Today’s post will launch a short series on healthcare innovations. The regenerative sciences and regenerative medicine field are themselves innovations. Moreover, they are at a critical point for the introduction of healthcare innovations. I would like to focus on empirical and precision regenerative healthcare as major healthcare innovations. Both empirical and precision medicine can lead to dramatic advancements in the field of regenerative medicine. Additionally, empirical and precision medicine both impact the future of medical device and pharmaceutical industries and those industries have impacts on regenerative medicine.
REGENERATIVE MEDICINE AS INNOVATIVE MEDICINE:
On November 16, 2017 Dr. Scott Gottlieb, then FDA Commissioner, issued a statement relating to regenerative medicine and the FDA’s new comprehensive regulatory policy approach for facilitating innovative products in the field. In the statement, Dr. Gottlieb said, “[o]ne of the most promising fields of science is the area of cell-based therapies and their use in regenerative medicine… We’re bearing witness to the beginning of a paradigm shift in the practice of medicine.”(1) There is much to unpack in these positive statements, but today the brief focus is on two things. First, it is important to keep in mind the distinction between the cell-based therapies and the practice of regenerative medicine. Secondly, regenerative medicine is a paradigm shift and is leading to innovative products to improve human health. As such, regenerative medicine fits within innovative healthcare. A future blog will discuss regulatory innovations that impact products and tools used in the regenerative medicine space.
The various cellular, or acellular, technologies derived from autologous sources and used as injections have involved physicians delivering these products blinded, for the most part, to the various products’ compositions. That is, patients have had their blood, bone marrow, and/or adipose tissue drawn/aspirated; centrifuged; volume reduced; and then injected without testing to know what the initial draw/aspiration contained and what was contained in the final product injected into the patient. The effect of this is that physicians have been hoping for consistent results in products that have significant patient-to-patient variability without having data to demonstrate what the variability is. Year-after-year, conference-after-conference, I and several other thought leaders have lectured on the need to change this scenario. I was proud to help Harvest Terumo build and maintain a large database of baseline (blood draw or marrow aspiration) and post-centrifugation cell analyses; however, none of these data were tied to patient outcomes. As such, the database failed to help address this problem in the field.
As an example of the problem, I typically point to platelet-rich plasma (PRP) and the normal range of platelet counts in whole blood; the normal platelet count in whole blood has a tremendous range (roughly 100,000-300,000 platelets per microliter). If physicians are unaware that their patient has 100,000 platelets per microliter and simply withdraws blood and centrifuges it (most benchtop systems provide a roughly a 3- to 7-times baseline in platelet count in the final product) the physician is also unaware of what could exist in a final product. In this scenario, this would mean that a final 5x product has only 500,000 platelets per microliter. It has been demonstrated with in vitro and in vivo studies that an ideal platelet count is between 1-2 million platelets per microliter in PRP.(2-4) Moreover, it was shown that to be considered an effective PRP with consistent successful clinical outcomes, PRP needed to have at least 1 million platelets per microliter.(4) In other words, physicians have been treating patients with “PRP” that may not actually be PRP for many patients because it could be well below 1 million platelets per microliter. This scenario should have been considered unacceptable to physicians, patients, regulatory bodies, and medical boards. The published literature on PRP has often not included platelet counts (baseline and post-centrifugation), as such, it is difficult to assess results of patient outcomes in such studies. It would be unknown if non-responders were the result of “PRP” that was severely underpowered (with respect to platelet or cell counts) or if PRP was truly ineffective for the pathology being investigated because it was adequately powered from a biologic perspective. As an example, “PRP” with 500,000 platelets per microliter functioned only as well as platelet-poor plasma in endothelial cell proliferation assays.(3)
In that same statement from Dr. Gottlieb, he does include additional information about making deceptive claims to patients and other actions that jeopardize “the legitimacy and advancement of the entire field.” While many physicians are working diligently within the field of regenerative medicine, care must be taken to ensure that the products being offered to patients truly meet standards that can be supported with scientific data. Without testing and documenting the products, physicians may be unknowingly misrepresenting the product being injected into the patient. A product with half of the platelets required to meet the minimum platelet count for consistent successful clinical outcomes should probably not be marketed as PRP.
It is a major problem for physicians to inject products while blinded to the product’s composition. This problem is easily addressed with an inexpensive and rapid test that uses a small sample of the baseline and final product. Moreover, if for example, it is found that a patient has low platelet counts in the baseline, physicians could consider additional volume reduction to boost platelet count per microliter in the product being injected. As large data are acquired that connect product characterization and analysis with patient demographics, pathologies, and outcomes, the regenerative medicine field will be able to ascertain what effective therapies exist for various pathologies and begin to identify and assess true responders and non-responders (empirical medicine). This allows for generating product and practice standards. As responders/non-responders are investigated, the field may also find there is/are biomarker(s) that may have a role(s) in the response rate of patients. Such research requires product sampling, banking, tracking patient outcomes, tying outcomes and product characterization together, and probably investigating the samples in greater detail to reveal any potential differences between responders and non-responders.
EMPIRICAL MEDICINE AND PRECISION MEDICINE AS HEALTHCARE INNOVATIONS IN REGENERATIVE MEDICINE:
Between intuitive medicine and precision medicine is empirical medicine (Fig 1). “The practice of empirical medicine occurs when a field has progressed into an era of ‘pattern recognition’ – when correlations between actions and outcomes are consistent enough that results can be predicted in probabilistic terms” (p. 45).(5) As large data are compiled, analyzed, and published, the field will advance into empirical medicine and after that, precision medicine can be developed. The first goal should be to characterize the biologics used in all procedures in regenerative medicine. This is a necessary step in developing empirical medicine. Precision medicine operating without an empirical foundation would be returning to a system of physicians practicing blindly (with little or no peer-reviewed publications on to base clinical decision making) and something for which we should all have an aversion as it is contrary to evidence-based medicine and empirical foundations. The ability to precisely diagnose the conditions being treated in regenerative medicine exists. The field now needs to precisely measure the products being used by regenerative medicine physicians in the treatment of patients. Lastly, by incorporating product characterization, physicians are also able to document the therapies utilized and also incorporate those data into patient charts rather than simply relying on the manufacturers marketing materials stating that the system products 3-7 times baseline in platelets or nucleated cells.
A major innovation in healthcare is the growing trend of personalized and precision medicine. Precision medicine will change the pharmaceutical world as volumes per compound will have to decrease dramatically. While cellular therapy products that meet Public Health Service Act 361 according to the requirements set forth in 21 Code of Federal Regulations 1271.10(6) are not regulated as pharmaceuticals (drugs), it should be obvious to see how testing of baseline blood or marrow allows physicians to create a precision medicine approach to patients undergoing therapy with these cellular therapy tools. Easily obtained data can help physicians ensure the products they inject into patients actually meet the existing and forthcoming data available for when products are effective in various pathologies and patient populations. Even more, physicians could calculate how to reduce volumes to meet specific product characterization goals. What has often been referred to as “hyperconcentration” (volume reduction greater than typical for the system being utilized) will increase the number of platelets per microliter in PRP. Hyperconcentration could potentially have other consequences if the volume is reduced greatly (e.g., various cell populations might be eliminated or dramatically reduced and that could impact PRP efficacy). However, without testing and tracking these potential data points, it remains unknown. Precision medicine transforms the field from intuitive medicine (using therapies with unknown efficacies) and then allows physicians to tailor products to individuals based upon empirical medicine. Precision medicine should not precede empirical medicine, rather precision medicine should flow from empirical medicine.
We are at an exciting time in medicine and the fields of regenerative sciences and regenerative medicine continue to grow. However, great care must be exercised to grow these fields well. Regenerative medicine decision making should be based upon peer-reviewed publications that have solid empirical data. It should no longer be tolerated to have publications without cellular characterization data on the products incorporated and physicians should no longer be satisfied injecting products for which they are unaware of even those most basic composition and characterization data.
Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D. on FDA’s comprehensive new policy approach to facilitating the development of innovative regenerative medicine products to improve human health. Nov 16, 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm585342.htm Accessed April 3, 2019.
Giusti I, Rughetti A, D’Ascenzo S, et al. (2009). Identification of an optimal concentration of platelet gel for promoting angiogenesis in human endothelial cells. Transfusion;49(4):771-8.
Kevy SV, Jacobson MS, and Mandle R. (2011). Defining the Concentration and Composition of Platelet-Rich Plasma (PRP). Lecture September 15, 2011.
Marx RE, Carlson ER, Eichstaedt RM, et al. (1998). Platelet-rich plasma: Growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod;85(6):638-46
Christensen CM, Grossman JR, and Hwang J. (2017). The Innovator’s Prescription: A Disruptive Solution for Health Care. McGraw Hill: New York, NY
US FDA. Code of Federal Regulations Title 21 Part 1271.10. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=1271.10 Accessed April 27, 2019.