The U.S. Food and Drug Administration posted a warning letter issued to American CryoStem Corporation of Monmouth Junction, New Jersey, and its Chairman/Chief Executive Officer, John S. Arnone, for marketing an adipose-derived stem cell product without FDA approval and for significant deviations from current good manufacturing practice requirements, including some that raise potential significant safety concerns, putting patients at risk.
“As part of our comprehensive policy framework for the efficient development and regulation of cell-based regenerative medicine, we’re going to be stepping up enforcement activities against those who manufacture and market products in ways that put patients at risk,” said FDA Commissioner Scott Gottlieb, M.D. “We see great promise from the field of cell-based regenerative medicine, but there are also novel risks. Our goal is to implement our new policy framework in a way that helps this promising field advance, while making sure that we address issues that can put patients at risk. It also means taking an efficient, risk-based approach to making sure that products undergoing more than minimal manipulation, which makes them subject to FDA’s review and approval, and particularly products intended to treat serious and/or life-threatening disease or conditions, must prove that they deliver the benefits they’re promising to patients.”
The FDA recently inspected American CryoStem and found that American CryoStem was receiving and processing adipose tissue into a product called Atcell and then marketing such product without the required FDA approval. Though the product is intended for autologous use (use in the same individual from which it was recovered) the manner in which it is being processed involves more than minimal manipulation of the adipose tissue. These manufacturing steps alter the original relevant characteristics of the tissue and have the potential to introduce contamination of the product, creating risks of harm to patients. As a result, under existing law, the product is required to undergo FDA review to ensure the treatment is safe and effective.
Under the FDA’s risk-based enforcement strategy, the product also creates concerns as a result of the way it is being administered into patients’ bodies and how it is promoted for the treatment of serious or life-threatening diseases or conditions. The unapproved product, Atcell, is being distributed directly to physicians to treat patients for a variety of serious or life-threatening diseases or conditions, including anoxic brain injury (caused by lack of oxygen), Parkinson’s disease, amyotrophic lateral sclerosis (ALS), stroke, and multiple sclerosis (MS). Physicians are directed by the company to administer Atcell by various routes of administration, including intravenously, intrathecally (injection or infusion into the central nervous system) and by aerosol inhalation.
Compounding these risks, the FDA’s inspection also uncovered evidence of significant deviations from current good manufacturing practice requirements in the manufacture of Atcell that pose significant additional risks, such as potentially being contaminated with microorganisms or having other serious product quality defects. Specific deviations included unvalidated processes, an inadequately controlled environment, lack of control of components used in production, and a lack of sufficient and validated product testing.
“The use of Atcell raises potential significant safety concerns, due in part to the fact that there is little basis on which to predict how the product will perform in a patient,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “In addition, this product may also cause harm to patients who may put their trust in an unproven therapy and make the decision to delay or discontinue medical treatments proven to be safe and effective.”
American CryoStem was issued a list of inspectional observations (FDA Form 483) at the conclusion of the inspection. The firm has responded to those observations; however, the FDA has found that the response inadequately addresses the observations and fails to recognize that to lawfully market Atcell, a valid biologics license must be in effect. While in the development stage, an investigational new drug application, or IND, must be in effect to lawfully distribute Atcell for clinical use.
The FDA has requested a response from American CryoStem, within 15 working days, that details how the violations noted in the warning letter will be corrected. Companies that do not correct violations may be subject to enforcement action such as seizure, injunction, and/or prosecution.
As highlighted last month with the release of the FDA’s comprehensive regenerative medicine policy framework, the FDA’s final guidance (Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use) clarified the FDA’s interpretation of “minimal manipulation” and “homologous use.” These two concepts are defined in current regulations to establish the legal threshold for when a product is subject to the FDA’s premarket approval requirements. For those products that are subject to such oversight under existing law, the FDA intends to apply a risk-based approach to enforcement, taking into account how products are being administered as well as the diseases and conditions for which they are intended to be used. The FDA does not intend to exercise such enforcement discretion for those products whose use poses a potential significant safety concern. This was the case with Atcell.
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