A lot of folks think that following the rules laid down by the FDA can be a challenge, due to the uncertainty of words used in 21 CFR 1271 or alleged ambiguities in the Agency’s guidances issued to assist stakeholders to follow the right regulatory path. But, in the case of American CryoStem Corporation (ACSC; Princeton, NJ ), it would seem that the corporation didn’t pay much attention to a number of examples the FDA has provided through the years about potential violations of provisions of 1271 before opening their doors.
Based on the information contained in the FDA’s Warning Letter issued to ACSC on January 3, 2018, it would appear that ACSC receives a patient’s adipose tissue in their laboratory facility in order to produce SVF (stromal vascular fraction, a single cell suspension obtained most often by enzymatic digestion of adipose tissue), which the FDA indicates is placed into culture, expanded, frozen down and returned to the physician who ordered the procedure so the patient can be treated in the USA.
Here are the things that are non-compliant as listed in the above brief description of their services:
- Autologously-derived cells are being cultured, frozen down and then returned to a physician for treating the patient.
- The patient-derived adipose tissue is being digested by enzymes to produce SVF.
- The processing is being performed at a centralized laboratory.
Of the three items, only Item 3 presents a bit of a new wrinkle in how the FDA viewed ACSC’s commercial operation compared to past 1271 offenders like Intellicell Corp or CellTex. Warning letters were issued by the FDA to both organizations back in 2012. Yes, 2012.
There are some common themes in the three Warning Letters the FDA has issued:
- Fat tissue is received from physicians and processed with enzymes (ACSC and CellTex) or mechanically disrupted (Intellicell) to produce SVF.
- ACSC and CellTex culture the SVF material, thereby expanding the number of so-called mesenchymal stem cells (MSCs).
- Intellicell just returned the ultrasonically cavitated adipose preparation, which I call fuzz balls, but the FDA referred to as SVF.
- The FDA cited each company for an overly broad statement of treatment utility, including treatments provided by IV administration.
The ACSC Warning Letter cites the same precedents the FDA previously cited in dealing with Intellicell and CellTex. For example, the FDA pointed out to ACSC that digesting adipose tissue alters its original relevant characteristics as a structural tissue, which means the processing is above minimal manipulation—in violation of 1271.10(a)(1). Compounding that sin, the FDA further indicated that ACSC culturing of the SVF to expand cells also is in violation of the minimal manipulation rule. This parallels exactly the regulatory focus in the CellTex Warning Letter. Intellicell was cited just for altering the original relevant characteristics of the adipose tissue, since they didn’t offer a culturing option, so they still ran afoul of 1271.10(a)(1).
All three companies were cited for violation of the homologous use rule [1271.10(a)(2)], since the companies cited the therapeutic utility of the preparations in treating a wide variety of pathologic conditions. For example, according to the FDA, ACSC had records indicating that the preparations they generated would be used to treat “anoxic brain injury, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), stroke and multiple sclerosis”, among other conditions. Needless to say, the FDA thinks that the fat-derived preparations provided by the companies had nothing to do with the “basic function or functions of adipose tissue (e.g., to provide cushioning and support)”, which means the treatments aren’t homologous use.
However, as indicated in Item 3 above, the FDA stated in the ACSC Warning Letter that ACSC didn’t qualify for any of the exceptions outlined in 1271.15, which contains a subsection (15b) covering the same surgical procedure exception that allows physicians/facilities meeting certain requirements to avoid having to register with the FDA. This point wasn’t raised with either Intellicell or CellTex, but I had long thought that a centralized laboratory facility for processing adipose tissue would not be allowed to operate, since a centralized facility where adipose tissue is received one day, processed and the resulting SVF shipped out the next day fails to meet the conditions of the same surgical procedure exception outlined in 1271.15(b).
From a quick look at the ACSC website, it would appear they operate several laboratories in Hong Kong, Tokyo and southern China, for which they claim “Our technologies allow shipment of any processed cellular sample stored in any of our laboratories to treatment facilities anywhere in the world where cellular therapy is approved.” Notice the caveat “…where cellular therapy is approved.” How did they not figure out that SVF and cultured SVF preparations weren’t approved in the US before they started offering that service domestically? As it stands, it seems to me they just wanted to see how long they could operate a non-compliant adipose processing/culturing laboratory in the USA before changing their business model to compete with CellTex.