The definition of “minimal manipulation” of cells is rearing its head again as the FDA has sent RTI Surgical Inc. (RTI) a letter regarding the company’s map3 cellular allogeneic bone graft.
FDA Challenges RTI Over “Minimal Manipulation”
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Secondary
“Altering Characteristics”
An October 9, 2014 letter sent by Mary A. Malarkey, Director Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research said the company’s processing “does not meet the definition of minimal manipulation for cells or nonstructural tissues.” Specifically, the FDA says the company’s process “alters the relevant biological characteristics of the cells.”
map3 Chips Allograft
map3 Chips Allograft consists of 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 says the multipotent adult progenitor cells included as a component in map3 “do not meet all of the criteria in 21 CFR 1271.1 O(a).”
Failure to Perform Tests
Additionally, Malarkey’s letter said it appears that RTI is not performing all of the necessary donor testing for the bone marrow component of the product. “You must test a specimen from the donor of viable, leukocyte-rich cells or tissue for evidence of infection due to cytomegalovirus (CMV), to adequately and appropriately reduce the risk of transmission.”
Company Response
Company President and CEO Brian Hutchison said in a press release that the company will work “diligently” to fully address any concerns or questions the FDA has. “We have carefully considered the regulatory pathway of this important implant from the beginning of development, and we continue to be confident in the science behind our map3 allograft.”
According to the statement, the company has submitted an initial response to the FDA letter, and is preparing a “comprehensive package of data to address the Agency’s comments and provide clarifying information regarding the technical components of the implant processing. We believe we understand the basis for questions and points raised by FDA in the letter and at this time, we feel confident that in developing map3 and processing of map3, we properly considered the relevant regulatory questions. Additionally, the company has removed the website pending thorough review and revisions as needed.”
The website had included information that the multipotent adult progenitor cells, “provide a unique set of angiogenic cytokines that affect the regulation and differentiation of vascular endothelial cells, thus promoting the growth of new blood vessels.” Therefore, argues the FDA, the multipotent adult progenitor cells are dependent on the metabolic activity of living cells for their primary function. “This cellular product is not intended for autologous use or allogeneic use in a first or second degree blood relative; accordingly it does not meet the criterion in 21 CFR.”
The company has 32 other orthobiologic products on its website.
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Discussion
This is a fascinating development. In my practice we've seen similar outcomes with the revised protocol. The key differentiator seems to be patient selection criteria. Has anyone else noticed the correlation with BMI thresholds?
Great point. I'd push back slightly on the conclusion, the sample size in the cited study is too small to draw population-level inferences. That said, the directional signal is compelling and worth a larger RCT.
We implemented a similar approach last year. Early results are promising but we're still gathering 12-month follow-up data. Happy to share our protocol if anyone is interested.
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