Last week, FDA published a January 3, 2018 Warning Letter issued to American CryoStem for marketing Atcell—an adipose tissue derived stem cell product—without FDA approval and for several drug current Good Manufacturing Practice (GMP) violations observed during FDA’s  July 2017 inspection of American CryoStem’s New Jersey facility.  In a related press release, the agency cited the company as the latest in a series of stepped up enforcement activities to implement its comprehensive policy framework released in November 2017.

The Warning Letter and press release provide insight as to how FDA will apply its November 2017 guidance on “minimal manipulation” and “homologous use” for human cell and tissue products (HCT/Ps), including the 36-month enforcement discretion period for autologous products that do not raise “potential significant safety concerns.”

As described below, FDA found that the product did not qualify to be regulated only as an HCT/P because it did not meet the criteria for homologous use or minimal manipulation, which means that the product generally cannot be marketed without an approved Biologics License Application (BLA).  However, more significant is FDA’s determination, reflected in the Warning Letter, that even though the product was intended for autologous use, it does not qualify for enforcement discretion under the guidance because it raises “potential significant safety concerns.”  The risk determination in the letter identifies: (1) the intended, non-homologous use for serious or life-threatening diseases; (2) the more than minimal manipulation during processing that alters the original relevant characteristics of the adipose tissue; and (3) the higher-risk routes of administration, which “could cause a range of adverse events, from infections to death.”  In addition, the GMP deviations relating to sterility assurance, described below, likely amplified the agency’s concern about the risks associated with the routes of administration.

The agency determined that Atcell is not only an HCT/P subject to section 361 of the Public Health Service Act (42 USC 264), but also constitutes a biological product requiring licensure because it fails to meet the criteria 21 CFR 1271.10(a). Among FDA’s reasons for that determination were the following:

• The manufacturer’s objective intent, as reflected by the labeling, advertising or other indications, was to treat patients for a variety of serious or life-threatening diseases or conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis (MS), and anoxic brain injury.  The product is administered to patients intravenously, intrathecally (injection or infusion), or by aerosol inhalation.  The agency determined that Atcell failed to meet the “homologous use” requirement (21 CFR 1271.10(a)(2)) because the product is used to treat a variety of diseases and conditions, and, therefore, is not intended to perform the same basic function(s) of adipose tissue “(e.g., to provide cushioning and support).”
• Atcell also did not meet the “minimal manipulation” requirement (21 CFR 1271.10(a)(1)) because of the adipose tissue, which FDA characterizes as structural tissue, is processed into stromal vascular fraction (SVF) and expanded in cell culture, and both of these processing steps alter the original structural characteristics of the adipose tissue relating to reconstruction, repair, or replacement.

The Warning Letter further alleges that the company’s GMP violations, some of which raised microbiological safety concerns, posed additional significant health risks to patients.  At the close of FDA’s July 2017 inspection, the agency issued a Form FDA 483 (the 483), which documented a number of observations involving GMP deviations and objectionable conditions.  The observations made by FDA during its inspection included:

• Batches were manufactured and distributed without a validated aseptic process.
• The cleaning and disinfection processes in aseptic processing areas were not validated.
• The company did not perform environmental or personnel monitoring as assurance to prevent contamination.
• Release testing was not performed for each batch of product to assure proper identity, strength, quality, and purity prior to release and distribution.
• No procedures were established for sampling and testing drug components and containers and closures (e.g., vials).
• The company did not have a written testing program to determine appropriate storage conditions and expiration dates.
• The company failed to use appropriate air filtration systems for production areas. The biological safety cabinets (BSC) used to fill Atcell were located in an uncontrolled production area.
• There was no separation or other controls to prevent contamination or mix-ups from the company’s research and development activities, which were occurring adjacent to the aseptic processing of Atcell.

In issuing the Warning Letter, FDA concluded that the company’s responses to the 483 were “inadequate, incomplete or lack sufficient detail,” and the “Corrective Action Plan” and written procedures submitted in response to the 483 were inadequate.  The agency stated that the company failed to acknowledge that a BLA license is required to lawfully market the product, or an IND must be in effect to distribute the product for clinical use.  In its press release, FDA also requested that healthcare professionals and consumers report any adverse events related to treatments involving Atcell.

The Warning Letter provides insights into how and when FDA will implement the 36-month enforcement discretion period for autologous products that do not raise “potential significant safety concerns,” as announced in its November 2017 guidance.  For example, mirroring the guidance, the Warning Letter emphasized that the product’s routes of administration – intravenous, intrathecal (injection or infusion into the central nervous system), and aerosol inhalation – are associated with higher risk.

Also like the guidance, the Warning Letter stressed that American CryoStem aggressively promotes Atcell for a variety of non-homologous serious and/or life-threatening diseases and conditions.  FDA called out a public interview statement by the company’s Chief Operating Officer that breakthrough technologies like Atcell “are about sending cells the same way you send any other drug to a doctor.”  In addition, FDA asserted the position it took in the guidance that the agency may pre-determine the original relevant characteristics of a particular tissue.  Here, FDA continued to maintain that to qualify for regulation solely as an HCT/P, adipose may be used only as a structural tissue, such as for cushioning and support; by extracting SVF, American CryoStem, in FDA’s view, automatically disqualified Atcell for such treatment.

The message from this Warning Letter appears to be that FDA will apply its enforcement discretion for 36 months judiciously.  Manufacturers whose HCT/Ps have more than one factor that FDA will consider in evaluating if the product raises “potential significant safety concerns” would be wise to do everything possible to minimize risks from factors within their control.  Closely scrutinizing promotional material for statements implying non-homologous intended use or stressing other higher-risk features is one such exercise that appears to be increasingly prudent.  Ensuring adequate control of over manufacturing processes clearly is another.

We will continue to closely monitor and report on FDA’s continued focus on stem cell technologies and any further developments on related enforcement activities.