MARGARET FOSTER RILEY
REGENERATIVE MEDICINE is perhaps the technology of the twenty-first century. It holds the promise of eliminating organ shortages, rebuilding limbs, and curing disease. Much of this has until now only existed in science fiction. But regenerative medicine has also inherited the twentieth-century ethical issues and political baggage associated with stem cell research. And in the United States, the primary regulator, the Food and Drug Administration (FDA), must regulate under statutes that are decidedly mid-twentieth century.
These are new technologies, and the scientific aspects of how they function are still being worked out. This raises safety issues in their application. In addition, because these are living cells, this is likely to be more complicated and more individualized than the chemical technologies FDA has a hundred years of experience regulating. Moreover, regenerative medicine, or more precisely the technologies comprised under that name, progenitor and stem cell technologies and therapies, also seems to be a battleground where many political, legal, and philosophical conflicts are waged.
I. WHAT IS REGENERATIVE MEDICINE?
Put simply, regenerative medicine is “use of natural human substances, such as genes, proteins, cells and biomaterials to regenerate diseased or damaged human tissue” (Orlando et al. 2011). But the central focus of regenerative medicine is pluripotent cells (stem cells that are capable of differentiating into more than one cell type). Regenerative medicine may be amazingly complex; it is a multidisciplinary field involving biology, engineering, and medicine. It involves stem cells: embryonic, fetal, adult, and induced pluripotent stem cells. It may require biomechanical design: biomaterials and biomolecules, including nanomaterials, designed to support the organization, differentiation, and proliferation of cells into functional tissues. It may require informatics to do things like support gene expression and protein expression and interaction analysis as well as tissue and cell modeling and manufacturing. Or, it may be as simple as removing stem cells from the body of a person, storing them, and then returning them to the body of the same person.
A. The Cell Sources
Stem cells used for regenerative medicine may be autologous, using cells from the intended recipient; allogenic, using human cells from a different donor than the recipient; or xenographic, using cells from other species (Tigerstrom 2008). All stem cells have the ability to reform and support a complete tissue from a single cell and the ability to self-renew. A number of different stem cell types may be involved.
So-called adult stem cells are found among differentiated cells in tissues or organs but are more plastic and can renew themselves and differentiate into some or all of the specialized cell types (NIH 2012). Hematopoietic stem cells (HSCs) in the bone marrow were discovered in the 1950s. Mesenchymal stromal cells (MSCs) have received the most recent attention (Lalu et al. 2012). Because adult stem cells, relative to embryonic stem cells, have been relatively uncontroversial, there is a tendency to assume that adult stem cells are well understood. However, there is little experience with in vivo processes of self-renewal, differentiation, and function and how the context of their use may affect their function (NIH 2012).
Embryonic stem cells (hESCs) are totipotent, meaning that they can differentiate into any cell type. In addition, hESC cell lines are easier to create and may remain useful for longer periods and provide greater research and therapeutic benefits (NIH 2012). The behavior of hESCs may differ considerably from MSCs and other adult stem cells, and this may have implications for therapeutic uses.
Of course, hESCs must be derived from an embryo, and for now, that usually means destroying the embryo, which is ethically problematic for some people (NIH 2012). Federal funding for derivation of hESCs, the part of the process that involves destroying the embryo, is now prohibited, although federal funding can be used for cells derived using existing or nonfederal sources so long as NIH guidelines are followed (Executive Order 2009). Induced pluripotent stem (IPS) cells were created, at least partly, to avoid the ethical issues raised by hESCs. Because they were created using a viral vector and they are not yet well understood, their clinical utility has been limited although potentially important (Takahashi et al. 2007; Chin 2009).
B. What Are the Safety Issues with Regenerative Medicine?
Generally, all biological products pose additional safety issues compared to traditional drugs and devices. Unlike drugs that are made up of comparatively simple chemical molecules, biological drugs are made up of far more complex proteins, cells, or even whole organisms. Since they need to be produced in precise conditions, they introduce additional safety in manufacturing concerns. They are harder to characterize, reproduce, and sometimes may be inherently unstable.
In addition, regenerative medicine poses unique safety issues. Because at its core it involves pluripotent cells, it has safety issues that are unique to those cells. These include increased possibilities of tumorigenicity, the potential for genetic abnormalities, and additional issues of immunogenicity (Goldring et al. 2011). Many of these issues are more prevalent with hESCs and iPSCs than therapies involving MSCs, but they hypothetically exist for all stem cell types (Lalu et al. 2012). Whether the full effects of these cells can be predicted, tracked, and controlled is still often an open question. As with any new technology, the biggest safety issue may not be the known risks but the unknown risks.
II. THE REGULATION OF REGENERATIVE MEDICINE
It is possible to argue that regenerative medicine is both under- and overregulated. But, overall, stem cell technology may be one of the most regulated technologies in the world. FDA finalized comprehensive regulations for cell-based therapies in 2004. Because of the ethical issues raised by hESCs, voluntary guidelines were issued by the National Academy of Sciences. Many academic institutions that conduct stem cell research have institutional stem cell research oversight committees. The very influential International Society for Stem Cell Research (ISSCR) has issued voluntary guidelines for hESC research and for Clinical Translation of Stem Cell research. NIH has a registry for hESC lines used with federal funding. Europe recently developed an overarching legislative policy tailored to new technologies including regenerative medicine (EC, Regulation (EC) No. 1394). Australia, Canada, and a number of Asian countries have laws on stem cell research and clinical translation. And in the United States, many states also have laws that affect stem cell use and research. Worldwide regulation of these products is not harmonized; the same product may be regulated as a device in one country, a drug in another, and completely unregulated in another (Kemp 2006).
The most important regulator, however, is FDA, which controls the approval process for new therapeutic products in the United States. Without that approval, none of these products can be used in the United States—and the United States is still the most important market for this type of technology. In an ideal world, FDA could construct regulations that would perfectly fit the issues raised by the technology. Such regulation would effectively protect patients from the potential safety issues but allow sufficient flexibility for quicker introduction into the market as FDA and industry gain experience. This, of course, is not an ideal world. FDA’s authority is constrained by the statutes from which its authority emanates, the Food Drug and Cosmetic Act (FDCA) (21 USC § 301 et seq.) and the Public Health Service Act (PHSA) (42 USC § 262 (Sec. 351) and § 264 (Sec. 361)), neither of which could have anticipated this technology. Moreover, most of this technology has developed at a time when Congress was in no hurry to expand FDA’s authority.
A. How Does FDA Regulate/Propose to Regulate Regenerative Medicine?
Because of the diversity of potential products, regenerative medical products do not fit squarely within any of the three main classifications: drug, biological drug (biologic), or device. Many of these products involve a combination of features that could make them eligible for two or even three categories. FDA typically classifies such a product according to its primary mode of action (21 USC § 353(g)). Because the major characteristic of regenerative medicine is the use of pluripotent cells, most products are subject to FDA’s regulations regarding “good tissue practice” and many are classified as biologic drugs or devices (21 USC § 321 (g) and (h)).
FDA did not formally regulate most tissue or cellular products until the 1990s. First, it was unclear whether tissues should be regulated as drugs or medical devices or biologics. Second, it was uncertain whether all tissue products required the full oversight and testing that the approval process for those products required (Merrill 2002). FDA’s first forays into tissue regulation were with heart valve allografts, which were treated as devices. FDA then turned in a different direction, seeking comprehensive regulation of tissue intended for human transplantation. FDA proposed a tiered risk-based approach for regulation of all “human cellular and tissue based products” (HCT/Ps) (FDA 1997). A major goal of the proposed regulations was to more clearly answer the question of which therapies merited the full treatment of the biologic/drug/device approval process and which could be regulated under the more limited regulatory controls designed to control communicable disease (Merrill 2002). The complete HCT/P rubric became final in 2004 and applies to all regenerative medicine’s clinical technologies (Current Good Tissue Practice for Human Cell, Tissues, and Cellular- and Tissue-Based Product Establishments, 21 CFR 1271).
Under the regulation, HCT/Ps are articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. These include cellular therapies and combination products consisting of cells/tissue with a device and/or drug. They do not include vascularized organs for transplant, whole blood or blood products, secreted or extracted human products (except semen) (21 CFR 1271). All HCT/Ps are subject to Current Good Tissue Practices and registration under Section 361 of the PHSA, but tissues that are only minimally manipulated and that are used for their normal (homologous) function in the person from whom they were obtained do not require premarket approval. Cells and tissues that are extensively manipulated, combined with non-cell/non-tissue components, or used for nonhomologous functions are regulated under Section 351 of the PHSA and the FDCA as biological drugs or devices requiring premarket approval (21 CFR 1271.20).
B. Challenges to FDA Regulation
Most of the regenerative-medicine industry has not seriously questioned FDA’s authority to regulate in this manner, and most concerns have been focused on speeding the approval process, clarifying scientific standards, and harmonizing FDA regulation with global regulation (Alliance for Regenerative Medicine). However, a number of clinics using autologous MSCs for clinical treatments of diverse conditions have vehemently opposed FDA authority. These laboratories extract adult stem cells (usually from blood, marrow, or fat) from patients, select and expand them, and then implant them into the patients to treat arthritis, multiple sclerosis, and many other conditions (Berfield 2013). Some of these clinics are engaged in outright fraud (60 Minutes 2010), others appear to be more legitimate, but they share a common refusal to acknowledge FDA’s authority to regulate their activities as clinical experimentation. These companies believe that they are offering a treatment and therefore a service within the normal practice of medicine. As such, they believe that they are regulated only by state law and their activity is outside FDA’s authority.
In 2012, FDA moved to stop a number of these stem cell clinics from selling their treatments, claiming that the “treatments” constituted unapproved drugs. One company, Regenerative Sciences, mounted what was ultimately an unsuccessful challenge. In 2014, FDA obtained an opinion in the Regenerative Sciences case that provides FDA significant, but not ironclad, support for its regulatory rubric for the use of such cells (U.S. v. Regenerative Sciences 2014:1314). The question before the court was whether Regenerative Sciences’ autologous stem cell “mixture,” “Regenexx,” constituted a drug or biologic product subject to FDA regulation or whether it was an intrastate method of medical practice subject only to state law. Regenerative Sciences operated only in Colorado. Regenexx involved taking MSCs from a patient’s bone marrow and expanding them using growth factors from the patient’s blood. The expanded cells were then combined with a drug shipped in interstate commerce and then injected into the patient at the clinic.
In a strongly worded opinion, the Court of Appeals affirmed the lower court ruling that Regenexx was an adulterated and misbranded drug under the FDCA (U.S. v. Regenerative Sciences 2014:1314). The court also found that both the PHSA Sec. 361 HCT/P regulations and the PHSA Sec. 351/FDCA requirements applied because Regenexx was more than “minimally manipulated” (U.S. v. Regenerative Sciences 2014:1322). Finally, the court held that the interstate commerce requirement was also met (U.S. v. Regenerative Sciences 2014:1320).
There is insufficient room here to fully analyze the claims raised in the Regenerative Sciences case. However, it is worthwhile to look at a few issues as they have implications for FDA’s authority with this technology going forward.
1. Are Autologous Treatments Different?
There is a common presumption among proponents for minimally regulated stem cell clinics that “your own cells can’t hurt you.” It is certainly true that risks of infection and potential immune reactions are significantly reduced by the use of autologous cells, but it is worth remembering that the very nature of cancer is having one’s own cells become the engine of destruction. And all stem cells hypothetically carry risks of increased malignancy (Goldring et al. 2011). Thus, FDA’s reluctance to assume such treatments are safe without actual clinical proof seems appropriate. The real questions should be how much proof is necessary—and what standards will FDA use?
There are also some regulatory oddities that are raised by autologous cells. FDA regulates all HCT/Ps under Section 361 of the PHSA whose focus is the prevention of communicable disease. In Regenerative Sciences, the court was persuaded by FDA’s argument that removal of the cells created the risk of contamination, which in turn carries with it a potential for communicable disease. That may not withstand scrutiny with another court. Autologous cells that are properly handled and combined only with autologous growth factors bear little risk of contamination. FDA might logically counter, however, that proper handling requirements are the purpose of the regulation. It is nonetheless possible that another court might reasonably find that autologous cells, used under the oversight of a physician, that do not meet the full FDCA definitions of drugs, should escape basic regulation under Section 361 of the PHSA as well. That would make those products largely unregulated.
2. When Is Cell Therapy a Drug?
Since the first experiments with autologous cells manipulated ex vivo and reimplanted for structural repair in the mid-1990s, companies have argued that the technique should not be regulated as a product but rather as a service (Hyman, Phelps, and McNamara 1996). FDA has never acceded to that view. Of course, just because FDA says it is so does not necessarily make it so. But the FDCA drug definition was deliberately written broadly to accommodate future scientific developments, and the courts have backed up FDA’s claims that products lacking many drug characteristics may still qualify as drugs (United States v. An Article of Drug…Bacto-Unidisk, 1969:798).
“More than minimal manipulation,” the standard under which a product moves from Section 361 controls to being considered a drug, is an ambiguous term. The question of what constitutes “minimal manipulation” has always been controversial. FDA defines it as changing the “biological characteristics” of the material (21 CFR 1271.3(f)). While these words do not appear in any of the relevant statutes, they can be implied from the drug and device definitions. A process that alters the relevant biological characteristics affects the “structure or function” of the cells or tissue involved (21 USC § 321 (g)(1) and 21 USC § 321 (h) (3)).
Based on FDA’s 1996 discussions with industry, it appears that FDA intended this to be an evolving standard so that if experience showed that the biological characteristics of the cells were not altered by the process, they could later be considered “minimally” manipulated (FDA 1997). FDA did “downregulate” cell selection as not constituting more-than-minimal manipulation under the 1997 proposed rules (FDA 1997). However, no other significant changes have been made since then. Moreover, this standard does not allow for easy downregulation when a process may be found to change the biological characteristics of a cell or tissue but where it is still found to be safe. FDA might assert authority to regulate the product as a drug but decline enforcement authority. But the standards may not be clear.
3. Practice of Medicine
The concept that FDA does not interfere with the “practice of medicine” has become a bit of a sacred cow concerning FDA’s authority to regulate drugs and therapies. FDA itself is wont to repeat it as a mantra. The doctrine has its roots in the fierce protection of professional authority that was sought by physicians throughout the twentieth century even as government was extending aid to the health care enterprise and otherwise increasing regulation of industry players (Starr 1982). Thus, physicians are primarily regulated through state licensure requirements, a process that is itself significantly under the control of physicians. For FDA specifically, the principle is focused on the physician exemption from drug and device approval requirements. Physicians are not required to seek approval for new unlabeled uses of existing approved drugs or devices that they choose to use in the treatment of their patients (Chaney v. Heckler 1983:1180; 21 USC § 396 (2000)). There is no doubt that this off-label use has usually allowed for better medicine and potentially lowers costs. But the practice of medicine exemption is often presented as a much broader doctrine that means FDA cannot touch any aspect of the practice of medicine, often with little analysis as to why it exists, what its limits are, and whether it is worth protecting in all situations. It is perhaps not surprising that many of the stem cell clinics are operated by surgeons. At least until recently, most innovative surgery did not involve drugs and devices and was therefore conducted without FDA oversight—and is often conducted without any oversight (Reitsma 2005).
In any event, as the court found in Regenerative Sciences, the question here is actually easier (U.S. v. Regenerative Sciences 2014:1319). The approval requirements of the FDCA have always represented a limit on the practice of medicine. Although it is often appropriate for physicians to prescribe approved drugs off label, it is never acceptable for physicians to prescribe unapproved drugs. Therefore, the first question is not whether FDA’s requirements limit the practice of medicine but rather whether the “treatment” constitutes a new drug or biological drug. Since the court answered that in the affirmative, it found that FDA has the authority to limit the practice of medicine to that extent (U.S. v. Regenerative Sciences 2014:1319).
4. Commerce Clause
One of the central questions posed by Regenerative Sciences was whether FDA had jurisdiction to regulate “the mixture” since almost all of the activity occurred intrastate. The Court of Appeals applied a traditional interpretation of the Commerce Clause, finding that since such cell therapy substantially affects commerce (U.S. v. Regenerative Sciences 2014:1320; citing Wickard v. Filburn 1942), there was a sufficient nexus with interstate commerce. That determination is somewhat controversial. First, the FDCA became law before the more expansive interpretation of Wickard was decided. Second, in the Supreme Court’s Obamacare decision (NFIB v. Sebelius 2012:2566), four of the justices seemed predisposed to a narrower interpretation of the breadth of the commerce clause. In NFIB, however, Justice Roberts affirmed that Congress’s power to regulate interstate commerce includes intrastate activity that substantially affects interstate commerce and also affirmed the continued vitality of the Court’s opinion in Raich (NFIB v. Sebelius 2012:2589–93; Gonzales v. Raich 2005:1). The FDCA’s power to regulate the interstate market for stem cell and other therapeutic products would be substantially undercut if it could not regulate products that stem cell clinics offer for sale in a solely intrastate market. This would seem also support the court’s determination in Regenerative Sciences; it is also possible though for another court to interpret it quite differently. And we of course don’t know what the Supreme Court would do in this context.
Under the facts of Regenerative Sciences, the Court of Appeals’ Commerce Clause determination was significantly bolstered by the fact that a component of the mixture, doxycycline, was shipped in interstate commerce (U.S. v. Regenerative Sciences 2014:1320–21). It is likely, however, that many autologous cell products could be produced without a component shipped in interstate commerce. If a narrower interpretation of Commerce Clause authority were to be imposed, many of those products might escape FDA regulation under the FDCA. FDA might still retain authority under the PHSA because the focus of that statute is on the prevention and control of communicable disease. Because of that focus, the PHSA gives FDA even broader Commerce Clause authority than does the FDCA, and arguably supersedes conflicting state powers, and allows even more expansive incursions into the traditional spheres of the practice of medicine. But it also has limitations in that the statute arguably does not confer authority related to efficacy of a product, just safety.
III. WHAT SHOULD FDA DO GOING FORWARD?
As the foregoing discussion demonstrates, the D.C. Circuit, certainly an influential court, has found that FDA has authority for the positions it takes on the regulation of regenerative medicine generally and clinics offering autologous MSC treatments specifically. This judicial support for the HCT/P rubric, a creative but certainly not statutorily mandated regulatory scheme, is extremely valuable for FDA going forward. It means that FDA’s enforcement efforts in requiring compliance with its regulations have real teeth. This should aid the agency’s efforts to eliminate potentially unsafe and unproven stem cell treatments in the United States.
But FDA’s regulations may be so onerous that the result is the “off-shoring” of many of these treatments. They will still be offered to patients, just not in the United States. Several of these companies have left the United States and there is considerable “stem cell tourism” involving these types of technologies (Cyronoski 2013). Indeed, Regenexx, the expanded stem cell product at issue in the Regenerative Sciences case, is now offered only in the Cayman Islands. Ironically, in demanding a more rigorous pathway to market, FDA may actually be exacerbating potential safety issues since these offshore products are subject to little significant regulation. Although some patients will not travel for the treatments, many will. Moreover, it is unlikely that that is the end of the story; the issue has become politicized. There has been considerable backlash against the perception that FDA is overstepping its authority in regulating these stem cell procedures. Even Texas Governor Perry questioned FDA’s authority to regulate these companies and promised to make Texas “the stem cell capital of the United States” (Berfield 2013).
It also means that there may be significant delays in bringing legitimately less risky stem cell products to market. FDA should find some “middle way” to speed and shortcut pathways for certain stem cell therapies even if it has the authority to demand full clinical study. When FDA chose not to treat HCT/Ps as devices but rather as drugs, it gained broader and more specific oversight authority. But it lost flexibility. There is no abbreviated pathway like the device 510(k) notification pathway for drugs. In addition, unlike devices, there is no clear pathway to “down classify” stem cell products to less risky classifications as the agency and industry gain experience. It is not just the stem cell clinics that are complaining. There is evidence that the costs of large clinical trials are a roadblock to much clinical translation of many of the technologies that are part of regenerative medicine (Nature [editorial] 2013). This is so widespread that the ISSCR guidelines offer a “responsible innovation” approach as an alternative to clinical research (ISSCR 2008). Proponents of that approach argue that such innovation constitutes a “middle way” between research and treatment appropriate for a small number of seriously ill patients (ISSCR 2008). Under certain circumstances, innovative but not-yet-approved treatments would be available for patients who have no alternatives, especially where funding opportunities for traditional clinical trials is insufficient. However, such an approach has some considerable risks in that it may lack appropriate oversight and may also expose large numbers of patients to ineffective or even dangerous therapy (Sugarman 2012). At a minimum, FDA would need to determine what level of preliminary safety and efficacy standards is appropriate. It is not clear that this pathway in practice would be much different from some of the fast-track pathways that are already available (Nature (editorial) 2013).
The best way may be to alter the “minimal manipulation” and homologous use standards. Those standards are easy to apply but may be overinclusive. There may be situations where the biological characteristics of the cells or tissues are altered but their behavior is predictable, safe, and effective. FDA needs to seek alternatives and find ways to achieve the downregulation for certain therapies that was envisioned in the 1990s. The current body of science may be insufficient for FDA to establish alternative standards now. FDA missed an opportunity to gather useful data from the rampant use of stem cells in animals by failing to provide guidance until that use was widespread. There are few reports of injuries in such animals but little data that supports efficacy (Cyronoski 2013a). Industry and FDA also need to partner more effectively to build that data in humans. Industry has had little incentive to publish studies of techniques that have not succeeded, but that knowledge is crucial to developing alternative standards.
IV. FUTURE ISSUES
While it is by no means a perfect fit, the statutory structure of the FDCA and PHSA has provided sufficient authority for FDA to regulate regenerative medicine. But that may end as the technologies evolve. FDA is ill suited to make determinations that go beyond safety and efficacy but instead focus on whether it should be ethically permissible to do something. This has been a question lurking in the background in both gene therapy and potential technologies like human cloning and so-called “three-parent” embryos. FDA’s authority to regulate those areas is certainly questionable (Merrill 2002). Thus far, ethical questions are on the periphery of FDA’s regulation of regenerative medicine. Nevertheless, FDA could find itself grappling with questions of ethics in the not-too-distant future. So far, the field of regenerative medicine is characterized by replacing diseased or damaged tissue. But the same technologies may be used for enhancement as well as replacement. The decision about whether such enhancement is ethically acceptable is outside the statutory safety and efficacy rubric in which FDA functions. FDA may be wise to avoid wading into that debate.
V. CONCLUSION
Regenerative medicine is a field that holds great promise but will require significant investment and creativity—more than scientific creativity—to succeed. It will also require significant luck in avoiding political quagmires that could hamstring the development of the technology. FDA’s role will be essential. It must try to develop responsive and nimble regulation, thus helping the technology—and itself—avoid some of those political pitfalls.
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