Our Bodies, Our Cells: FDA Regulation of Autologous Adult Stem …

By Mary Ann Chirba, J.D., D.Sc., M.P.H. and Alice A. Noble, J.D., M.P.H.

Stem cells have been an endless source of fascination and controversy since Dolly the sheep was cloned in 1996. This months announcement of a cloned human embryo from a single skin cell [1] came on the heels of Sir John B. Gurdon and Dr. Shinya Yamanakas 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 NIHsclinicaltrials.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 months 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 physicians ability to treat a patient with that patients 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.[2]

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 Clinics 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 patients 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 Regeneratives lab director that the RegenxxTM Procedure cell product constituted a drug under the Food Drug and Cosmetics Act[3] and a biologic under the Public Health Service Act.[4] 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 physicians 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).[5]

The FDAs 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 FDAs 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 patients 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 worlds 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 patients cells for the sole purpose of restoring that patients function and reducing that patients 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 FDAs 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 physicians practice. Further, interstate commerce existed because the Procedure used drugs shipped from out-of-state.

The court also upheld the FDAs ability to regulate a patients
own cells. Although a close call, the court explained that the RegenexxTM cell product falls within the FDCAs technical definition of a drug because it is an article intended to affect the structure or function of the body . [6] 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.[7] 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 Procedures many steps [8] could constitute more than manipulation under 351 and, in any event, the agencys 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 Parkinsons disease has not responded to available treatments).

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Our Bodies, Our Cells: FDA Regulation of Autologous Adult Stem ...