Policy ForumSTEM CELLS

U.S. Regulation of Stem Cells as Medical Products

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Science  07 Dec 2012:
Vol. 338, Issue 6112, pp. 1296-1297
DOI: 10.1126/science.1229918

A recent decision by a U.S. District Court judge could have profound implications for the increasing number of U.S. clinics that advertise putative “stem cell treatments” for a wide range of clinical, rejuvenation, and aesthetic applications. In United States v. Regenerative Sciences LLC et al., the court upheld the authority of the Food and Drug Administration (FDA) to require the premarketing approval of human stem cell–derived products that meet any of several broad criteria (1). The court concluded that the cultured autologous mesenchymal stem cell–based product at issue in the case is subject to FDA regulatory oversight, as it meets criteria for classification as a biological drug, and its manufacture, distribution, and sale constitute interstate commerce. Although the court described the decision, which has been appealed, as “a close question,” this new ruling reaffirming FDA authority has prompted heightened interest in the regulation of stem cells as medical products.

Safety, Efficacy, Commerce, and Practice

The relevant federal regulations in Title 21, part 1271 of the Code of Federal Regulations (C.F.R.) call for establishments engaged in the manufacture of human cell and tissue products that meet any one of certain criteria to comply with registration, donor-eligibility, good-manufacturing, and quality-assurance requirements (2). These criteria include “more than minimal manipulation” of cells (such as by extended ex vivo culture or treatment with growth factors) and nonhomologous uses (such as the use of blood-forming stem cells in heart or brain tissue). This regulatory framework subjects all such stem cells and other cell-based products to regulatory review as biologics (drugs derived from living materials, rather than by chemical synthesis).

Also at issue in the recent case was the question of whether administering autologous cells to patients solely on an intrastate basis constitutes interstate commerce. The court followed precedent in ruling that any drug containing a component from out of state triggers the interstate commerce clause, which is crucial, as the FDA only has authority over commercial activities that involve the crossing of state lines. The defendants had contested this point, and it seems likely that FDA authority to regulate stem cell–based interventions delivered within the borders of a state will remain a point of contention.

Mesenchymal stem cells. CREDIT: C. MAHAPATRA/WIKIPEDIA

Analyses of the FDA framework for regulating human cell and tissue products have largely focused on safety issues associated with pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells (3, 4), which have not been extensively tested in clinical trials. In contrast, the overwhelming majority of clinical studies involving administration of stem cells test the use of somatic stem cells. In randomized controlled trials, such cells have generally been well tolerated (57). In settings with poor oversight, however, the use of putative stem cells has been accompanied by severe adverse reactions, including death (8, 9). In addition, regulatory approaches to evaluation of the efficacy of stem cell products also remain little discussed.

Critics of the current federal regulations have proposed that, once safety is established, new treatments should be allowed to enter the health-care market and that efficacy should be evaluated through postmarketing reporting; some commentators think that premarketing requirements should be relaxed for stem cell treatments (10). Such critics believe the existing regulatory framework delays the movement of these interventions to market and impedes access to a potentially revolutionary form of medicine (11).

Arguments opposed to the present regulatory framework in the United States further assert that channeling stem cell interventions down the same regulatory pathway as the pre-market review process for other types of drugs imposes a mass-production manufacturing model on individually “customized” autologous stem cell procedures. But the notion that a custom intervention can be marketed wholesale and directly to consumers is problematic and does not, in any case, appear to apply to apparently indistinguishable ex vivo-manipulated products marketed for wide ranges of conditions. Also, the mere fact that a product uses processed autologous cells does not mean that it is therefore customized.

Legal, ethical, and scientific questions concerning the optimal system for regulatory governance over stem cells also surrounded a policy approved by the Texas Medical Board in April 2012 (12, 13). The policy permits physicians in Texas to administer human stem cells as investigational agents if patients consent to such procedures, the cells are provided as part of a clinical study, and the study protocols are approved by an institutional review board (IRB) or what the Texas Medical Board confusingly describes as “FDA/National Institutes of Health.” The policy is controversial because it appears to challenge the regulatory authority of the FDA by stating that researchers can choose between submitting their research protocols to the FDA or local IRBs. Commentators have been sharply divided over the meaning, scope, internal consistency, and legal status of this policy. Whether it was intended to supplement or challenge federal oversight of stem cells remains unclear.

Whatever the intended purpose of the policy, it seems likely that in the event that stem cell clinics and banks in Texas are inspected by FDA investigators, they will draw upon these new rules should they decide to challenge the FDA's authority by claiming that administration of stem cells to patients on an intrastate basis falls within the scope of medical practice and the Texas Medical Board's purview and is therefore not subject to FDA oversight. This view was echoed by Texas Governor Perry at a recent meeting sponsored by one such company, Celltex Therapeutics (14). As noted above, the recent District Court ruling hinged in part on a close analysis of what constitutes interstate commerce and what distinguishes state regulation of the practice of medicine from federal regulation of interstate commerce.

Efficacy, Ethics, and Law

Would allowing the sale of products of unknown effectiveness provide a reasonable, ethical, scientifically credible alternative to the current standard of requiring rigorous premarketing trials to establish safety and efficacy? The history of medicine suggests that it would not. In 1905, more than 28,000 so-called “patent medicines” were sold freely on the U.S. market without any requirement to show efficacy or, for that matter, safety (as the Pure Food and Drugs Act was not passed until the following year). Essentially, none of these products remains available or in demand today; this is presumably because many of them did not work (15). Similarly, after the 1962 Kefauver-Harris amendment expanded premarket requirements to include establishing efficacy, post hoc studies resulted in the withdrawal from the market of nearly 40% of products tested.

Furthermore, obtaining informed consent from patients requires describing both risks and benefits to prospective treatment recipients. Valid efficacy data are needed if clinicians are to responsibly describe benefits and risks, compare stem cell–based interventions with alternative procedures, and help patients make informed decisions. It seems clear that patients agree to pay for treatment, even when it is described as “experimental,” because they believe that they can expect meaningful benefit from receiving stem cells and that the likelihood and degree of potential benefit outweighs that of potential harm. Without convincing evidence for efficacy, stem cell interventions to are not likely become part of the science-based practice of medicine, particularly in commercial form.

Controlled, randomized clinical trials of any intervention are needed to assess toxicity, to establish safety and dose, and to determine whether a given intervention is efficacious in treating a particular condition (16). Postmarketing studies typically do not produce the same quality of evidence, because the agent being studied is not compared against a placebo or alternative in a control group; recipients and health-care providers are not blinded, and there is no effort to address well-known biases; and randomization does not occur. In short, for scientific and ethical reasons, both safety and efficacy need to be studied in registered controlled trials, and data should have to be presented to a competent regulatory authority and reviewed before stem cell interventions enter the marketplace.

Are stem cells truly safe and efficacious when used in the treatment of human medical conditions? Rigorous scientific testing and decades of clinical experience with bone marrow and other tissues rich in hematopoietic stem cells has shown their great utility as a component of treatments for cancers and other diseases of the blood and immune systems (17), and the FDA has already approved three allogeneic cord blood–derived products for such uses. The use of bone marrow—and, later, peripheral and umbilical cord blood—to reconstitute the blood system after cancer treatment was introduced in academic settings before the current requirements and only entered standard of care for certain indications after years of clinical testing. Many other types of stem cells are currently being tested for use as therapies for particular conditions; however, the FDA is right to keep the gateway to the American medical market closed until well-designed clinical trials find evidence of both safety and, crucially, efficacy.

Global Challenges

Whereas the European Union and Canada—which have established regulatory frameworks similar to those in the United States—have been broadly effective in preventing clinics from selling unapproved stem cell interventions, several other countries have struggled when faced with the challenge of addressing domestic proliferation of clinics marketing stem cell “therapies.” In Japan and Australia, for example, current legislation provides enormous latitude for individual physicians to market autologous stem cells directly to patients without first obtaining approval from national regulatory bodies. As a result, both countries have numerous clinics that advertise purported autologous stem cell treatments for an astonishingly wide array of unrelated medical conditions and do so with virtual impunity, as has been noted with concern by scientists working in those countries (18, 19).

Similarly, China (20) and India (21) have yet to establish legally binding regulations over stem cell interventions, enabling a great many spurious stem cell clinics to operate openly, and enticing large numbers of domestic and international patients to pay thousands of dollars for treatments of doubtful safety and medical value. Both countries are now working to develop stricter regulations intended to close this gap. Ironically, despite its stringent regulatory requirements, the United States is also home to numerous companies that offer ostensible stem cell–based treatments in apparent violation of the law (22).

Regulatory systems that require extensive independent oversight and premarket scientific testing of drugs and devices for safety and efficacy are undeniably confronted with issues of high costs, long development times, and the potential for public frustration when interventions once viewed as promising fail to demonstrate their worth. But if patients are to have confidence that marketed health-care products, including cell-based ones, are not only safe to take but are worth taking at all, then conformity with scientific and regulatory standards is essential.

Much of the contemporary debate concerning federal regulation of stem cells and other emerging biomedical technologies focuses on whether hurdles to market entry should be lowered. Given the efforts by various companies to bypass efficacy requirements and to promote their inadequately tested products directly to consumers, perhaps the more meaningful question is whether the regulation of stem cell–based interventions in the United States needs to be more rigorously enforced through injunctions and seizures with significant consequences for violators who, by their actions, jeopardize public health and patient safety; undermine trust in the integrity of the health-care system; and risk damaging the field of stem cell research.

References and Notes

  1. United States of America v. Regenerative Sciences, LLC et al., Civil Action No. 2010-1327 (RMC) US District Court DC (2012); https://ecf.dcd.uscourts.gov/cgi-bin/show_public_doc?2010cv1327-47.
  2. U.S. C.F.R., Title 21, Part 1271 (2012); www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1271.
  3. M. F. Pera, M. Munsie, Submission to the NHMRC Public Consultation—Stem cell treatments: A quick guide for medical practitioners, and Frequently asked questions: A resource for patients (National Health and Medical Research Council, Canberra, Australian Capital Territory, 2012).
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