Is Platelet Rich Plasma the Next Therapy to be Regulated by the FDA?

Cell based medicine is under tremendous scrutiny. Regenerative Medicine, popular with many physicians and patients because it uses autologous platelet rich plasma (PRP) for indications such as tendon and cartilage healing[1-2],[3], is under assault from regulators. While these cells have the potential to change medicine by repairing tissues or prompting tissue healing through paracrine effects[4], subtle changes to 21 CFR 1271.1 made in 2005 means that activating PRP at the bedside makes it a federally regulated drug.

If you value PRP as a medical treatment, then you need to take action. You must attend the 2nd Annual International Congress of Regenerative and Stem Cell Medicine. This conference is presented by the International Cellular Medicine Society (ICMS) and is the only meeting dedicated to bringing together physicians who are actively using cell based medical techniques to treat patients. Sign up for the Conference HERE

How did the FDA change its mandate to start regulating the practice of medicine?
The problem began in 2005, when the FDA dramatically, and quietly, changed its regulatory approach with potential to upset the usual wall between medicine and mass drug production.  Historically, the FDA has never had the power to control any aspect of the relationship between a doctor and a patient.  In 2005, the agency  made changes to the 361 Public Health Service (PHS) act to classify certain autologous cells as biologic drugs requiring pre-market, federal approval before sale in interstate commerce.[5]  Before 2005, in 21 CFR 1271 the FDA only had authority over tissue transplants, for example, where one patient's organ, tissue, or cells were transplanted to another person.  This made sense to reduce the risk of communicable disease transmission.  Prior to 2005, the agency also had the power to declare certain transplanted cells as drugs, for example someone else's cells that were mass produced in vials for mass distribution or those sent to a central processing center interstate.  However, after 2005, this same rule was applied to all human tissue.  For the first time, this gave the agency authority over the tissues in our patient's bodies used to treat your disease as part of a surgical procedure.  

How is PRP considered a drug?
21 CFR 1271.3(f)(2) defines two categories of cells to be regulated.  The cells can be either more than or less than "minimally manipulated".  If they are more than minimally manipulated, they must have drug approval status, just like a new antibiotic.  The defining line is if the processing of the autologous cells changes the "relevant biologic characteristics" of the cells.  The problem for PRP is the coagulant activation with calcium and/or thrombin commonly used by physicians prior to surgical use or injection.  Wide variations in platelet concentrations exist between patients and there are no standardized levels of calcium and thrombin for clinical application, even though it has been demonstrated that even slight alterations in dose of these activation agents can produce wide variations in platelet growth factor release and kinetics.[6]  In essence, this activation significantly alters the relevant biologic characteristics of the cells, hence making activated PRP a new drug requiring an Investigational New Drug (IND) application per 21 CFR 1271.3(f)(2).

Is this an imminent risk?
Yes. The problem with 21 CFR 1271.3(f)(2) is the assertion by FDA that certain processing steps for autologous cells somehow turns those cells into drugs.  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 mass production risk, something the agency has traditionally regulated.  Turning PRP or stem cells 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 fertility procedures?  Certain high risk surgeries?  Certain high risk surgeries involving cells?  Congress has always prohibited the agency from having any authority over the practice of medicine and as discussed, there is great societal benefit in keeping it that way. 
To illustrate the problems with regulations that turn a medical procedure into a drug, consider a recent publication showing that a routine MRI magnetic field changes the biologic characteristics of stem cells.[7]  This paper shows that a common MRI dramatically changes several important characteristics of adult stem cells such as gene expression and bone forming ability, making them "more than minimally manipulated" cells per 21 CFR 1271.3(f)(2).  If the doctor creates a dilute adult stem cell mix using a bone marrow aspirate and a bedside centrifuge, places these into a patient's spine during surgery to promote fusion, and then orders and MRI, do the stem cells used in the patient become federally regulated drugs after a routine MRI?  

What can physicians do to protect this therapy?
The first step is to join the ICMS. We are the only physician guided nonprofit organization dedicated to protecting cell based medicine. Second, attend the 2nd Annual International Congress on Regenerative and Stem Cell Medicine. At this conference, you will hear experts in the fields of PRP, BMAC and  stem cell medicine. You will also join a group of physicians and researcher who will define the future of cell based medicine.

[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] Alhadlaq, A. and J.J. Mao, Mesenchymal stem cells: isolation and therapeutics. Stem Cells Dev, 2004. 13(4): p. 436-48.
[5] Halme, D.G. and D.A. Kessler, FDA regulation of stem-cell-based therapies. N Engl J Med, 2006. 355(16): p. 1730-5.
[6] 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.
[7] 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.