douglas sippby Sorapop Kiatpongsam and Douglas Sipp

Costs, risks, benefits, and a call for regulation

For some patients with debilitating illnesses, hope seems only a plane ride away. Though the scientific mainstream has dismissed stem cell clinics operating outside standard medical practice, patients continue to go. Patients and providers accuse the biomedical establishment of inaction and excessive caution; the biomedical establishment accuses providers of selling false hope to patients who have exhausted all available options. The resulting impasse arguably stands as the greatest current threat to the advancement of stem cell therapies, and the strongest evidence of the need for regulatory frameworks capable of addressing the needs of the diverse stakeholders in the 'offshore' stem cell drama.

Stem cells have risen to fame for their great medical promise. It is a promise that remains to be fulfilled. In countries around the world, however, a growing number of physicians are bypassing the traditional routes to therapeutic validation. For profit or glory, they offer stem cell-based therapies to patients willing to travel far and pay dear. This free market approach to experimental medicine, in which doctors and entrepreneurs exploit patient trust and take advantage of the dearth of cell therapy regulations in many countries, seems destined to end badly. The need for clear and enforceable rules is clear, but in order to be fair and effective, such rules need to be grounded in an understanding of the needs, desires and vulnerabilities of multiple stakeholders.

Those who hope to see patients receive stem-cell therapies have very different wants, fears, and responsibilities. Researchers must winnow biological truths from the chaff. Clinician-scientists need to determine (from incomplete and potentially irrelevant animal studies) whether and when to begin trials in human patients. Investors and companies must allocate limited financial resources and manpower to maximize returns. Policymakers and authorities must monitor the field the best they can to set funding levels and regulatory frameworks. And patients have to sift through hype and jargon to decide whether to participate in the ultimate test of a stem cell-based treatment, using their own bodies as testbeds.

As these stakeholders tackle the uncertainties of unregulated interventions, they are guided by sometimes conflicting goals. The many gray areas and opposing claims have sowed confusion about what stem cells might do in the body and how they should be introduced to healthcare markets. Equally important are the formulation of best-practice guidelines and rules of professional conduct for would-be stem cell practitioners and the establishment of mechanisms to ensure they are followed. The International Society of Stem Cell Research recently took an important step to the former goal with the publication of its Guidelines for the Clinical Translations of Stem Cells., which are available on the society's website.

Perhaps as early as 19921, clinics around the world began offering treatments based on (putative) stem cells for indications ranging from facial wrinkles to autism. Faced with the questions, hopes, and economic promise of stem-cell procedures, authorities in the countries where such procedures are performed have shown a reluctance to act. In place of thoughtful regulations that could advance clinical translation, there is a vacuum that harbors disreputable practitioners and threatens to consume the hopes and funds of patients as well as the good ideas and reputation of scientists.

Cost-benefit analyses (and their biomedical cousins, risk-benefit analyses) can supply a framework to navigate within gray zones. They help assess the value of possible outcomes of a given course of action relative to the hazards that following it might entail. But with unproven stem cell therapies, risks that are tolerable to one actor might be unacceptable to another; conversely, benefits prized by some stakeholders may be valueless to others. The patient willing to gamble her life in a controversial procedure is almost necessarily more risk-tolerant than an administrator charged with maintaining public health and safety. A fly-by-night clinic is surely less concerned about reputation damage (and more about bottom-line profits), than a more established hospital.

Previous analyses have weighed the costs, risks and benefits of various regulatory approaches to emerging biomedical fields including gene therapy2, reproductive medicine3, and the compensation of donors of oocytes in somatic cell nuclear transfer research10. After a prolonged solicitation for public commentary, the International Society for Stem Cell Research has issued a set of guidelines intended to lay out best-practice standards for the clinical translation of stem cell research, making recommendations for quality control, preclinical work, clinical trials, and ethical evaluation4.

But we know of no comparable attempt to catalog the costs, risks, and benefits of human stem-cell interventions as perceived by the diverse stakeholders involved. This effort could be useful not only for those charged with drafting wise regulations, but also to all those who seek to understand the issues fully. We do not presume to make recommendations on how individual states should handle their sovereign affairs; instead we hope here only to provide a précis of how different groups might weigh the questions.

Patients

Patients and their loved ones collectively drive the demand for 'offshore' procedures, but they cannot be treated as a homogenous group. The severity of their conditions, as well as availability of established therapies varies wildly, posing a range of ethical conundrums. We know of no demographic analysis of these patients, but if anecdotes and advertisements reflect the market, stem cell clinics target patients with a wide array of conditions. Some offerings seem trivial, such as spa-like sessions promising anti-aging effects. Others are heart-breaking, promising to alleviate congenital blindness, paralysis or life-threatening conditions like amyotrophic lateral sclerosis, congestive heart failure, cancer and AIDS. It is generally accepted that patients suffering from incurable, life-threatening conditions should be given greater autonomy in exploring all possibilities, including those that have not been validated by clinical trials. The question becomes increasingly problematic for less severe conditions, particularly if decisions are being made by caretakers on behalf of minors or the cognitively impaired. But even in non-fatal conditions, patient autonomy must be respected.

The ability of patients to make their own decisions is predicated, however, on their receiving accurate information, including any possible downsides of procedures. But the glowing claims made by many providers do not explain that their procedures lack evidence from controlled, randomized trials, let alone describe potential adverse outcomes. It appears unlikely from the claims made on company websites that patients are given this information before embarking. It is also unclear whether patients with chronic conditions are told that receiving a stem cell injection may make them ineligible to participate in future clinical trials, or that they have limited recourse in the face of malpractice or adverse events. The burden of informed consent is so high, we believe, that an independent organization capable of supplying accurate, unbiased information is critical.

Stem cell clinics and physicians

On the supply side for stem-cell clinical interventions is the motley array of clinics and physicians who advertise and provide treatments. The economic cost-benefit ratio for these actors appears to be distinctly more favorable than that for patients. A significant proportion operate in countries such as China, Thailand, India, Russia, or various Caribbean and Latin American nations, in which facilities and employment outlays are presumably low, and where they are able to operate unencumbered by costs such as those for malpractice insurance or follow-up studies. With $20,000 being the typical base cost for a stem cell procedure (a price point that is surprisingly consistent across geographic regions), clinics that have reported treating several hundred to as many as several thousand patients from overseas have each already generated millions to tens of millions of dollars in revenue5.

Profit may not be the sole motivator for physicians engaged in these unsubstantiated treatments; some surely hope to be pioneers in an exciting field and honestly believe that their treatments work. But in addition to the potential for wealth and acclaim, practitioners also face censure and ostracism from the international medical community, and possible future fines, loss of medical license, or prosecution in the event that restrictive new laws or regulations are enacted, or existing ones come to be enforced. Nonetheless, the proliferation of these clinics shows that some combination of profit, ambition, and conviction often outweighs risks of financial losses, legal action, and scorn.

Regulatory authorities

Within the United States and other countries, federal agencies police against unfounded medical claims and certain unsafe practices. However, there is no international authority that can set and enforce regulations on the administration of stem cells or their derivatives to patients, so the burden falls largely on individual countries. (Professional societies cannot be expected to assume this function, see below). While governments may benefit from tax revenues paid by stem cell providers, and local economies may generate some revenue by providing services to patients from abroad, regions also risk damage to their reputations, particularly if a death or adverse event becomes well publicized. (Although this is presumably attenuated by the reluctance on the part of some patients to admit that they have been mistreated). Reputational risks are a particular concern for locations that seek to brand themselves as destinations for more routine medical tourism such as knee replacement or cosmetic surgery; this competitive and lucrative market requires that destinations become known for world-class medical care, reliability and transparency. Conversely, smaller governments may benefit from establishing and enforcing strong regulations to prevent irresponsible business activity to avoid questions of complicity and corruption, such as were raised in Barbados in 2006 during a scandal surrounding the Institute for Regenerative Medicine6.

Scientific and medical establishment

As the availability of unregulated commercial stem cell "therapies" has grown, so have the concerns of the global research community. Some openly worry of parallels to the scandals that stalled progress in gene therapy over the past decade7. Given their unpredictability and tumorigenicity, pluripotent stem cells seem particularly risky for unvetted clinical use, but interventions using any "non-self" stem cell could potentially trigger graft versus host disease and other forms of immune rejection, inflammation, and nosocomial infection.

In the absence of any government regulation that would prevent the practice, at least one prominent medical tourism hospital, Bumrungrad International in Bangkok, Thailand, has set a policy that it will provide only stem cell treatments that have been proven effective (such as for hematological diseases). A statement on its website specifically explains that if in the future the hospital does conduct clinical research, "the experimental nature of the treatment will be clearly explained; we will adhere to guidelines of the Thai FDA and Medical Council, even if such guidelines are not yet official law; and we will not attempt to profit from experimental treatments not yet proven."9 This effort to distance Bumrungrad from other Bangkok facilities that offer stem-cell treatments for cardiovascular and central nervous system disorders serves as an example of how concern for reputation for quality of care can trump the profit motive.

The scientific and medical community could protect patients and its own reputation by providing unbiased public information on the state of the science and creditable medical research. The consensus within the international scientific community is strongly against providing unvalidated stem cell treatments on a commercial basis; the scientific mainstream does not profit from procedures offered by 'offshore' clinics. Thus, while it is in the best position to evaluate clinics' claims, it is also open to accusations of bias. Creative solutions, perhaps the involvement of neutral "third parties," could help patients receive quality information. Not only would this help to neutralize some of the more egregious claims from profiteers and put a compassionate face on the field, it would also lessen the need for potentially heavy-handed government intervention, which could hinder even legitimate clinical trials.

If the scientific and medical community waits for regulation and intervention to be developed by other players, it may happen too late or not at all. And it is of course desirable that technical knowledge and expertise guide policy when regulations of any rapidly evolving technology are set forth. The effectiveness of preemptive self-regulation has been demonstrated previously by, for example, the precautionary principles espoused by scientists in the field of recombinant DNA following the Asilomar Conference in 1975.8 The ISSCR guidelines, are a move in this direction. These highlight the need for well-designed clinical trials while acknowledging a place for investigator-led medical innovation, so long as it is conducted in line with the ethical obligation on the part of the physician to do no harm. Self-issued guidelines, however, carry no legal force, and the ISSCR may be hesitant even to censure members who engage in dubious practices due to the risk of litigation.

Despite the efforts of well-meaning parties, this is not a mess that is likely to sort itself out. It seems certain that rules issued by the scientific community will continue to be ignored by many unregulated clinics, and a downside of self-regulation is the potential for conflicts of interest within the scientific and medical communities. (In fact, soon after ISSCR announced plans to draft clinical guidelines, a loose for-profit consortium of clinics announced their own standards of excellence, which fall far short of those within the established scientific community). Thus, the intervention of groups outside the scientific community will be necessary. A broad alliance of patient and disease advocacy groups, such as the Coalition for the Advancement of Medical Research in the United States, might be capable of balancing the desire for rapid progress with concerns over scientific validity.

Any attempt to formulate balanced and appropriate regulations must take into consideration the wants, needs, and values of extremely diverse groups, as well as maintain the built-in flexibility to accommodate unforeseen scientific developments. That rubric is complicated. The fundamentals, however, are simple: those who claim to have achieved improvements or outright cures using stem cells have a moral obligation to clear away the uncertainties. Regulatory authorities have an equal obligation to ensure that they do so.

 

Source: Nature

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