Prior to the FDA issuing the final versions of two Guidances (see my views and links below)
- Winners and Losers Emerge at Long Last After the FDA Issues Two Guidances
- Same Surgical Procedure Exception Guidance: What Does “Such HCT/P” Really Mean? Part One
- Same Surgical Procedure Exception Guidance: What Does “Such HCT/P” Really Mean? Part Two
physicians ignored FDA’s prohibition against their use of processed adipose tissue to treat musculoskeletal pathologies with enzymatic, ultrasonic or subsonic disruption methods being used in clinics to produce non-compliant preparations. The regulation in 21 CFR 1271 outlining these limitations was finalized in the mid-2000s. Physicians ignored the obvious and established adipose tissue processing protocols in their clinics to treat patients with SVF (stromal vascular fraction; made by enzymatic digestion of adipose tissue) or FB (fuzz balls from mechanical disruption). I suspect the blatant disregard for 1271 moved the FDA to issue a draft Guidance on the do’s and don’ts for working with adipose tissue at the end of 2014, which was also ignored by many physicians everywhere.
Since Guidances issued by the FDA clearly indicate that they are not enforceable, and I have never seen the FDA use a Guidance in a warning letter, I guess physicians thought they didn’t have much to worry about and went on their merry way digesting and disrupting patients’ adipose tissue hither and yon. I hope physicians who ignored the language of 1271 and the advice the FDA provided in its draft Guidance on adipose tissue have returned to reality, and will stop engaging in their non-compliant creation of unapproved drugs following the issuing of the two final Guidances on November 16th.
Although the FDA eliminated the draft Guidance on adipose tissue, it loaded up the final Guidances with plenty of references to handling adipose tissue and information of interest to SVFing and FBing physicians and networks of clinics. I will group the comments for review, starting with the following (with edits):
Same Surgical Procedure Exception:
Example 7-1 indicates that “…lipoaspirate is centrifuged to facilitate removal of debris and extracellular fluid…The adipose tissue remains “such HCT/P” because nothing else is added to the adipose tissue, only minor handling is performed…”
Example 7-2 indicates that “(a)dipose tissue is recovered by tumescent liposuction and processed (e.g., enzymatic digestion, mechanical disruption) to isolate cellular components…Cell isolation would typically cause the adipose tissue to no longer be “such HCT/P” and the establishment would generally not be considered to qualify for the exception…”
Minimal Manipulation and Homologous Use:
“…the determination of whether an HCT/P is minimally manipulated is based on the effect of manufacturing on the original relevant characteristics of the HCT/P as the HCT/P exists in the donor and not based on the intended use of the HCT/P in the recipient.”
“HCT/Ps may perform multiple functions and FDA acknowledges that structural tissue contains cells…(but) HCT/Ps are considered either structural tissues or cells/nonstructural tissues.”
“Adipose tissue is typically defined as a connective tissue…While adipose tissue has multiple functions, because it is predominantly composed of adipocytes and surrounding connective tissues that provide cushioning and support to the body, FDA considers adipose tissue to be a structural tissue…”
“To evaluate whether processing of adipose tissue would meet the regulatory definition of minimal manipulation, you should consider whether the processing alters the original relevant characteristics of the adipose tissue relating to its utility to provide cushioning and support.”
“…to assess whether a processing step alters the original relevant characteristics of a structural tissue relating to its utility for reconstruction, repair, or replacement, you should consider the effects of the processing on the properties that contribute to the specific tissue’s function in the donor…”
In this set of statements, the FDA provides insight into how the Agency views the bits and pieces in the human body that manufacturers and physicians collect for creating HCT/Ps. Most importantly, the FDA has established a processing standard for physicians only, who definitely will want to meet the “such HCT/P” requirements in order to avoid registering with the FDA. The key phrase for understanding how the exception in 1271.15(b) applies to adipose tissue is “…only minor handling is performed…” from Example 7-1 above. This language means that if you look sideways at autologous adipose tissue you most likely will exceed the standard for “such HCT/P” and will be forced to register.
Non-physician manufacturers already had to register and list their HCT/Ps, so the FDA thought it helpful to provide examples with other tissues that track what I have shown above for adipose tissue. The fact that the FDA acknowledged that tissues can have multiple functions and are composed of cells reflects an attempt to provide more context to explain the regulatory framework. Thus, adipose tissue is considered to be a structural tissue only. Furthermore, the state of adipose tissue in the donor limits the type of processing it can undergo, since a manufacturer can’t alter the “original relevant characteristics of a structural tissue…” in order to produce the HCT/P for implantation.
I will continue my review in the next post of relevant statements pulled from the two Guidances to highlight the current thinking of the FDA on how healthcare professionals should be approaching their use of autologous adipose tissue in their clinics.