Why unproven, risky medical practices elude legal restrictions
When the Hungarian police arrested four people at a Budapest hospital that offered unlicensed stem cell treatments this July, it clearly showed the Hungarian government's will to enforce its established regulations on medical practice.1 This was not the first legal action against a rule-skirting clinic — watchdog Stephen Barrett reports how the United States sought to prosecute the owners of the stem cell company Biomark on 51 counts of fraud before they fled the United States in 2006.2 (The couple that ran the company is awaiting extradition in South Africa after failing in a two-year legal challenge to that country's extradition treaty with the United States3.) A clinic in Barbados closed down after negative media reports4, and the governments or medical councils of Ireland5, the Netherlands6, and Belize7 have also closed down stem cell treatment centers that were violating local rules.
Nonetheless, many countries fail to stop stem-cell providers from charging patients huge sums to administer unproven therapies, either because appropriate regulations do not exist or because they are not enforced. There are many reasons for this, ranging from uncertainty about how stem cells, particularly those collected from and re-administered to patients, fall within a regulatory framework, to insufficient resources or authority for regulators to enforce policies, to direct opposition to such regulation. Below, we describe how China, India, Thailand and the United States all attempt to curtail the profit-driven administration of unproven therapies, and consider reasons why such practices continue.
In the first half of 2009, China took concrete steps to limit the marketing and use of stem-cell-based treatments for medical conditions in which their effectiveness remains unproven. On 1 May, China's Ministry of Health passed a rule mandating ministry approval for any procedure deemed to be risky, ethically complex or unverified (which they classed as "Category 3" procedures)8,9. Penalties were unclear, but a news report published in China at the time of the announcement suggested that these would be fines of up to 3,000 yuan (roughly US$440)10. While this amount may seem paltry when compared to the $26,300 price tag for a single round of stem cell treatments brokered by Chinese company Beike Biotechnology in Shenzhen, it should be remembered that a physician's average official salary in China is less than $10,000; the fine far exceeds the payment that would be received for most domestic medical procedures.
Of greater concern than the size of the fines is the fact that the decision-making process remains opaque. With the notoriously close ties between China's many stem cell purveyors, its municipal and military hospitals, and universities at every level, opportunities for agreements behind closed doors abound. Beike, for example, was established through funds from the Shenzhen municipal government and describes collaborations with many of China's top schools and hospitals, including Tsinghua University, Beijing University, Hong Kong University of Science and Technology, and No. 3 Army Medical University in Chongqing11. Hongyun Huang, another of China's well-known providers of stem cell treatments12, similarly got his start at Chaoyang Hospital in Beijing, which according to its website is, "subordinated to Beijing Municipal Health Bureau and also the third clinical medical school of Capital Medical University" (http://www.bjcyh.com.cn/english/index.shtml). Close ties with hospitals are particularly relevant for globally oriented companies like Beike, which pays $10,000–$12,000 per patient to the hospital that delivers the treatment to a foreign patient, according to Alex Moffett, chief executive of Beike Holdings. Although prohibited by the Ministry of Health, surreptitious gifts of cash in 'red envelopes' from patients to physicians is already a cultural norm13, so paper regulations are unlikely to slow the infusion of easy money from a transient population of patients with no effective legal recourse in the event of mishaps.
The same month that the Chinese regulations went into effect, the Thai Medical Council completed a draft regulation covering stem cell clinical trials14. The proposed rules do not apply to the blood and immune system disorders for which bone marrow transplantation is a well-established therapy. Instead, they would simply require stem-cell providers to register studies with the Medical Council of Thailand, thereby introducing a degree of independent oversight. Currently, many companies and clinics in Bangkok, such as the private company TheraVitae and Bangkok Heart Hospital, offer stem cells for indications ranging from skin care to heart failure. The efficacy of the procedures is far from established, but these operations exploit loopholes in current laws that require oversight and protection of human subjects undergoing experimental procedures. The autologous stem cells delivered by many of the stem cell clinics, for example, are not considered as drugs under the Thai Drug Act, and so are not subject to approval or monitoring by the Thai Food and Drug Administration (FDA).
Unexpectedly, however, the announcement triggered a backlash from some sectors of biomedical research. A number of scientists protested that the rules as currently written would hamper legitimate research, and one scientist even claimed that the legislation would force him to move his studies to Singapore or Laos15. This counter-current was lent even greater strength by resistance from the National Research Council of Thailand, one of the largest sources of scientific funding in the country, although it is unclear why legitimate scientists would object to independent monitoring of clinical trials. In any case, at the time of writing the rules have yet to be implemented.
A significant factor in the conflict in Thailand appears to be the government's mixed messages. Even as the Thai Medical Council and FDA had begun to voice concerns, the national Board of Investment granted approval for business activities to TheraVitae, a company providing autologous stem cell treatments to foreign patients with cardiovascular diseases, and featured the company prominently in a brochure on investment opportunities in biotechnology16. While Bumrungrad International, the largest medical tourism hospital in the country, has explicitly set a policy of waiting for the results of clinical trials before offering any novel stem cell treatments, many other large Bangkok hospitals that cater to wealthy Thai and foreign patients, such as the Bangkok Heart Hospital and Piyavate Hospital, provide treatments that have never passed such rigorous review. These procedures bring revenue not only to the hospitals, but also to various facilitators and cell-processing agents. In Thailand, as in China, it remains to be seen how this contest between scientific and economic interests will be resolved.
The Indian Council of Medical Research (ICMR) issued its own comprehensive guidelines on stem cell research and its application two years ago17. These clearly state "there is no approved indication for stem cell therapy as a part of routine medical practice, other than bone marrow transplantation (BMT). Accordingly all stem cell therapy other than BMT (for accepted indications) shall be treated as experimental". The guidelines also set forth requirements for the registration and monitoring of clinical trials by multiple government bodies. But these have yet to be passed into law, and companies and clinics continue to advertise a wide range of stem cell treatments. Similarly to Thailand and China, many Indian states have aspirations to become hubs of medical tourism, and as in those countries, governmental support for stem cell research appears to be based as much on the potential economic benefits as it is on the drive toward knowledge creation. Beike, which now has partner companies in both Thailand (Beike Holdings) and India (Beike Biotech India), has announced that it will undertake its first clinical trial in India, through a collaboration with Fortis Healthcare in New Delhi, which runs a nationwide network of hospitals geared toward medical tourism18. Interestingly, the trial will be of a stem cell therapy for diabetic foot ulcer, while the diseases currently listed as "treatable" on Beike's main website are all disorders of the nervous system, although Beike lists no studies documenting clinical efficacy. Many other companies advertising stem cells for clinical use in India also refer to "ICMR approved" clinical trials that are underway, but, given the multi-tiered system of registration and approvals recommended in the ICMR's own guidelines, it does not appear that this alone would satisfy the full requirements for approval of a trial. What's more, in at least one case, it appears that a private hospital has falsely claimed to have received approval for clinical stem cell transplantation from the ICMR19.
The United States has its own body of rules for the testing and clinical application of stem cells, which rest on the fundamental definitions set forth in Part 1271 of Title 21 'Food and Drugs' of the Code of Federal Regulations, which deals generally with human cells, tissues and cell- and tissue-based products. Any cells that are from a source other than the patient receiving them, that are more than minimally manipulated, or that act throughout the body or through metabolic activity fall under US FDA requirements for clinical trials and marketing. Numerous US-based companies circumvent this law by recruiting patients to cooperative hospitals in other countries, but several stem cell businesses are challenging the rules themselves. In February 2009, for example, Colorado-based Regenerative Sciences, which markets an autologous mesenchymal stem cell treatment for cartilage repair, opted to sue the FDA and the Department of Health and Human Services for damage to its business after receiving a warning from the FDA that it was possibly in violation of the Food, Drug, and Cosmetic Act20.
The founder of that company, pain management specialist Christopher Centeno, also launched the American Stem Cell Therapy Association (now the International Cellular Medicine Society) to promote a self-regulating model in which the clinical use of autologous stem cells would be regulated not as biologics, but as a medical procedure. This has apparently resonated with many patients, as evidenced by the uproarious response against the notion of the FDA treating your own cells as drugs in online communities like Stem Cell Pioneers and Safe Stem Cells, but as with many other clinics operating in regulatory grey zones, it is difficult to tell to what extent (if any) online comments are in fact simply viral marketing strategies. Another company, StemTech Labs, which advertises cord blood therapies (and whose website noticably does not list any sort of address/location for the company, but does list more than 100 conditions supposedly treatable by umbilical cord blood cells), has also issued a document targeting US physicians that suggests the FDA rules may be bypassed via putative loopholes that allow for "the use of processed and unprocessed cells by physicians in the US". The company also offers to ship cord blood cells from its Ecuadorean partner company for $5,00021.
Multiple factors impede appropriate regulation of stem cell clinics, including competing financial interests; sluggish or entrenched legal systems; activism on the part of companies and advocates; overburdened regulators; uncertainties over the legal status of cell therapies; and a sense of unwillingness to restrict the autonomy of patients urgently seeking care. This disaffection sometimes even extends to fields of stem cell research other than the particular sort being advertised or promoted; adult stem cell proponents frequently dismiss human embryonic stem cell research as either a waste of time and money, or even a plot by the medical establishment to stave off a threat to the status quo22.
While the requirements for scientific testing and caution prior to the introduction of novel cell-based treatments into medical use that are in place in the United States and Europe may not be perfect, there does not appear to be a better alternative for protecting patients from exploitation and possible harm. The efforts to introduce such requirements with specific regard to stem cell applications in countries such as China, Thailand and India should be welcomed, not resisted or evaded, by those who truly wish to contribute to the advancement of this hugely promising field. Likewise, the enforcement of rules in countries where they already exist must be viewed as a necessary safeguard to prevent missteps and tragedies of the kind that have so often occurred when medicine is based on faith and hope in advance of evidence.
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Sipp, D. The rocky road to regulation. Nat Rep Stem Cells (2009). https://doi.org/10.1038/stemcells.2009.125
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