Editorial: Dr. Christopher Centeno’s FDA Critique

Dr. Christopher CentenoBio: Dr. Centeno is board certified in Physical Medicine and Rehabilitation and Interventional Pain Management. He is one of a handful of practicing physicians with clinical experience in the use of culture expanded mesenchymal stem cells for the treatment of musculoskeletal disorders. He has published numerous research studies on the use of adult stem cells and diagnosis and treatment of traumatic injury.

Is Activated Platelet Rich Plasma or Bone Marrow Aspirate a Drug to be Regulated by FDA?

Cellular medicine is a growing trend in orthopedic care, with many physicians using autologous platelet rich plasma (PRP) for indications such as tendon and cartilage healing.[1-2] [3]  In addition, many spine surgeons have begun using bone marrow aspirate concentrate (BMAC) to enhance spinal fusion. Physicians have traditionally used 510K cleared medical devices (bedside centrifuges) to prepare PRP and BMAC. However, what these same surgeons may not be aware of is that subtle changes to the federal drug code (21 CFR 1271.1) made in 2004, when applied to activated PRP and certain uses of BMAC, purport to make these autologous substances federally regulated drugs requiring an extensive and costly Biologics License Application (BLA). 

The problem began in 2004, when the Food and Drug Administration (FDA) dramatically, and quietly, changed its regulatory approach with potential to upset the traditional wall between surgical care and drug regulation. Historically, the FDA has never had the power to control any aspect of the relationship between a doctor and a patient.[4-6] In 2004, the agency made changes to the 361 Public Health Service Act (PHSA) act to classify certain autologous cells as biologic drugs requiring pre-market, federal approval before interstate distribution.[7] Before these changes in 2004, the FDA only had authority over allogeneic tissue transplants. This portion of the 1271 regulation serves the important function of preventing communicable disease transmission from donor to recipient. However, after these 2004 changes, the tissue transplant regulations were altered by the agency to also apply to all human tissue, with caveats for certain autologous tissues being regulated the same as mass produced drugs.  For the first time, this gave the FDA the authority over certain aspects of surgical procedures. 

21 CFR 1271.1-1271.3 defines two categories of cells to be regulated, which the agency call Human Cells Tissues or Products (HCT/P’s). The HCT/P’s can be either more than or less than “minimally manipulated.” If they are more than minimally manipulated, they must first have premarket drug approval, just like a new antibiotic. If they are less than minimally manipulated, they can be treated as the practice of medicine. The dividing line between HCT/P’s treated like drugs and those left largely unregulated is if the “processing” of the autologous cells changes their “relevant biologic characteristics.” While PRP that is simply used “as is” from a 510K cleared device is less than minimally manipulated and left unregulated, PRP that is coagulant activated with calcium and/or thrombin falls into a different category. This is because recent research demonstrates that even slight alterations in the dose of these activation agents can produce wide variations in platelet growth factor release and kinetics.[8]  This means activation significantly alters the relevant biologic characteristics of the platelets (growth factor release) and thus qualifies PRP as “more than minimally manipulated”, hence making activated PRP a new drug requiring a BLA new drug application per 21 CFR 1271. In addition, in its own documents, the FDA clearly refers to the term “activation” as constituting more than minimal manipulation.[9]

BMAC suffers from the same premarket drug approval problems when it’s mixed with other substances that would alter the biologic characteristics of the key cells in the mix, namely mesenchymal stem cells (MSC’s) that promote bony fusion.[10] Take for example a surgeon’s use of a bedside centrifuge to process a bone marrow aspirate commonly utilized to promote spinal fusion. Many manufacturers recommend activating the BMAC with coagulant agents such as thrombin before surgical use. However, coagulant activation makes the BMAC a drug based on data showing that it changes the biologic characteristics of MSC’s within the mix.[11-13] In addition, from multiple publications, it’s clear that many of the biologic characteristics of MSC’s are altered by the commercially available BMP’s that many surgeons also use simultaneously with BMAC to promote bone growth.[14-15]

Are these autologous cells drugs? We believe there are significant problems with this regulatory paradigm. For example, consider a recent publication showing that a routine MRI magnetic field changes the biologic characteristics of stem cells.[16] This paper shows that a common MRI techniques dramatically change the gene expression and bone forming ability of MSC’s, making them “more than minimally manipulated” cells per 21 CFR 1271.3(f)(2). If a surgeon creates BMAC using a bone marrow aspirate and a bedside centrifuge, places these into a patient’s spine during surgery to promote fusion (not mixing them with another agent), and then orders an MRI for another reason, do the stem cells used in the patient become federally regulated drugs after a routine MRI? 

Are activated PRP or BMAC + Coagulants +/- BMP’s new federally regulated drugs? Will federal agents be knocking on your O.R. door anytime soon or requiring a one million dollar upgrade to your operating room to make it follow current Good Manufacturing Practices (drug factory guidelines)? In summary, the problem with 21 CFR 1271 is the assertion by FDA that certain processing steps for autologous cells makes those cells federally regulated drugs and that it’s rules apply to physicians practicing medicine. Any surgical or medical procedure by definition is the practice of medicine representing a one-on-one risk to the patient, not a one-on-many, drug mass production risk, something the agency has traditionally regulated. Turning autologous PRP or BMAC into drugs is not supported by any common sense argument. Furthermore, the agency’s decision to insert itself into the practice of medicine by creating these regulations, sets a dangerous precedent. Where does this line get moved to in the future? Do certain compounded drugs get assigned a drug manufacture risk? Certain high risk surgeries? Certain high risk surgeries involving cells or drugs? Perhaps the judge in U.S. v. Evers (United States v. Evers, 453 F. Supp. 1141 (M.D. Ala. 1978)) put it best when he opined “Congress did not intend the Food and Drug Administration to interfere with medical practice as between the physician and the patient.” Surgeons and their patients have a great interest in keeping it that way.

1. Anitua, E., et al., Autologous fibrin matrices: a potential source of biological mediators that modulate tendon cell activities. J Biomed Mater Res A, 2006. 77(2): p. 285-93.
2. Sanchez, M., et al., Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc, 2003. 35(10): p. 1648-52.
3. Lacci, K.M. and A. Dardik, Platelet-rich plasma: support for its use in wound healing. Yale J Biol Med, 2010. 83(1): p. 1-9.
4. People v. Privitera. California Reporter, 1977. 141: p. 764-774.
5. Use of Approved Drugs for Unlabeled Indications, D.o.H.a.H. Services, Editor. 1982.
6. Chaney v. Heckler, in 718 F.2d. 1983, District of Columbia Cir. p. 1174-1177.
7. Halme, D.G. and D.A. Kessler, FDA regulation of stem-cell-based therapies. N Engl J Med, 2006. 355(16): p. 1730-5.
8. Martineau, I., E. Lacoste, and G. Gagnon, Effects of calcium and thrombin on growth factor release from platelet concentrates: kinetics and regulation of endothelial cell proliferation. Biomaterials, 2004. 25(18): p. 4489-502.
9. USFDA, Establishment Registration and Listing for Manufacturers of Human Cellular and Tissue-Based Products, CBER, Editor. 1988.
10. Panetta, N.J., et al., Mesenchymal cells for skeletal tissue engineering. Panminerva Med, 2009. 51(1): p. 25-41.
11. Wautier, F., et al., Regulation of nestin expression by thrombin and cell density in cultures of bone mesenchymal stem cells and radial glial cells. BMC Neurosci, 2007. 8: p. 104.
12. Catelas, I., et al., Human mesenchymal stem cell proliferation and osteogenic differentiation in fibrin gels in vitro. Tissue Eng, 2006. 12(8): p. 2385-96.
13. Huang, C.Y., M.A. Deitzer, and H.S. Cheung, Effects of fibrinolytic inhibitors on chondrogenesis of bone-marrow derived mesenchymal stem cells in fibrin gels. Biomech Model Mechanobiol, 2007. 6(1-2): p. 5-11.
14. Kim, H.J. and G.I. Im, Combination of transforming growth factor-beta2 and bone morphogenetic protein 7 enhances chondrogenesis from adipose tissue-derived mesenchymal stem cells. Tissue Eng Part A, 2009. 15(7): p. 1543-51.
15. Shea, C.M., et al., BMP treatment of C3H10T1/2 mesenchymal stem cells induces both chondrogenesis and osteogenesis. J Cell Biochem, 2003. 90(6): p. 1112-27.
16. Schafer, R., et al., Functional investigations on human mesenchymal stem cells exposed to magnetic fields and labeled with clinically approved iron nanoparticles. BMC Cell Biol, 2010. 11(1): p. 22.