American Journal of Law & Medicine

Cells as Drugs?: Regulating the Future of Medicine


Regenerative Sciences, LLC, a Colorado company run by physicians, created the Regenexx-C (Cultured) ("Regenexx-C") procedure to treat bone pain. The procedure involves harvesting a patient's own mesenchymal stem cells (MSCs), (1) expanding the cells ex vivo, and then injecting the resulting cellular product into the site of injury, usually an injured joint. (2) The MSCs then repair the damaged tissue. (3) On July 23, 2012, the United States Food and Drug Administration (FDA) won a permanent injunction against Regenerative Sciences in district court, preventing the company from offering the procedure because the MSCs were adulterated and misbranded "drugs" under the Federal Food, Drug, and Cosmetic Act (FDCA). (4) The Court of Appeals for the D.C. Circuit recently upheld the ruling. (5)

In many respects, United States v. Regenerative Sciences, LLC presented the perfect fact pattern for addressing the question of whether FDA has jurisdiction over cellular therapies. The procedure at issue involves an autologous cellular transplant, in which a patient's own cells are used to treat his or her medical condition. (6) The regulation of autologous transplants implicates issues of medical autonomy that the regulation of allogenic transplants, which occur between two people, does not. In fact, no one has challenged FDA's ability to regulate allogenic transplants. The cells used in allogenic transplants look more like traditional pharmaceuticals, which have their origin outside of the patient. In contrast, since the cells or tissues used in autologous transplants originate in the patient, patients may feel that they own the cells.. (7) Framing the issue in this way understandably generates accusations of paternalism against FDA, and also, anger among patients who want unrestricted access to the healing mechanisms of their own body parts.

The underlying rationale for such regulation, however, is much more nuanced. FDA only regulates autologous cellular transplants for safety and efficacy when the cells are "more than minimally manipulated." (8) Cells are considered more than minimally manipulated when they undergo procedures that call into question the chemical identity of the resulting cellular product. (9) Possible changes in the product's identity implicate new safety concerns, and placing the onus on the manufacturer to prove a product's safety and effectiveness is a reasonable safety measure. The regulation of such therapies is consistent with FDA's statutory authority..

The regulation of more than minimally manipulated cells is also consistent with the government policy of regulating the substances that one may put into his or her body. The intrusion on personal autonomy is no greater than that presented by any other FDA regulation. In theory, more than minimally manipulated cells no longer resemble the patient's naturally occurring cells, and therefore, are a new substance well within FDA's regulatory authority. Cells that are only minimally manipulated-- for example, those that are only frozen--more closely resemble the patient's actual cells, and government regulation of these cells may raise substantive due process questions. The more the final product resembles the patient's naturally occurring cells, the greater the affront to personal autonomy. FDA avoids these issues, however, because it only regulates manufacturing procedures of minimally manipulated products so as to "prevent the ... spread of communicable diseases" and not for safety and efficacy. (10) FDA cannot, therefore, prevent a patient from accessing minimally manipulated products derived from their own cells.

However, the regulation of more than minimally manipulated autologous cellular therapies is inconsistent with a more basic philosophical tenet of drug regulation: eliminating the information asymmetry that exists between the drug manufacturer and the consumer. (11) Congress expanded FDA's regulatory authority numerous times throughout the twentieth century in response to manufacturers selling harmful products. (12) Consequently, drug and device manufacturers must publicly vet their products in carefully controlled clinical trials before FDA will consider a New Drug Application (NDA). (13) FDA approval of an NDA signals to the public that a drug is safe and effective for medical use, thus significantly mitigating the information asymmetry that exists between the manufacturer and the consumer. The Regenexx-C procedure, on the other hand, occurs between a doctor and patient. State tort law and medical licensing boards regulate the information asymmetry inherent in these relationships. Traditionally, FDA has not asserted jurisdiction over the doctor-patient relationship. (14)

This Note analyzes the legal issues surrounding autologous cell therapies and concludes that, although FDA regulation of autologous tissue therapies is a legal exercise of authority and based on sound scientific principles, FDA should allow people access to these therapies because concern for patient autonomy outweighs the safety risks. (15) FDA can still regulate the manufacturing process less stringently without requiring a showing of efficacy and, at the same time, allow patients access to the healing properties of their own tissues. (16)

Part II of this Note provides the relevant regulatory and legal background of autologous cellular therapies. This Part also analyzes the appeals court opinion that upheld FDA regulation of an autologous stem cell transplant as a drug and biological product (biologic). Part III provides an analysis of the relevant legal issues. First, the appeals court's decision may limit FDA regulation of cellular therapies under its Commerce Clause powers. Second, because the plain language of the applicable statute permits FDA to regulate autologous cellular therapies as a drug or biologic, for medical practitioners, the relevant inquiry becomes whether a novel cellular product is minimally manipulated so as to escape stringent FDA regulation. Using Regenexx-C as an example, this section outlines standards relevant to the minimal manipulation inquiry. Part IV recommends that FDA allow patients access to autologous cellular therapies based on theories of patient autonomy and information asymmetry. Part V contemplates the broader issues raised by these developments.


A. FDA Regulation of Drugs and Biologics

FDA administers the regulatory regime that governs the drugs and biologies at the center of the Regenerative debate. FDA regulates drugs pursuant to the FDCA (17) and biologies pursuant the Public Health and Safety Act of 1942 (PHSA). (18) An article may be regulated under both statutes simultaneously. (19) FDA, pursuant to the PHSA, may also regulate the manufacturing process of articles not considered drugs or biologies so as to prevent the spread of communicable diseases. (20)

1. Regulation of Drugs Under the FDCA

The FDCA prohibits the introduction of any drug that is adulterated or misbranded into interstate commerce. (21) The prohibition includes any adulterated or misbranded drug that is "held for sale ... after shipment in interstate commerce." (22)

A "drug" is defined as an "article[] intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease ... intended to affect the structure or any function of the body." (23) The intended uses of a drug "refer to the objective intent of the persons legally responsible for the labeling of drugs" and can be gleaned from a label, advertisement, or any oral and written statements by the manufacturer. (24) The broad-sweeping definition of a drug also includes any singular ingredient intended for use as a component of a drug. (25) The term drug, therefore, covers much more than what is understood colloquially.

FDA may bring an enforcement action against a company if a drug is adulterated or misbranded. A drug is adulterated if it does not conform to current good manufacturing practices (cGMP), which ensure the safety, quality, and purity of drugs. (26) FDA has set out detailed manufacturing regulations and guidelines. (27)

Misbranding occurs when a product's label contains a defect. FDA heavily regulates drug labels to ensure the information they contain is truthful and correct. (28) There are two different standards for misbranding that depend on whether the article is a non-prescription drug or a prescription drug. For non-prescription drugs, the label must contain "adequate directions for use" (29) such that a "layman can use the drug safely and for the purposes for which it is intended." (30) A prescription drug is one that, because of its potential dangerous effects or toxicity, can only be prescribed by a doctor or other licensed practitioner. (31) Since prescription drugs require a physician's supervision, they need not include adequate directions for use by a layman and qualify for exemptions created by statute and regulations. (32) At a minimum, however, prescription drugs must bear the symbol "Rx only." (33) Manufacturers violating these standards are subject to FDA enforcement actions for marketing and selling a "misbranded drug." (34) Courts primarily issue permanent injunctions when a drug is found to be adulterated or misbranded. (35)

The FDCA subjects drug manufacturers to an extensive regulatory regime. (36) Included within that regime is FDA's process of approving new drugs before they can be marketed. (37) New drugs are those drugs that are "not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested." (38) Pursuant to its statutory authority, FDA may only approve a drug if it is both safe and effective for its intended use. (39) FDA carefully monitors the drug approval process to ensure that a drug's sponsor (most likely a large pharmaceutical company) conducts the relevant scientific and clinical investigations to prove a drug's safety and effectiveness. (40) The FDCA prohibits the marketing of a drug that has not completed this approval process. (41)

Before beginning the approval process, a sponsor must conduct in vivo animal studies to assess the pharmacology and possible toxicities of the drug in order to demonstrate that it is "reasonably safe" before beginning human clinical trials. (42) The sponsor then submits an Investigation New Drug Application (IND) to FDA that includes information such as the results of the preclinical studies, detailed manufacturing information, detailed protocols for clinical studies, and the qualifications of investigators overseeing the studies (usually doctors). (43) FDA's primary concern at this stage of the process is to ensure the safety of future research participants. (44)

After receiving an IND, a sponsor conducts clinical trials in three phases. (45) At each phase, the sponsor administers the drug to an increasing number of participants to assess safety and efficacy. (46) Phase I studies focus on the drug's safety for further clinical evaluations. (47) Phase II includes continuing safety evaluations, but FDA's primary focus at this point is to determine a drug's efficacy. (48) In Phase III, the sponsor conducts expansive studies to collect a statistically significant amount of data to allow FDA to make an informed decision. (49) Overall, throughout the closely monitored clinical trial process, FDA assesses the "scientific quality of the investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval." (50)

After completing all the relevant human studies under an IND, a drug sponsor must submit documents for marketing approval to FDA. These documents include: an NDA full reports of clinical investigations regarding safety and efficacy, a list of the drugs ingredients, a full written statement of the composition of the drug, a full written description of the manufacturing process, samples of the drug as required, and examples of proposed labels. (51) Based on the information in the NDA, FDA evaluates the safety and effectiveness of the drug, assesses its viability through a cost-benefit analysis, decides what information the drug label should contain, and determines whether the manufacturing and quality control measures will "preserve the drug's identity, strength, quality, and purity." (52)

Even after approval, drug manufacturers must maintain extensive and detailed sets of clinical data so that FDA may assess safety and efficacy of the drug for as long as it is on the market. (53) The drug manufacturer must report any adverse events related to the drug's use immediately to FDA. (54) FDA may also require manufacturers to complete additional post-approval scientific studies or clinical trials, known as Phase IV studies. (55) Finally, FDA may require that manufacturers implement a comprehensive "risk evaluation and mitigation strategy" (56) to ensure that the benefits of the drug continue to outweigh the risks in light of new scientific information. (57)

2. Regulation of Biologies Under the PFISA

FDA also administers certain sections of the PHSA. …

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