Physicians using FDA-compliant therapies (BMC and PRP are the only ones currently) are frustrated by having to compete with over-the-line, lunch-sponsoring, media-savvy, modern day snake oil sales organizations who say whatever it will take to charge patients for receiving miracle cures. Some physicians wonder why it takes the FDA so long to deal with these “bad actors”. My response is that although the FDA might appear to have superpowers as a Federal agency, in fact they have to follow the laws enacted by Congress and their associated polices when dealing with targeted entities. Consequently, it can take a while for the Agency to bring the hammer down on a non-compliant company or physician.
One of the best illustrations of the process the FDA must go through in dealing with potentially non-compliant entities was recently illustrated by the case of RTI Surgical, who received a Warning Letter from the FDA last November 8, 2017. I am sure you missed it, what with all of the hoopla surrounding the subsequent release by the FDA of the Same Surgical Procedure Exception Guidance and the Minimal Manipulation and Homologous Use Guidance the following week. However, RTI Surgical has been on my radar from the first time they received an Untitled Letter way back on September 26, 2014.
RTI Surgical, Inc. (Alachua, FL) sells a product whose trade name was redacted in the Warning Letter, but which had been identified in the Untitled Letter as “map3™Chips Allograft” product. The Untitled Letter is available by clicking here. Back then the product was described by the FDA in the Untitled Letter as being:
“…a scaffold composed of demineralized bone matrix and cortical cancellous chips, as well as cultured bone marrow-derived multipotent adult progenitor cells, cryopreserved in a suspension. All these constituents are processed from the same human donor. The final packaged product includes the demineralized bone matrix, cortical cancellous chips and the multipotent adult progenitor cells.”
The FDA’s primary objection to the product as sold by RTI Surgical back then was that RTI used culture expansion of bone marrow taken from the same cadaver that also was the source of the other bony bits included in a kit. The FDA stated that including cells obtained by culture expansion exceeded the minimal manipulation standard listed in 1271.10(a)(1), rendering the product a biological drug.
As one might expect for a company whose showcase product was the target of an Untitled Letter, the company began an elaborate and prolonged dance with the FDA. Following an on-site FDA audit conducted in April 2017, the FDA issued a Warning Letter late last year. They confirmed that RTI has continued to “…manufacture the (b)(4), which fails to meet all the criteria in 21 CFR 1271.10(a)…Specifically, your processing of the (b)(4)…alters the relevant biological characteristics of the cells.”
Although the details relating to the cellular nature of this component of the non-compliant product have been redacted in the Warning Letter, the Agency indicates that the “redacted” material is composed of viable, donor-derived cells, whose sole therapeutic benefit is associated with their metabolic activity. If you look at the language of the Untitled Letter and the verbiage in the Warning Letter it would seem to suggest that RTI continued to culture bone marrow-derived cells and to provide them as a cryopreserved suspension of, presumably, viable cells.
Thus, the FDA stated once again in their 2017 Warning Letter that materials were being processed in a way that exceeded the minimal manipulation standard, as well as having donor-derived cells present in a product intended for use in unrelated recipients that depended on their metabolic activity to provide their primary, therapeutic function. So, nothing new. Except that it now is November 2017—more than three years after the initial Untitled Letter was sent to RTI Surgical.
What is so instructive about the Warning Letter is that the FDA provided a historical review of the interactions with RTI:
- Audit conducted in April 2014.
- Untitled Letter issued on September 26, 2014.
- There was a meeting with FDA on December 11, 2014.
- FDA sent a written response to RTI’s legal counsel on April 2, 2015, in which they confirmed the substance of the Untitled Letter.
- FDA sent out a reminder on April 24, 2015 that RTI could file a Request for Designation to get a “formal” decision on the offending cellular component’s status.
- RTI filed an “informal submission” to the Office of Combination Products (OCP) at some point.
- The OCP sent out a letter on August 12, 2016 in which, based on the information RTI had provided, they provided a preliminary finding that the product was a biological drug and not regulated solely under 1271.
The next milestone is the FDA conducting its on-site audit in April 2017.
The sequence of events and the time lags involved as shown above illustrate how a company is able to work the regulatory process to its financial benefit. The FDA just can’t squash non-compliant companies like RTI, but instead are forced by law to move in a deliberate and deliberative manner. Of course, if a company’s products represent an immediate threat to the health and welfare of the public, the FDA can move in and take over an entity overnight. Most of the companies who would seem to me to be selling non-compliant products do so with good legal advice, which enables them to continue making money for several years. Hence the frustration of physicians who want to play by the rules.