed to the free-for-all atmosphere surrounding regenerative therapies in the USA. For example, the FDA cited “healthcare providers” explicitly in the introductory section of the Guidance on Minimal Manipulation and Homologous Use. I suspect they did that to make sure that physicians who previously thought they could use a white lab coat like some kind of deflector shield to fend off the FDA now clearly understand that they too are subject to the dictates of 1271 as illustrated in the Guidances.
The FDA also directly addressed the issue of multi-functional tissues and how they would regulate them. For example, they acknowledged that adipose tissue has a variety of physiological functions in addition to cushioning organs and other internal structures. They acknowledged that structural tissues have cells in them, including stem and progenitor cells. But there is no joy for the dozens of speakers at the two-day hoedown the FDA hosted last September who gave impassioned presentations on the need for the FDA to recognize the multi-functional complexity of adipose tissue. The FDA essentially said that there are two kinds of tissue in the body: structural tissues like adipose and bone; and cells/non-structural tissue like cord blood or parathyroid tissue. Consequently, adipose tissue will be considered from this point forward as a structural tissue—whether you like it or not.
The one bit of joy that the FDA provided to the plastic surgery community was their reversal of an utterly crazy statement in the draft guidance on adipose tissue that indicated it was a non-homologous use to augment or reconstruct breast tissue with autologous fat grafts. When I first wrote about this ridiculous declaration nearly three years ago, I predicted that the FDA would come to their senses and find a way to consider this critical treatment as a homologous use. So, the fans of using adipose tissue at point-of-care weren’t completely shut out.
Earlier in the post I had made a comment about the Same Surgical Procedure Exception Guidance surviving more or less intact from the draft version. What I meant by that is that the impact of the section in 21 CFR 1271 that is covered by this Guidance, 1271.15, still hangs on something the FDA calls “such HCT/P”. What is curious, though, is the FDA decided to give us a way to streamline our thinking about 1271, in which we are instructed to think about whether we are working with a material that meets the FDA’s definition of “such HCT/P”, and if we do, we don’t need to register with the FDA or ponder whether the material meets the four criteria outlined in 1271.10(a). While this would seem to give a lot of latitude to the folks who work with autologous materials at point-of-care (POC), in fact this is one of the most restrictive aspects of the two guidances.
Finally, there is a somewhat ominous comment the FDA included in the Introduction to the Minimal Manipulation and Homologous Use Guidance, which reads as follows:
“…we are informing manufacturers, healthcare providers, and other interested persons that over the next 36 months, we intend to exercise enforcement discretion under limited conditions with respect to the investigational new drug (IND) application and premarket approval (biologics license application (BLA)) requirements, for certain HCT/Ps.”
Keep in mind that I am not a regulatory attorney, but my read of this statement is that the FDA intends to check anyone who currently is making an HCT/P for use at POC for their compliance with 1271, as explored in these Guidances, and if they are found wanting, the FDA will squeeze them to get on the right path (e.g., IND and BLA), or force them to stop what they are doing. Notice it says, “…for certain HCT/Ps”, which I suspect mostly includes networks of physicians or individual clinics that engage in SVFing. I also hope that the amniotic fluid product hawkers will get the boom lowered on them. But, most importantly, the FDA seems poised to deal more actively with healthcare providers. The thoughts the FDA published in these Guidances are not enforceable. However, in my opinion having the FDA highlight “healthcare providers” in the above passage doesn’t bode well for the physicians engaged in non-compliant regenerative medical therapies.
As promised earlier, I will be expanding on some of the topics I briefly covered in this post, starting with the Same Surgical Procedure Exception Guidance in the next post.