This article is more than 5 years old. Information may no longer be current.
Regulation of cells as drugs revisited
Click Here to Manage Email Alerts
Editor's note:
Last month’s Orthopedic Medical Legal Advisor column addressed a legal case concerning adult stem cells mixed and re-injected into orthopedic patients with the goal of treating a variety of arthritic complaints. In its ruling, the court held that such activity was subject to FDA regulation since stem cells, once mixed or manipulated outside the body, constitute a drug that is properly within the FDA’s regulatory authority. The case involved the medical practice of Christopher J. Centeno, MD, whom we invited to write this month’s column. He raises additional legal points and concerns that help us understand the ruling of United States v. Regenerative Sciences in its entirety, and its potential implications on our medical practices.
B. Sonny Bal, MD, JD, MBA and Lawrence H. Brenner, JD
Orthopedic Medical Legal Advisor Co-editors
In the United States, two separate government systems of medical regulation exist, i.e., federal and local. The FDA is the prime example of federal medical regulation, and it regulates drugs and medical devices sold in interstate commerce. Local medical regulation is entrusted to state medical boards, and various local departments of health. The medical practice of a physician is not directly regulated by the federal government, but by the state in which he or she practices medicine. These separate regulatory systems have been designed such that physician autonomy and judgment can be properly exercised without over-regulation from competing federal and local agencies.
An example of how federal and state regulatory mechanisms work together is the decision by a physician to use a new device or drug in an off-label manner. While the FDA can approve a new drug or device to treat a certain disease, it cannot tell physicians how to prescribe that drug or device in actual clinical practice. Physicians have broad discretion in using any medical device or product as they see fit, and in any responsible dose or configuration.
One interpretation of this separation of regulatory mechanisms is that much like the separation of the branches of government, such division of regulatory authority serves as an internal check against concentration of power. The physician is charged with doing whatever it takes to save, protect, extend or improve life, whether the federal government has approved of it. In point of fact, the court in the 1978 legal case of United States v. Evers stated that “A free, progressive society has an enormous stake in recognizing and protecting this right of the physician.” In Evers, the FDA had challenged an Alabama health facility that promoted and advertised the use of chelation therapy as an antidote for a variety of ailments.
Christopher J. Centeno
U.S. v. Regenerative Sciences
The significance of the ruling in United States v. Regenerative Sciences is in the expansion of the FDA’s regulatory power beyond the balance sought in the system of checks and balances. Regenerative Sciences involves my medical practice; in 2005, we began to use autologous stem cells derived from bone marrow as part of orthopedic treatments. At that time, the regenerative and healing potential of adult stem cells had been well recognized in the medical literature, although precise clinical guidelines for their use were lacking. We first obtained multiple regulatory opinions to verify that our proposed use constituted the proper practice of medicine that was not subject to FDA oversight.
B. Sonny Bal
For a period of 2 years, we went through an institutional review board, and worked closely with experts to translate stem cell therapies from a large animal to a human model. After this considerable investment of time and resources, we treated many patients who were considering knee replacement surgery, for example, and who reported remarkable improvements in their pain and function with an injection of their own cultured stem cells.
By 2008, we had treated hundreds of patients, published imaging case studies, and had prepared two papers addressing our outcomes with stem cell injections in the knee joint that showed favorable complication rates. At that time, the FDA informed us that by using the patient’s own cells for injection, we were distributing unapproved drugs into interstate commerce. When our counsel challenged this position, the FDA launched an investigation of our medical practice and the small laboratory attached to it, where we prepared the autologous stem cells for injection. We were accused of several violations, including those pertaining to Good Manufacturing Practices (FDA rules for mass producing and distributing drugs); even though neither actual safety nor quality concerns were identified.
In the legal action that followed, the U.S. District Court was dismissive, based on the legal doctrine of “ripeness.” This doctrine generally means that courts will not hear legal cases unless there is a controversy that has led to actual damages. Thus, if the government wants to condemn your home to build a freeway, you may be able to argue in favor of a preventative injunction, but actual lawsuit for damages must await demolition of the house first. In our case, the court believed that the FDA had only challenged our practice, rather than take any action beyond that step, rendering the underlying issue insufficiently “ripe” for legal review.
Interestingly, during 2012, the Supreme Court confronted a similar set of circumstances in Sackett v. Environmental Protection Agency, and ruled that immediate judicial review of compliance orders is required. But the legal rights and protections offered by Sackett were not available to us at the time.
We did not hear from the FDA for another year or so, until the agency returned to conduct a second inspection of what it called our “drug factory.” To encourage resolution of this ongoing controversy, we filed for a temporary restraining order, in response to which the FDA finally filed a legal action in 2010 seeking an injunction to stop our use of autologous cultured stem cells. In the federal litigation that followed (United States v. Regenerative Sciences) we raised many issues, such as the lack of direct FDA authority over the practice of medicine, FDA over-reach of cell-based regulations beyond what was authorized by Congress and the FDA’s failure to follow proper rulemaking in establishing regulations that turned cells into drugs. The judge ruled for the FDA earlier this year and the legal case has been appealed to the U.S. Court of Appeals for the D.C. Circuit.
Impact on medical practice
If you do not culture a patient’s own cells for injection, Regenerative Sciences may appear to have little relevance to your medical practice. However, the implications of this legal case run deeper. The FDA has now extended its regulatory authority beyond cultured stem cells and continues to move the demarcation between tissue and drug every year, in favor of increased regulation of tissues. In the last few years, the FDA has shifted many new cell therapies from the tissue/medical practice column into the drug category. This has included cord blood cells, despite their safe and efficacious use in pediatric cancers for several decades.
Increased FDA regulatory authority has also impacted medical devices, for example, the Menaflex artificial meniscus device, which was initially approved as a surgical implant was taken off the market because it relied on the action of cells, and therefore, needed a much more stringent approval that applies to new drugs. A concern for physicians is that that at some point, FDA regulation will encroach upon the practice of medicine, thereby crossing the fine line that separated federal regulation from state regulation of medical practices. As it stands, FDA regulations state that mixing approved drug A with approved drug B leads to a combination product that requires new approval for its use. While such approval may be appropriate in certain cases, the law means that a physician mixing approved drugs such as Marcaine (bupivacaine, sanofi) and Depo-Medrol at the bedside is producing a new drug and distributing it in interstate commerce.
Lawrence H. Brenner
Regulation over tissues and cells
The FDA’s regulatory reach into stem cells began with a proposal in the 1990s that eventually led to the rules captured in the Code of Federal Regulations under 21 CFR 1271. Many powerful organizations filed written commentary during the hearings related to these regulations in the 1990s. This list included the American Society of Clinical Oncologists (ASCO), the Biotechnology Industry Organization, the American Red Cross and many small cell therapy companies. ASCO put it best when it stated the following concerns:
- “ASCO objects in the strongest terms to FDA’s proposed regulation of stem cell transplants. This misguided proposal is unnecessary…and exceeds FDA’s legal authority.”
- “…stem cell transplants are medical procedures. Their use is the practice of medicine, not the manufacturing of a drug as FDA asserts.”
- “A striking aspect of FDA’s proposal to regulate stem cell procedures is the virtual absence of any justification for the initiative.”
Despite this fierce opposition, the FDA went forth with its regulatory scheme. As the Regenerative ruling illustrates, the key question remains whether the FDA should define a biologic drug in terms of public health risk or in terms of specific changes made to an individual cell or tissue. As it stands, the law states that if handling and processing changes the “relevant biologic characteristics” of the cells or tissue, the resulting product becomes a drug.
In that case, at least in theory, activation of platelet-rich plasma with calcium or thrombin crosses the regulatory threshold, such that activation clearly changes the biologic activity of the platelets. Furthermore, how the tissue is used can raise regulatory concerns. The FDA states that if cells or tissue are used in a “non-homologous” application (i.e., serving a different function than in the body), then they are to be classified as drugs. In that case, removing a vein and making it serve the function of a cardiac artery crosses this arbitrary line, so by the letter of the law at least, this is a non-homologous use.
Impact on innovation
Many innovations in surgical disciplines have been driven by physicians. The Regenerative decision delivers a confusing message to physician innovators, in that it is difficult to know precisely where the federal guidelines pertaining to the definition of a drug will be interpreted by courts. Regulation must balance public welfare, while protecting innovation and advancement. A desirable scheme of regulation may be illustrated in the use of cell-based therapies by infertility physicians. Fertility therapies, despite the fact that they are often cultured similar to the Regenerative process (i.e., a 5-day blastocyst procedure), are not regulated FDA. Instead they are regulated by state medical boards and professional organizations. Many new therapies have been developed to improve fertility rates in infertile couples.
The decision in Regenerative has been appealed on the grounds that important legal issues related to federal law were left unaddressed in the ruling. It is possible that the DC Circuit will take a dim view of the FDA’s classification of stem cell therapies as drugs. Indeed,
In the meantime, our practice has moved the cultured stem cell technique out of the United States to the Cayman Islands. We will continue the same-day processing of bone marrow stem cells for our patients in Colorado, since the FDA categorizes this product as tissue rather than a drug. We believe strongly that when physician autonomy and patient benefit are in question, we need to remain engaged with the FDA to help align its regulations with common sense and reason.
For more information:
B. Sonny Bal, MD, JD, MBA, is an associate professor of hip and knee replacement in the department of orthopedic surgery, University of Missouri School of Medicine.
Lawrence H. Brenner, JD, is on the faculties of orthopedics at Yale University and the University of Southern California, and practices in Chapel Hill, N.C. Address all correspondence to Brenner at lb@lawrencebrennerlaw.com.
Christopher J. Centeno, MD, is founder and chief medical officer of the Centeno-Schultz Clinic in Broomfield, Colo.
Disclosure: Centeno is chief executive officer and shareholder in Regenerative Sciences.