URJHS Volume 12

Regulation of an Emerging Medical Treatment

Caitlyn Reese
Fort Lewis College

Key Words: Stem cells, Adult stem cells, FDA regulation, Biologics, Experimental medicine, CellTex Therapeutics

Abstract

In the past decade, scientific studies have shown that adult stem cells may have the potential to treat dozens of degenerative diseases and change the future of medicine. However, some private companies have preemptively begun using adult stem cells in unregulated human trials, and the FDA has been forced to shut down several facilities across the U.S. Regulation of this new biotechnology is necessary in the interest of public safety because there is not yet enough clinical evidence to support current use of adult stem cells.

Introduction

Adult stem cells are defined as cells within a fully developed human tissue or organ that have not yet differentiated into cells with a specific function. The purpose of these cells in the body is to renew damaged or dead tissue where regeneration is continuously necessary, e.g., skin or blood. These cells have the potential to specialize into a desired function by artificial activation and subsequent implantation into a tissue where the cells can be influenced by surrounding functional cells.1 The discovery of stem cells as a potential medical treatment has invited the launch of many private companies in the U.S. within the past few years. These companies have since attempted to treat thousands of hopeful clients in so called "trials" for many illnesses including various types of blood cancer and other blood disorders, amyotrophic lateral sclerosis (ALS), type 1 diabetes, heart disease, COPD, Crohn's disease, and many other degenerative disorders.2 However, the FDA stated that the cells used in the process were artificially manipulated and therefore need to be federally regulated as a drug. Controversy began after a federal law suit against Regenerative Sciences in Broomfield, Colorado, was settled in favor of the FDA in July of 2012.3 The court granted a permanent injunction against certain treatments offered by Regenerative Sciences, which has since opened the door for further inspections into the practices of several other companies.4  In the interest of public safety, regulation of this new biotechnology is necessary because it has not been scientifically proven that adult stem cell treatments are either effective or safe. This goes ignored by private companies in the interest of profit, which is unethical.

The Procedure

Adult stem cells are regulated within section 361 of the Public Health Service Act and Title 21 of the Code of Federal Regulations (CFR) Part 1271, under the category of "human cells, tissues, and cellular and tissue-based products (HCT/Ps)."5 The basis for the FDA's recent shutdown was that harvested donor and patient cells were "more than minimally manipulated" making them a higher risk HCT/P product, and therefore the treatments must be licensed and shown to be effective and safe in a clinical setting.5(p.741) Most procedures performed in the U.S. use adipose (fat) stem cells or hematopoietic (bone marrow) stem cells for harvesting and use in the treatments.6,7 The harvesting process from bone marrow begins with administration of a chemotherapy agent such as melphalan as well as granulocyte-macrophage colony-stimulating factor (G-CSF), chemicals which cause the target stem cells in the bone marrow to migrate out into the blood where they can be collected.6(p.580) Once collected, the cells are activated into a state of proliferation using other chemotherapy agents, such as 5-Fluoruracil, before being infused into the patient.9,10 Harvesting of adipose stem cells requires that a large portion of fat be removed, broken down, and the cells then separated within a sequence of chemical solutions and growth mediums. The cells are then washed, isolated, and stored until the patient is ready for the procedure.8 Cells are then suspended in plasma growth factors and artificially activated with a special laser, before finally being infused into the patient.7(par.6) All of this artificial manipulation is the basis for the FDA's recent objection and rightfully so. The fact is that the cells are not simply removed and placed directly back into the body, in which case the cells would essentially be "personal property" of the patient; rather the cells are isolated, treated, and activated with various chemicals and procedures that are outside the scope of physiological processes. Furthermore, the processes by which the cells are collected and then activated into a state of differentiation are artificial and depend upon the use of machines or synthetic chemicals outside the body. The cells that are infused into the patient have been manipulated in a manner similar to that of the pharmaceutical components in a drug. In order to allow use of adult stem cells safely, the FDA, therefore, has the right to regulate their use, specifically as a biological drug.11  

Lack of Evidence

Another problem with these new companies selling stem cell treatments is that the procedures are not clinically proven. Most of the scientific community has questioned the ethics of these companies because there is not substantial evidence from approved clinical trials indicating that the treatments are effective. The standard routine for any new medicine is to run a "double-blind" study in which many subjects are given either the treatment in question or a placebo and where the subjects and the researchers are strictly prevented from knowing to which treatment group each subject is assigned. This double-blind protocol assures that the study results are not contaminated by patients who feel that they are recovering just because of a strong mental belief in the treatment, known by physicians as the "placebo effect." Currently, most of the adult stem cell companies administering treatments have performed no such double-blind studies. Even Dr. Jamshid Lotfi, a physician that conducted procedures at the now closed Celltex Therapeutics Company in Sugarland, Texas, admitted that there is not substantial evidence that the cells he implants have any positive effect.12 He claims that the patients he treats "act as their own control," and that he uses the way they improve to determine if the treatment is effective.12(par.10) To allow the treatment of patients with procedures that have not been sufficiently tested is at the least, unethical, if not actually harmful. Essentially, the patients in question are receiving false hope for a cure and may even believe the treatments are working when there are few valid studies showing improvements due specifically to an infusion of treated stem cells. The need for solid scientific evidence becomes even more of an imperative when treating patients suffering from terminal diseases.

Hidden Dangers

Companies such as Celltex and Regenerative Sciences do inform the patients that the procedures are not FDA approved and that results are not guaranteed in current trials.13 Lotfi of Celltex even assures patients that the infusions can't hurt, so there is no harm in trying12(par.10); however some studies have shown otherwise. The Kuopio University Hospital in Finland conducted a study on treatment safety by analyzing data from six different facilities that carry out adult stem cell treatments. The team of scientists gathered data on 1482 patients that had received treatments for various types of cancer, including Non-Hodgkin's Lymphoma (NHL), multiple myeloma (MM), breast cancer (BC), Hodgkin's lymphoma (HL), amyloidosis, and chronic lymphomatic leukemia. The study's purpose was to identify "treatment-related mortality" or "TRM" in these patients. Strict guidelines were set up to identify patients that had died due to the treatments, including death within less than 100 days. They ruled out deaths that occurred due to complications of the original disease. Of the 1482 patients that were included in the study, 42, approximately 2.8 percent, were TRMs. Of these 42 patients, 16 died from systemic infection and 29 died from organ toxicity, a complication of chemotherapy when an organ is overloaded with toxic chemicals. The resulting analyses also showed that certain patients had a greater risk of TRM depending on their diagnosis. The highest risk was in patients with amyloidosis at 24 percent, followed by those with NHL at 4.4 percent, and MM at 1.9 percent.14 Similar studies have also shown that TRM is a significant risk. A European Group for Blood Marrow and Transplantation study carried out over 12 years included 900 autoimmune disease patients treated with hematopoietic stem cells. This study showed an overall TRM of 5 percent, again with a higher risk in certain diseases, specifically multiple sclerosis, systemic sclerosis, and systemic lupus erythematosus.15 These data prove that to offer adult stem cell treatments as "harmless" is outright deceitful because there are serious risks involved. A standardized procedure with clinical data that analyzes risk factors is absolutely necessary to ensure as little risk of treatment-related mortality as possible for every patient. Of course, many of the private companies, such as CellTex, have conducted no such analyses. Both studies also showed that the potential risk for each patient can vary for each disease being treated. Every single disease that has the potential for treatment with adult stem cells needs to be studied in detail within a clinical trial, because the appropriate procedures, dosages, and risks will vary for each diagnosis. Use of each chemotherapy agent also needs to be studied and refined to further assess how much of each reagent is necessary for collection and activation of the cells, because too much of any one of these chemicals can ultimately lead to organ failure. For a company to avoid addressing such risks directly with clients and the public is not only reckless but dangerous and unacceptable.

Safety Violations

One of the risks identified in both TRM studies described above was that of systemic infection. This is one of the most obvious issues that need to be addressed. When harvesting stem cells from a person's body, either a puncture into the bone marrow is created or a site is cut open to collect fat cells and an open wound is left that needs proper care. This would be the most basic and hopefully the least likely possibility for infection because wound care should be fairly self-explanatory to a group of medical professionals. However, the cells are removed and soaked in various chemicals or exposed to mechanical manipulation, all of which must be done in an external container. Such containers have a greater potential for bacterial or fungal contamination if not properly sterilized and are likely the source of past cases of infection. The professional working with the cells would also have to be properly dressed in sterile clothing and consistently use proper sterilization techniques. What is disturbing is that many companies were not taking such precautions. When the FDA conducted an inspection of CellTex Therapeutics in Texas, a myriad of problems and safety violations were found. The observational report from the FDA included several troubling violations such as lack of standard written procedures to avoid "microbiological contamination," lack of control procedures to test the uniformity and effectiveness of cells used in the treatments, lack of quality control procedures, mislabeling of cell products, failure to keep accurate records, failure to check and maintain equipment, the use of cells believed to be unviable, and many other serious problems.16 Other companies that the FDA inspected and sanctioned recently include Regenerative Sciences in Broomfield, CO, Young Medical Spa in Landsdale, PA, and Intellicell BioSciences in New York, NY.5(p.740) In the Regenerative Sciences inspection, the FDA reported that "the laboratory did not operate in conformity with good manufacturing practices (CGMP)."17(p.4) Intellicell also did not meet CGMP regulations and, along with Young Medical Spa, was sanctioned for violating the "homologous use requirement."5(p.741) This means that donor cells were being transplanted into a tissue with a different function, which qualifies the cells as higher risk HCT/Ps under CFR Part 1271, subjecting them to regulations that require proof of safety and efficacy.5(p.741) These regulations are in place to prevent contamination of the cells and infection in the patient.5(p.740) It is quite alarming to think of the hundreds of patients that have been treated in these unacceptable environments. Not only is it unethical to offer treatment in these facilities, it should be a crime. It was a necessary step for the FDA to shut down CellTex and many other companies engaging in unsafe practices. By forcing companies to have standardized and sterile procedures, the FDA could potentially save thousands of lives, and prevent the future of stem cell treatments from being discredited by their improper use in private companies.

Cost

Prominent scientists have also questioned the ethics of the current "trials" these companies are conducting in that they lack scientific structure and because the participants are being charged tens of thousands of dollars to participate. An important standard in a double-blind study is that the subjects are not charged any money. This avoids adding a desperation placebo effect,12(par.11) enhanced by the fact that the subjects are pouring their life savings into this one treatment option—with a cost of around $7,000 per injection.12(par.8) Doug Sipp, creator of a website called the Stem Cell Treatment Monitor dispelled some of the hype about the newly formed companies.18 Sipp pointed out that there was plenty of promising research being conducted with the cells19,20,21  but that many of the current companies making use of the treatments are run by "unscrupulous characters who seek to preempt that responsible and ethical research and turn a quick buck (or several million) by using the words 'stem cells' in their advertising."18(par.3) Indeed, it is unethical to charge people to be treated with medicine that is highly experimental and that has not been adequately proven in a clinical setting. The motto "buyer beware" may come to mind, but if the treatments did not seem so sophisticated, many people would certainly shrug off these companies' advertisements as untrustworthy due to their lack of FDA approval. Yet, people are rushing in to hand over their savings, even with no guarantee. Wouldn't it be more reasonable to invest in creating FDA approved trials and treatments that could offer patients proof of a realistic recovery, without having to gamble away their hard earned money? The FDA needs to step in and force these companies to produce effective treatments that are safe and proven.

The Opposition

There are many people who feel that the FDA either does not have the jurisdiction to manage stem cell treatments or that the recent shutdowns are only acting to impede progress for an innovative new therapy.22 However, the adult stem cells being used in current treatments meet the definitions for several categories of products regulated by the FDA, including the definition for HCT/Ps."5(p.741) This category is defined as "articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient."23(p,1730) Adult stem cells certainly fit this category and also fall under the classification of "high-risk" and "nonhomologous" because they are harvested from the body, then activated and infused into a different bodily site within the patient.5(p.740) Others argue that because the cells are coming from the patients themselves, that there should be no regulation necessary.12(par.2) This argument is invalid because the cells are more than "minimally manipulated" as shown by the significant amount of manipulation within the procedures that take place outside the body that have potential for contamination. Regulated standard procedures are necessary to ensure client safety and to lower the risk of treatment-related mortalities. Still others have argued that once standardized procedures are created that will ensure safety, the companies should be allowed to reopen and conduct what are called "post-market" studies in which client data is analyzed after treatment. Such critics claim that the current shutdown is simply obstructing the progress of a valuable new medicine and a booming new industry. This is insufficient because double-blind studies would still be completely bypassed and no standardized "pre-market" clinical studies would be conducted.22(p.1297) The treatments would continue to lack reliable scientific evidence for efficacy and would prevent any refinement of different treatments for various diseases. What the public often fails to realize is that when the government steps in, it is usually for good reason. Companies such as CellTex and Regenerative Sciences were on the verge of bringing back the age of selling unapproved medical procedures to unsuspecting clients, not to mention using facilities that fail to uphold standard safety precautions. To allow such risky practices is to open up the gate for every other person with a medical background to sell anything they please and market it as effective. There are standards for drugs and biologics so as to prevent abuse and manipulation of people that are already in dire circumstances. It would not be conducive to progress to allow such people to be taken advantage of in their time of need. Regulation is the only thing protecting us from the days of "cure-all elixirs" and use of whiskey and cocaine for toothaches.

Conclusion

Adult stem cells are an amazing scientific discovery that has the potential to change the future of medicine. It is unethical, however, to jump into business of making money by treating people with experimental procedures that have yet to be supported by true scientific evidence and, furthermore, to carry out such procedures in dysfunctional facilities. The FDA has the right, even a duty, to step in and regulate these companies because they are using cell products that are significantly manipulated using strong chemical and mechanical means, not unlike other cell infusion preparations regulated by the FDA.11(par.3) To think that these procedures were being carried out without any standardized protocol or regulation is quite scary. People suffering from debilitating conditions deserve true chances at treatment that are sure to be safe and that have been clinically proven for each specific disease. To offer anything less, not to mention for copious amounts of money, is wrong.

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