TRANSLATIONAL AND CLINICAL RESEARCH Medicine on the Fringe: Stem Cell-Based Interventions in Advance of Evidence ALAN C. REGENBERG,a LAUREN A. HUTCHINSON,b BENJAMIN SCHANKER,c DEBRA J. H. MATHEWSa a
Johns Hopkins Berman Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland, USA; bThe London School of Hygiene and Tropical Medicine, University of London, London, United Kingdom; cBoston University, Boston, Massachusetts, USA Key Words. Stem cells • Therapy • Bioethics • Clinical trial
ABSTRACT Stem cell-based interventions (SCBIs) offer great promise; however, there is currently little internationally accepted, scientific evidence supporting the clinical use of SCBIs. The consensus within the scientific community is that a number of hurdles still need to be cleared. Despite this, SCBIs are currently being offered to patients. This article provides a content analysis of materials obtained from SCBI providers. We find content that strains credulity and almost no evidence of SCBIs being delivered in the context
of clinical trials. We conclude that until scientific evidence is available, as a general rule, providers should only offer SCBIs in the context of controlled clinical trials. Clients should be aware that the risks and benefits of SCBIs are unknown, that their participation is unlikely to advance scientific knowledge, and they are likely to become ineligible to participate in future clinical trials of SCBIs. We recommend steps to promote patient education and enhance global oversight. STEM CELLS 2009;27:2312–2319
Disclosure of potential conflicts of interest is found at the end of this article.
INTRODUCTION Medical tourism is on the rise [1, 2]. The Internet provides a ready means for people to identify interventions that are not available or are too expensive in their home countries; they can then travel abroad to access these interventions. One specific form of intervention that is helping to fuel the rise in medical tourism is stem cell-based interventions (SCBIs), including those involving embryonic, umbilical cord blood, and adult stem cells [3]. SCBIs have been successfully used to treat hematologic diseases and we do not intend for these tested and established therapies to be included among the less well-established, putative SCBIs that are the focus of this article. SCBIs are thought to offer great promise as treatments for many diseases, including a number of currently intractable conditions. Frequently mentioned targets include Parkinson disease, multiple sclerosis, spinal cord injury, and heart disease. The oft-cited clinical promise of SCBIs has been used to justify public funding of stem cell research [4]. Preclinical trials for a wide variety of SCBIs are yielding positive results [5, 6]. However, only a few early clinical trials are underway to test SCBIs for such conditions as cardiovascular disease [7, 8] and Batten disease [9]. In addition, Geron Corporation has received approval to conduct clinical trials for their embryonic stem cell-derived intervention for spinal cord injury [10]. Medical tourism for SCBIs is in part driven by the ethical controversy surrounding the use of human embryos in research, which has in turn led to substantial international diversity in laws and policies regulating embryonic stem cell research [11]. In addition to national and state policy, each country typically has a regulatory body responsible for
reviewing and approving medical interventions. For example, in the United States, the Food and Drug Administration (FDA) Center for Biologics Evaluation and Research has been explicit in expressing their intention to add SCBIs to the list of biologic products that they regulate. For the purposes of FDA review and approval, most SCBIs will be treated similarly to drugs [12, 13]. The FDA requires the completion of an investigational new drug (IND) application before conducting clinical trials of novel drugs or biologics [14]. Approvals of IND applications and initiation of human clinical trials depend on the submission of pharmacological and toxicological data from preclinical studies to establish reasonable evidence of safety and efficacy [15]. Thus, in the United States, IND approval is a prerequisite of clinical trials designed to test the safety and efficacy of an intervention in humans. In addition to the clinical trials mentioned, there is evidence that numerous biotech firms are working toward IND approval and clinical trials for a variety of SCBIs [16]. Similar oversight structures exist internationally. For example, the United Kingdom relies on the Medicines and Healthcare products Regulatory Agency [17]. The European Medicines Agency also provides oversight for European Union member states [18]. Japan has the Ministry of Health, Labor and Welfare [19]. China has the State Food and Drug Administration [20]. Presumably, the SCBIs currently being advertised on the Internet are not prohibited, or at least are not prevented, by local oversight in the jurisdictions in which they are delivered. Regardless of the stance of the regulatory regime directing medical intervention approval, there is currently little internationally accepted, scientific evidence supporting a proof of concept or efficacy for SCBIs, and the consensus within the scientific community is that a number of hurdles need to
Correspondence: Debra J. H. Mathews, Ph.D., M.A., 624 N Broadway, Baltimore, MD 21201, USA. Telephone: 443-287-5690; Fax: 410-614-9567; e-mail:
[email protected] Received November 19, 2008; accepted for publication May 12, 2009; first published C AlphaMed Press 1066-5099/2009/$30.00/0 doi: 10.1002/stem.132 online in STEM CELLS EXPRESS May 21, 2009. V
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all, 37 SCBI delivery locations were identified across providers. Looking at the global distribution, 19 intervention delivery sites (51%) are in Asia, nine delivery sites (24%) in Europe, eight delivery sites (22%) in Central America/Caribbean, and one (3%) in Africa. Six providers list separate locations for administrative offices. Although four of these are located in the United States, no intervention delivery locations are listed within the United States. The other separate administrative offices were located in South Africa and The Netherlands. Figure 1. Intervention delivery locations.
be cleared before SCBIs are ready for use in the clinic [21– 25]. In addition, Lau et al. [26] reviewed published clinical evidence and found that it did not support the clinical use of SCBIs. Despite this paucity of evidence and consensus among scientists, SCBIs are being offered to patients [3, 27]. In this article, we examine content from SCBI providers. We discuss what providers offer and to whom and how they are advertising their services. We conclude with recommendations for patients, physicians, and the stem cell community.
METHODS SCBI providers were identified using strategies designed to emulate those used by a patient seeking treatments. Between April and August 2007, Google searches were performed using the key words ‘‘stem cell treatment’’ and ‘‘stem cell therapy.’’ Google news alert and Lexis/Nexis searches were programmed with these same search terms to monitor media accounts of patients receiving SCBIs. Disease advocacy bulletin boards such as CareCure Community [28], Multiple Sclerosis Resource Centre [29], ALS Therapy Development Foundation Forum [30] and Yahoo health groups: Stem Cell Safety [31] were reviewed to find mentions of providers in patient discussions. Identified providers were located through Internet searches. Twenty-four SCBI providers were identified and assigned numbers; they are referred to by number throughout the article. All but one provider had an accessible web site. Data presented in this article are from the remaining 23 providers. E-mail messages were sent to the providers requesting additional information about their SCBIs. E-mail replies and additional information were received from 10 providers. To better understand the SCBIs and the providers offering them, we conducted a content analysis of providers’ web sites and additional information. Data were collected in the following categories: provider locations, SCBI costs (all costs were converted to US dollars on September 3, 2008 [32]), conditions for which SCBIs are offered, cell sources, cell product ‘‘dosages,’’ SCBI delivery methods, cell quality assurance procedures, provider credentials, risks, and benefits. In addition, available client case studies were examined and client demographics and SCBI data were collected for individual cases. This sample of SCBI providers is not exhaustive, but rather a list of SCBI providers most readily identifiable using our search techniques and thus, includes providers likely to be identified by patients seeking SCBIs in these ways.
RESULTS
Provider Credentials Nineteen providers list staff with some sort of scientific or academic credentials (Table 1). Four (21%) of these refer to involved individuals with the prefix ‘‘Dr.’’ and no further clarification. Fifteen providers list some combination of specific credentials, primarily MDs and PhDs. Three among this group list additional professional distinctions such as fellowships in professional societies and board certifications. Two of the four sites not listing credentials make allusions to some grounding in science/medicine. One has a link on their web site to their ‘‘medical advisory board’’ with no further information. The other states that their ‘‘people have a background and vast experience in health, science, psychology, counseling, journalism and the stem cell industry.’’
Costs Twelve (52%) SCBI providers offer cost estimate information. Cost estimates ranged from $5,000 to almost $39,500 US dollars (Fig. 2). The manner in which providers present cost information is further categorized in Table 2. Four providers require payment in advance of intervention delivery, one of which includes details for completing wire transfers. Two providers specifically note that following the initial intervention, additional SCBI ‘‘boosters’’ may be required at additional cost.
Conditions All providers offer information about conditions for which their SCBIs can be used. The range of conditions is variable. Five (22%) providers offer SCBIs that target fewer than 10 specific conditions and nine (39%) providers offer SCBIs targeting between 10 and 30 specific conditions. The remaining nine providers present a vast array of conditions or even broad categories of conditions. Eight of these providers describe very diverse sets of open-ended categories of conditions such as ‘‘neurological disorders,’’ ‘‘blood disorders,’’ and ‘‘aging.’’ Some within this group also include specific conditions within broader categories. One provider restricts their list to the category of neurological conditions but includes all neurological conditions. Interventions for certain conditions are common across numerous providers (Table 3). Overall, an extremely diverse range of conditions is targeted. Examples of this diversity include: aging, impotence/fading potency, spinal muscular atrophy, dementia, osteoarthritis, rheumatoid arthritis, cancers, depression, Down syndrome, autism, Huntington disease, epilepsy, hepatitis B/C, cirrhosis, lupus, macular degeneration, male/female infertility, skin conditions (scars/burns/ulcers), bone damage, early menopause, blindness, glaucoma, pain, shingles, allergies, gangrene, spina bifida, and B12 and folic acid deficiencies.
Locations
Cell Sources
Of the 23 SCBI providers with updated web sites, 20 (87%) reported on the locations for operations (Fig. 1). Seven providers list multiple intervention delivery locations. One provider lists six different treatment centers and plans for licensing their stem cell technology to 20 locations by the end of 2009. In
All providers offer some information about the cell sources for their SCBIs (Table 1). Seventeen (74%) providers report using a single type of cell in their interventions, whereas the remaining providers report the use of multiple cell types. Among all providers, 11 (48%) report exclusively using cord
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Table 1. Available content by provider Provider
Credentials Medical Degree (MD/MBBS) Other academic credentials (PhD/ DSc) Prof. credentials/fellowships (FACC, FACS, FRCS) Generic prefix (Dr.) Cell sources Cord Blood (4) Adult, Autologous (7) Adult, Allogeneic (2) Adult, Unspecified (3) Fetal Tissue (7) Human Embryonic (3) Other (3) Xenotransplantation (2) CBI method Condition specific methods (e.g., diagnosis) Patient specific methods (e.g., condition severity) Injected/surgically implanted directly into affected site Injected into Spinal Cord Fluid Injected Intravenously Injected Intraarterially Injected subcutaneously Unspecified injection Cell Quality Assurances Purity (only stem cells) Infection free/sterile conditions for manufacture Cell potency/differentiation capacity Manufactured in adherence with standard practices Third party testing Benefits Clinically significant benefits for a majority Range of outcomes, benefits for a majority Benefits exceed current standard treatments Vague positive claims Not a cure Benefits not guaranteed Risks No risks/no side effects No reported side effects/adverse events among clients receiving their intervention No serious risks, only minimal risks/typical risks from implantation Both significant and minor risks No risk of immune rejection No risk of teratoma Provider
1
2
3
4
5
6
7
8
9
10
11
X X X X X X X X X X X X X X
12
13
14
15
16
X X
X X
X
X X
X X
X
17
18
19
20
X
X X
X
X
X
X
X X
X X X X X
X X
X
X X
X X
X X X X X
X
X
X
X
X
X X
X
X X X
X X
X
X
X
X X X X
X X X
X X
23
X X
X X
22
X
X
X
21
X
X X
X
X X
X
X X
X
X
X
X
X* X
X X X X X X X
X X X
X X
X X
X
X
X
X
X X
X
X X
X
X X
X
X X
X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X X X X
X X
X
X X
X X
X
X
X
4
5
X X X 6 7
8
blood or other adult stem cell-based interventions, eight (35%) report using some form of embryonic or fetal stem cell-based intervention, two (9%) use a combination of adult and fetal or embryonic cells, and two report xenotransplanting cells from nonhuman animals into human patients, either exclusively or in conjunction with human cells from adult and fetal sources. The provider using exclusively nonhuman animal sources uses cells taken from fetal and newborn rabbits. Three providers report using cells from more difficult to cate-
9
10 11 12 13 14
X
X
X 3
X
X
X
2
X
X
X X X X
1
X X
X
X
X
X
X
X X X
15
X
X
X
X
16 17 18 19 20 21 22 23
gorize, but apparently embryonic or fetal sources. These include ‘‘embryonic cells from the amniotic membrane,’’ ‘‘hematopoietic stem cells from the human embryonic liver,’’ and ‘‘cloned autologous embryonic stem cells.’’ One provider describes using interventions comprised of cocktails of cells from different sources: ‘‘Each specific stem cell type has its own special effects. The best results have been achieved through combination of different cell types, depending on mechanisms of certain diseases and stages of their progress.’’
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Table 2. Information about cell-based intervention costs Number of providers out of 23
No information about cell-based intervention costs Costs available on further client evaluation Range of costs depending on diagnoses and the intervention delivery method Single specific cost
8 3 6 6
Table 3. Conditions for which providers offer cell-based intervention Figure 2.
Multiple sclerosis Parkinson disease Stroke Diabetes Spinal cord injury Heart disease Cerebral palsy Traumatic brain injury Amyotrophic lateral sclerosis Alzheimer disease Duchenne muscular dystrophy HIV/AIDS
Cell-based intervention costs.
Intervention Delivery Methods Fifteen (65%) providers offer information about methods used to administer SCBIs (Table 1). Thirteen of this subset describe a variety of methods for cell delivery. They describe methods that vary, at least to some extent, on the basis of the specific condition and, in some cases, condition severity. Providers describe methods ranging from invasive surgical procedures to injections (intravenous, intra-arterial, or subcutaneous). Providers also describe the delivery of cells directly into the cerebrospinal fluid through lumbar puncture. Two providers note delivering cells by injection without further details.
16 16 15 13 12 11 11 8 8 6 6 3
Thirteen (57%) providers list some form of quality assurance information for the cell products that they use for SCBIs (Table 1). Nine (69%) of these 13 providers note cell products tested to be free of infectious agents. Seven (54%) note products manufactured in accordance with some form of international protocol or standards such as current Good Manufacturing Practice or Good Laboratory Practice. Six (46%) note cell products tested to ensure that they contain only the intended cells. Four (31%) provide information about the potency or differentiation capacity of the cell product. Three (23%) note testing by independent laboratories to verify assurances. One provider reports using animal product-free manufacturing practices, and another provider notes that their tissue procurement center is responsible for obtaining or verifying legally valid consents of all tissues donors.
have ‘‘generated an estimated 80% incidence of significant clinical benefit.’’ Another provider states that their SCBI ‘‘can substantially improve the flow of blood in a large majority of the patients treated, thus reducing chest pains and sharply increasing physical capacity.’’ Yet another provider urges those with AIDS, diabetes, or any ‘‘so called incurable diseases’’ to become their client, because they can, ‘‘assure you that the first round of treatment will give close to 100% success rate.’’ In contrast, eight providers (35%) explain that client outcomes are variable and that a range of beneficial outcomes is possible. Examples include, ‘‘Results range from very minor to very significant improvements’’ and ‘‘It is a process of repair that occurs at varying levels in different patients and disease states.’’ The largest group (48%) of providers is less direct in their assessment of benefits. Examples include: ‘‘embryonic cells can potentially repair and if needed rebuild practically all organs’’; ‘‘Substantial patient improvement from stem cell therapy has been documented’’; and ‘‘Adult stem cell therapies have produced life changing outcomes for individuals located all over the world.’’ Four providers specifically note SCBI benefits exceeding the current standard treatment for the targeted conditions, including previously incurable diseases such as multiple sclerosis, cerebral palsy, and Down syndrome. Three providers, while claiming benefits for a majority of their clients, also offer the caveat that these interventions are not a cure, and an additional three providers specifically note that benefits cannot be guaranteed.
Benefits
Risks
All providers make some reference to the beneficial nature of their SCBIs. There is, however, variation in the description of the benefits that clients receiving SCBIs should expect (Table 1). Five (22%) providers claim that their SCBIs will result in a clinically significant benefit to a majority of their clients. For example, one of these providers states that their cells
Some of the data about risks overlaps with the data reported in the section on cell quality assurance. As mentioned, 13 (57%) providers make efforts to reassure potential clients about the quality of the cell products used in their SCBIs, claiming that these will not be a source for risks such as infections, particularly chronic infections like hepatitis or HIV. Most providers
Dosage Three (13%) providers offer information about the dose of cells delivered. One provider states that they deliver between three to four injections of 3 million cells each. A second provider advertises their ability to deliver 5 to 10 million cells per intervention; they go on to claim that other providers only use 1.5 million cells. A final provider describes expanding autologous cells samples to ‘‘therapeutic levels’’ containing between 5 and 25 million cells.
Cell Quality Assurance
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Table 4. Case studies Country of origin (n ¼ 480) United States Italy Romania Spain China The Netherlands United Kingdom Canada Germany Australia Japan Greece Singapore Saudi Arabia South Africa India Other (29 countries) Indications (n ¼ 491) Amyotrophic lateral sclerosis Spinal cord injury Multiple sclerosis Heart disease Cerebral palsy Cancer Stroke Parkinson disease Traumatic brain injury Hepatitis C and liver fibrosis Anemia Diabetes (type 2) Other
181 60 49 18 17 14 13 10 10 10 9 6 5 4 4 4 52
(38%) (13%) (10%) (4%) (4%) (3%) (3%) (2%) (2%) (2%) (2%) (1%) (1%) (1%) (1%) (1%) (11%)
167 113 67 38 30 16 15 11 8 2 2 2 20
(34%) (23%) (14%) (8%) (6%) (3%) (3%) (2%) (2%) (
