The FDA issued two Guidances on November 16, 2017; one on homologous use and minimal manipulation, and the other on the Same Surgical Procedure Exception in 21 CFR 1271.15. See, “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception” for the text of the Guidance. Also, see the previous post: “Winners and Losers Emerge at Long Last After the FDA Issues Two Guidances” for my preliminary thoughts on the two Guidances issued on November 16th.
Let’s start with some background on 1271.15(b). The FDA can’t regulate the practice of medicine, but can regulate manufacturers of medically relevant materials. So, in view of what the FDA has defined to be HCT/Ps (see 21 CFR 1271.3 for definitions); It became clear that there were long-standing examples of surgeons using bits and pieces from a patient’s body to aid in a repair of a pathology that fell within the scope of the definition of an HCT/P. For example, vascular surgeons have for a long time used veins from patients (e.g., saphenous vein) in a coronary by-pass procedure. The surgeon cuts out a portion of a vein from the leg, trims it up and then sutures it into place in the patient’s heart.
Technically, the vascular surgeon has manufactured an HCT/P (the trimmed-up vein) and returned it to the patient during the same surgical procedure. However, the FDA acknowledged that this type of process would not create a risk of communicable disease or safety risk greater than the surgery itself, so the FDA allowed surgeons to be surgeons and wrote 1271.15(b), indicating that surgeons didn’t need to register with the FDA to perform this type of practice of medicine.
Notice that I referred to the risk potential associated with a procedure to obtain and process an HCT/P for subsequent return to the patient in a timely manner. Risk, therefore, forms the basis for the FDA to define the very few types of processes that meet the “such HCT/P” requirement. Here is the language taken from 1271.15 (with edits):
- 1271.15 Are there any exceptions from the requirements of this part?
(b) You are not required to comply with the requirements of this part if you are an establishment that removes HCT/P’s from an individual and implants such HCT/P’s into the same individual during the same surgical procedure.
Now, the FDA explains that in order to meet the essential features of this section of 1271, you need to do the following, as outlined in the Guidance (with edits):
Answer to Q2: For the exception to apply, an establishment must:
a. Remove and implant the HCT/Ps into the same individual from whom they were removed (autologous use);
b. Implant the HCT/Ps within the same surgical procedure; and
c. The HCT/Ps remain “such HCT/Ps;” they are in their original form.
The elements specified in parts a and b of the Q2 answer are pretty straight forward. However, the concept of “such HCT/Ps” required additional discussion from the FDA in the Guidance. And for good reason, since, in my opinion, this notion of “such HCT/Ps” is the critical controlling element that the FDA will rely on to put a damper on the free-for-all currently underway in the regenerative medicine arena.
The FDA begins its screw tightening in the answer to Q3 in the Guidance (with edits and highlights):
Answer to Q3: An HCT/P remains “such HCT/P” when it is in its original form. Generally, the only processing steps that will allow an HCT/P to remain “such HCT/P” are rinsing, cleansing, sizing, and shaping.
Further, as described in the answer to Q1, the assessment of whether an HCT/P is “such HCT/P” under 21 CFR 1271.15(b) is different from the assessment of whether an HCT/P is minimally manipulated under 21 CFR 1271.10(a). Accordingly, even processing that may be considered minimal manipulation within 21 CFR 1271.10(a), will typically cause the HCT/P to no longer be “such HCT/P” under 21 CFR 1271.15(b), if the processing is not limited to rinsing, cleansing, sizing, or shaping.
As highlighted, the FDA has created a dual standard for what meets the minimal manipulation requirement of 1271.10(a)(1) and the processing the FDA considers acceptable to produce “such HCT/P” as specified in 1271.15(b). Obviously, this will create a fair amount of confusion. However, returning to the vascular surgeon example above, the FDA considers the creation of a vascular graft to meet the standard of minimal manipulation that still results in “such HCT/P”, since all that has happened is that the vein was adjusted a bit (the “sizing” element highlighted above), but otherwise remains in its original form.
Anticipating this confusion to some extent, the FDA provided an answer to its Q7 in which they describe in Example 7-1 that if you just centrifuge a lipoaspirate to “…facilitate removal of debris and extracellular fluid…” it remains “such HCT/P”, so you can use it to your heart’s content and remain compliant, allowing physicians to invoke the exception outlined in 1271.15(b). The FDA further states that “(t)he adipose tissue remains “such HCT/P” because nothing else is added to the adipose tissue, only minor handling is performed, and the adipose tissue retains its original form…” If I may sum up: the FDA is telling us that after obtaining a lipoaspirate, about all you can do is wash the tissue and reduce the fluid volume if you want to meet the “such HCT/P” standard.
But the FDA goes for the adipose jugular by describing in Example 7-2 that physicians manipulating the lipoaspirate so that it is “…processed … to isolate cellular components…” would not be compliant with the same surgical procedure exception. And you might say, “Big Deal!” Except the FDA has announced elsewhere that healthcare providers need to pay heed to this Guidance and, potentially, its companion on minimal manipulation and homologous use. So, if a physician works with a patient’s fat tissue in a manner that doesn’t meet the requirement of producing “such HCT/P”, they can’t invoke the exception in 1271.15(b). The FDA indicated in Example 7-2 that processing of adipose tissue by “…enzymatic digestion, mechanical disruption…” rises above the manipulation acceptable to the guardians of “such HCT/P” and “…the establishment would generally not be considered to qualify for the exception…”.
Not qualifying for the exception in 1271.15(b) means that the physician and/or clinic would need to register. And once you register (or sometimes even before you register), the FDA will come to audit your operation. Several audits of SVFing clinics haven’t gone so well for the clinics. For example, Dr. Ginois, ex-Cell Surgical Network owner of three SVFing clinics, received a Warning Letter on December 30, 2015, while the recently minted PhD, Kristin Comella, of the US Stem Cell Clinic, received a scathing Warning Letter from the FDA on August 24th. I have reviewed the gory details and implications of her Warning Letter in recent posts: “FDA Hammers A Flaunter of the Rules Against Making and Treating Patients with Fat Tissue-derived Stem Cells – Part One.”
I will finish up my review of the Same Surgical Procedure Exception Guidance in the next post, with a focus on the curious way the FDA wants physicians to deal with 1271.15(b), which is the one really new feature of the final Guidance.