Stem cells have been an endless source of fascination and controversy since Dolly the sheep was cloned in 1996. This month’s announcement of a cloned human embryo from a single skin cell  came on the heels of Sir John B. Gurdon and Dr. Shinya Yamanaka’s receipt of the 2012 Nobel for Physiology and Medicine for their work with induced pluripotent stem cells. Pluripotent stem cells can be embryonic or induced. Embryonic stem cells (ESCs) can generally be obtained from human embryos or by cloning embryos through somatic cell nuclear transfer (SCNT), as was done for Dolly. Gurdon and Yamanaka demonstrated that pluripotent cells may also be formed by reprogramming adult cells to an embryonic state, resulting in induced pluripotent stem (iPS) cells without having to use eggs or cloning, or destroy embryos. However derived, pluripotent cells are capable of differentiating into virtually any cell type in the human body. This imbues them with great promise for scientific breakthroughs and medical advances, but also raises serious ethical, legal and safety concerns about their use.
Less controversial are “multipotent” adult stem cells (ASCs) which do not involve embryos or raise as many safety concerns as pluripotent cells. ASCs are found throughout the body. Their ability to differentiate is more limited than pluripotent cells but is vast nonetheless. The NIH’s clinicaltrials.gov site lists some 4500 ASC trials as compared with 27 for embryonic stem cells and 21 for induced pluripotent stem cells. Recent announcements of new stem cell treatments usually involve ASCs, such as last month’s news that a toddler born without a trachea received a new one made from her own adult stem cells. It is therefore no surprise that ASCs have captured the attention of researchers, investors, physicians, patients and – increasingly – regulators, both here and abroad.
A growing number of physicians routinely offer treatments involving ASCs to their patients which can be performed in their offices. Autologous adult stem cells, used to treat a variety of conditions, are harvested from the patient, processed, and returned to the same patient. It is no surprise that moving ASCs from laboratories to physician offices raises complex questions of law. We consider one of the more pressing ones: to what extent can the FDA regulate a physician’s ability to treat a patient with that patient’s own stem cells? In the coming months, the D.C. Circuit Court of Appeals will hear oral arguments on this very issue in United States v. Regenerative Sciences.
The Regenerative Sciences case originated in Colorado where Christopher J. Centeno, M.D. and John R. Schultz, M.D. practicing jointly through the Centeno-Schultz Clinic (the Clinic), developed and used the “RegenxxTM Procedure” (the Procedure) to treat joint, muscle, bone and related conditions. Drs. Centeno and Schultz are majority shareholders in Regenerative Sciences (Regenerative) which owns the Procedure, licenses it exclusively to the Clinic, and provided laboratory services as part of the Clinic’s use of the Procedure to treat patients. The Procedure involved taking blood and bone marrow samples from the patient at the Clinic; transporting them several miles to Regenerative where ASCs were isolated and cultured to “expand” or produce more cells; transporting them to the Colorado Genetics Laboratory for visual inspection to confirm the absence of genetic abnormalities; returning them to Regenerative; and some 4 to 6 weeks after initial extraction, transporting the resulting cell product to the Clinic for reinjection at the patient’s site of injury or degeneration. Patients reported significant improvement while avoiding the physical and financial costs of invasive surgery. In 2008 the FDA notified the two physicians, Regenerative and Regenerative’s lab director that the RegenxxTM Procedure cell product constituted a “drug” under the Food Drug and Cosmetics Act and a “biologic” under the Public Health Service Act. Consequently, the Procedure could not be used without first obtaining pre-marketing approval.
The FDA regulates medical drugs and devices under the FDCA and biologics under the PHSA, and requires some form of pre-marketing approval for many of them. In doing so, however, it typically deals with commercial pharmaceutical companies; state law governs physicians in the practice of medicine. Thus, while FDA regulations obviously affect the drugs, devices and biologics available for physician use, they normally do not target a physician’s actual treatment of a patient. Because medical advances routinely occur “at the bedside” without FDA oversight, the Regenerative defendants and the medical profession at large were deservedly surprised to learn that the FDA had decided to regulate autologous ASCs as human cell, tissue and tissue-based products (HCT/Ps).
The FDA’s HCT/P regulations can be found at 21 C.F.R. § 1271 and create a tiered framework based on PHSA §§ 351 and 361. We will not delve into its complexity here beyond saying that the agency predicates the extent of regulation on the degree of risk to a patient. PHSA § 361 provides minimal oversight of low-risk HCT/Ps that are, inter alia, 1) no more than minimally manipulated; 2) used for their same original or “homologous” purpose; and 3) autologous, i.e., the patient is treated with her own cells. PHSA § 361 manufacturers must comply with various registration and reporting requirements but do not need to obtain pre-marketing approval before using the HCT/P. In the FDA’s view, even though the RegenexxTM Procedure is used for autologous (same patient) purposes, it involved more than minimal manipulation. This made the resulting cell product a “biologic” under PHSA §351 and a “drug” under the FDCA.
Consequently, Regenerative had unwittingly become an “establishment” that “manufactured” § 351 HCT/Ps. Treating a patient with her own cells had become “marketing” in need of prior approval by the FDA. Without pre-market approval, the cell product – based on the patient’s own cells – had become an “adulterated” and “misbranded” drug and biologic under the FDCA and the PHSA. In effect, Regenerative would need to submit to the same pre-marketing approval process as Pfizer, the world’s leading pharmaceutical company with self-reported revenues of $59 billion for 2012. This was true even though Regenerative Sciences existed solely to enable its two physician-owners to extract, expand and re-inject a patient’s cells for the sole purpose of restoring that patient’s function and reducing that patient’s pain. Despite their dramatically different resources, Regenerative and Pfizer would be equally required to conform to Current Good Manufacturing Practices (CGMPs) and conduct formal clinical trials – quite the challenge when dealing with a patient who wants to use her own stem cells now as opposed to several if not many years in the future.
Litigation ensued and the case was eventually tried in the federal district court for the district of D.C. Regenerative challenged the FDA’s authority to regulate at all, arguing: 1) Congress never intended its Commerce Clause power to interfere with the practice of medicine; and 2) there was no interstate commerce since all activities were confined to Colorado. The court disagreed, reasoning that state practice of medicine laws do not preclude federal law from affecting and effectively regulating certain aspects of a physician’s practice. Further, interstate commerce existed because the Procedure used drugs shipped from out-of-state.
The court also upheld the FDA’s ability to regulate a patient’s own cells. Although “a close call,” the court explained that the RegenexxTM cell product falls within the FDCA’s technical definition of a “drug” because it is an “article … intended to affect the structure or function of the body ….”  It simultaneously qualifies as a PHSA “biologic product” because like a “therapeutic serum, … blood, blood component or derivative, protein … or analogous product,” it is “applicable to prevention, treatment or cure of a disease or condition in human beings.” Defendants’ website and pleadings showed that the RegenexxTM Procedure and ASC treatment were “intended to affect the structure or function of the body” and “applicable to prevention, treatment or cure of a disease or condition in human beings.” The FDA therefore had authority under both statutes to promulgate and enforce HCT/P regulations, and tie the degree of oversight to the degree of cell manipulation. The Procedure’s “many steps”  could constitute more than manipulation under § 351 and, in any event, the agency’s finding of more than minimal manipulation deserved “substantial deference” by the court. Accordingly, the court entered summary judgment for the FDA, dismissed all counterclaims, and permanently enjoined use of the RegenexxTM Procedure. On appeal, each side has essentially stood firm in their positions, with Regenerative receiving the support of amici American Association of Orthopaedic Medicine, the Association of American Physicians & Surgeons, Inc. and Tim Turner (whose Parkinson’s disease has not responded to available treatments).
At first glance, the idea of the FDA regulating our own cells looks like an outrageous invasion of individual privacy and denial of personal autonomy. If patients weigh risks and benefits of medical treatments every day, why prevent them from doing so with their own cells? This question is especially compelling where a patient has few or no effective therapies, and limited or no access to experimental treatments. That a treatment may be more risky in the hands of untrained or unskilled doctors is not unique to autologous adult stem cell therapies; this problem pervades medical practice.
Despite the intuitive appeal of defendants’ position, a closer look at the medical procedures, the applicable statutes and the trial court’s assessment of both indicates that the FDA has the stronger argument on all counts. Using components shipped between states has frequently sufficed as interstate commerce in past case law. The cell product and its intended use do fall within the statute’s literal and technical definitions of a drug and a biologic as well as the regulatory definition of a human cell, tissue or tissue-based product.
If the agency’s power and discretion to regulate are upheld, the facts of this case are problematic because the degree of manipulation determines whether an HCT/P must satisfy the burdensome criteria of § 351 or § 361’s comparatively milder requirements. The RegenexxTM Procedure involves “many steps” to isolate and expand the cells including “selective culture and expansion of a multitude of different types of blood-forming and rare bone marrow stromal cells using plastic flasks, additives and nutrients, and environmental conditions such as temperature and humidity, to determine the growth and biological characteristics of the resulting cell population.” Over the course of 4 to 6 weeks, the cell product is moved between several locations: the Clinic, the Regenerative Sciences lab, an outside testing lab, back to Regenerative, and back to the Clinic.
These facts create a strong case for finding minimal manipulation. Plus, courts routinely defer to agency rule-making, interpretation and enforcement especially in matters of science and technology. Although the arguments for each side are more complex and nuanced, the big picture seems to show that the stars are in alignment for the FDA which, in our assessment, will likely prevail at the appellate level. This is not to say that we hope the government succeeds in derailing autologous adult stem cell therapies. We simply think the rules of statutory interpretation and administrative procedure will weigh in the agency’s favor in this case, especially with this particular set of facts.
Regardless of how the D.C. Circuit resolves this case, one thing is clear: the FDA should re-examine its HCT/P regulations especially as applied to physicians treating patients with their own cells. Extracting a patient’s cells for subsequent reinjection undoubtedly carries risk – but so does banking one’s own blood or freezing eggs for later use. Conditioning the extent of regulation on the degree of manipulation may make sense on paper but is vague and confusing in practice, especially in the dynamic field of cellular therapies. In an age of relentless cost inflation and limited therapies for debilitating illness, it makes no sense to deprive patients of autologous therapies because their physician lacks the resources – and patients lack the time – to satisfy the pre-marketing requirements that oppress even Merck and Johnson & Johnson. The FDA is obligated to protect the public health as well as individual patients. Critical to this mission is striking the proper balance of risks and benefits, where the benefits include facilitating medical innovation. In the context of adult stem cell regulation, especially autologous cells, it is time for that risk-benefit balance to be recalibrated. Stem cell therapies, even autologous ones, should be regulated, but those regulations must be re-designed to fit the parties and products being regulated. To be blunt, it makes no sense for the FDA to insist that a practicing physician who is treating an individual patient must conform to the same pre-marketing and manufacturing requirements that bind large-scale, commercial pharmaceutical manufacturers that produce drugs in bulk for mass distribution. Moreover, the agency should not monopolize risk-benefit calculations to the exclusion of patients who, with the counsel of their physicians, want to make their own calls about using their own cells to treat their own conditions. Preventing them from doing so is already leading many patients to assume other and perhaps greater forms of risk, such as seeking treatments in foreign clinics that may or may not be up to the task.
Suing an agency is usually an uphill and often losing battle. We doubt that Regenerative Sciences and cases of its kind will do much to lower regulatory hurdles. Some form of regulation is needed, but the FDA must recognize that its current HCT/P framework is ill-suited to many kinds of cellular therapies. It could revamp its HCT/P framework entirely, but that will take time. In the near term, the agency should reach beyond existing expert advisory committees and public comment sessions. It should engage in a true collaboration with a wider group of physicians and surgeons who are already using or stand ready to use various types of autologous adult stem cell therapies, and the patients who have had or want treatment. It can also look to the guidelines of relevant organizations, such as the American Association of Blood Banks or various physician organizations. Only then can the FDA get a firm handle on what kinds of techniques and treatments present tolerable levels of risk when balanced with the need for innovation and the basic right of patients to use their own cells. After all, patients are the ones who must bear the burdens of illness, not the regulators, judges or attorneys.
[Cross-posted from HealthLawProf Blog]