Considering a stem cell treatment offer?

In recent years there has been a growing interest in so-called stem cell ‘tourism’ - where a person (often accompanied by their carer/family) travels to another country for a purported stem cell treatment that is not available in their home country. Many advertised treatments are clinically unproven, with little or no evidence for their safety and efficacy in specific conditions. The majority of treatments marketed as ‘stem cell treatments’ are autologous cellular therapies: stem cells are taken from the patient’s own body and re-injected into the patient’s own body to promote regeneration. Some clinics also claim to use donated cord blood, or embryonic and fetal cells, but it is hard to know what is being administered to recipients and difficult to scientifically verify.

Over the last couple of years, the University of Melbourne have been capturing the experience of Australians who have embarked on journeys in the pursuit of stem cell treatment. Participants in their research project have travelled overseas for treatments for various conditions including spinal cord injury, cerebral palsy, motor neurone disease and multiple sclerosis. Common destinations are China, India, Germany, Israel, the United States of America and Panama.

One of the early destinations of choice was the now infamous X-Cell Center that operated in Cologne and Düsseldorf in Germany. The X-Cell Center clinic was established in early 2007 by Cornelis Kleinbloesem, a Dutch entrepreneur with a background in pharmacy and clinical trials research. The creation of the X-Cell Center in Germany was in part due to new regulation by the Dutch government, which in 2006 introduced a moratorium banning unproven stem cell treatments and created new regulations concerning the differentiation of stem cells and a requirement to have a license for stem cell transplants. The new regulation took effect on 1 January 2007, stifling some of Kleinbloesem’s earlier business interests. By establishing the X-Cell Center clinic in Germany Cornelis Kleinbloesem was able to take advantage of a loophole that existed in German law due to a transition period that required European compliance standards to come into effect.

Capitalizing on stem cell hype

During its period of operation (2007-2011) the X-Cell Center treated many thousands of people, almost exclusively foreigners from various countries. Much of the success of the X-Cell Center was due to its ability to tap into the expectation surrounding stem cells. It capitalised on this global hype by selling stem cell treatments for some of the most debilitating conditions. According to the X-Cell Center website they offered to treat a myriad of conditions including diabetes, stroke, spinal cord injuries, multiple sclerosis (MS), cardiovascular disease, Parkinson’s disease, Alzheimer’s disease, amongst others.

Their website featured stories proclaiming ‘miracles’ of the power of stem cell treatments, such as a story of a former patient who was cured of diabetes[1]. The clinic was open about the treatment procedures - described in some detail on their website - but it is difficult to determine the level of risk that was elaborated to patients as many patients had different experiences. But in selling stem cell treatments the clinic did seek to downplay the risks associated with autologous stem cell treatments, stating: “The XCell-Center only uses ethically inoffensive adult stem cells for treatment and research”.

Patient experiences at The X-Cell Center

A key factor in the X-Cell Center’s success was the setting of its operations. By renting floors in Catholic Hospitals, such as the Dominikus Hospital in Düsseldorf-Heerdt, the clinic conveyed the impression of offering an ethically uncontentious treatment.

Visitors and patients alike have reported the clinic’s opulent reception area and the selling of a premium service, with treatments priced from 3,000 to 10,000+ Euros. But one of the biggest selling points for X-Cell Center was ‘brand’ Germany—relying on the country’s international reputation for high medical and manufacturing standards. As a participant in our research stated, going to Germany meant that they “felt reassured about what was happening as opposed to being in a [third world country]”. The experience of going to the X-Cell Center for treatment was sold as a tourist event, with patients being met at the airport or train station by a representative and accompanied to the clinic and offered transfers to and from the patient’s hotel.

Clinics such as the X-Cell Center exploit those vulnerable and in search of hope. Former patients have recounted their suspicions about the X-Cell Center. One research participant recalled their experience of treatment at the clinic:

I went into the room. The thing that did get me a little bit suspicious when I got there was they took my money straight away, which I think’s a little bit odd but, then again, I can understand that people are coming from overseas…and then, basically, they did the procedure the following day.

Another former patient also explains their experience:

When I was hooked up to the drip, before they injected the stem cells in, the manager of the place, a great, huge guy came out and he said, “Oh we haven’t got a receipt for the money,” so I had to make sure the money had gone into their account before they would put the stem cells in. On my return [to Australia]…my neurologist sent me to a haematologist and got my bloods checked, and he said there’s no evidence whatsoever to say that I have had a stem cell transplant.

These comments are just some from former patients; however, they suggest a business driven by money more than patient welfare.

Adverse events close the X-Cell Center

In 2010 the X-Cell Center came under increasing criticism when a 10 year old boy from Azerbaijan suffered severe internal bleeding in the brain after he was given treatment that involved injecting stem cells into the brain, and the death of an 18 month old from Italy who died from complications relating to a similar procedure. Following these adverse events, German regulators were able to close the X-Cell Center since subsequent investigation found that intra-cranial injections with blood cells produced more harm than benefit; further, there was no data to support X-Cell’s use of this treatment. The majority of the X-Cells Center’s patient data was generated by questionnaires administered via email or telephone rather than via scientific clinical methods. Therefore, in early 2011 the X-Center was instructed to adhere to new regulations in Germany that would require special application for continued therapies. Due to the issues outlined above, they were unable to obtain compliance. Later in 2011 the X-Cell Center filed for insolvency because German authorities denied the clinic further authorisation for stem cell transplantation.

But another clinic opens…

Not long after the closure of the X-Cell Center, Cornelis Kleinbloesem opened another stem cell treatment clinic called Cells4health in Beirut, Lebanon - again operating via a regulatory loop-hole, offering the same experimental stem cell therapies offered by the X-Cell Center, and again charging many thousands of dollars to vulnerable patients. This clinic is an international operation - it takes autologous cells from the patient’s bone marrow in the clinic in Beirut and then sends them to the UK’s Precious Cells laboratory for processing. Then the stem cells are sent back to Lebanon and injected into the patient. It would appear in this case that despite the lack of credible evidence to support the serial activities by Kleinbloesem, patient demand in the face of regulatory ambiguity or vacuum have allowed this concerning and potentially risky intervention to continue.

Lessons from X-Cell

We can learn several things from the controversy surrounding the X-Cell Center. First, there is a need for enforced advertising standards that limit the health claims that can be made about experimental therapies such as autologous stem cell treatments. Second, the public needs more information about stem cell interventions - and autologous stem cell treatments in particular - to limit risks posed to patient welfare. Third, regulation can be used as a tool to shut down clinics using questionable clinical techniques. And finally, the issue of borderless health care, especially for experimental therapies that exploit vulnerable patients, could be described as a human rights issue. We'll return to this last point in a later post.

Notes and acknowledgements 

• Authored by Casimir MacGregor, Alan Petersen and Megan Munsie
• The authors are currently involved in a research project, titled High hopes, high risks: a sociological study of stem cell tourism, funded by the Australian Research Council (DP120100921).
• [1] www.xcell-center.com/news -  The X-Cell Center website was accessed via the web archive: http://web.archive.org/
• Thanks to Ira Hermann of Stem Cell Network NRW for reviewing this article.
• Edited by Kate Doherty

"Well I can't get any sicker than I am… it's worth the risk. It's worth trying…you hope that it's a solution"

Sylvia (not her real name) is one of a growing number of patients seeking access to unproven stem cell treatments to treat a debilitating chronic illness. Despite widespread support for tighter regulation and monitoring, the market for unproven stem cell treatments appears to be expanding. In Australia, for example, there has been a dramatic rise in the number of private stem cell clinics, from two to more than forty in just three years.

In this article we seek to situate the patient experience within a socio-political context. We examine whether access to as yet unproven interventions is a human rights issue, taking a closer look at the Stamina therapy controversy and patient activism in Italy.

The Stamina Foundation: unproven stem cell treatments in the Italian courts

The so-called Stamina method is a controversial unproven stem cell ‘treatment’ developed by Davide Vannoni (a professor of psychology) from the work of Ukrainian and Russian researchers (Abbott, 2013). The Stamina method was said to turn mesenchymal stem cells (MSC) from the patient’s own bone marrow into neural stem cells in order to treat neurodegenerative conditions. Vannoni set up the Stamina Foundation to help advance the application of this therapy. Many patients were treated from 2006, first from a clinic in Turin, and then later San Marino and other cities across Italy, even though the safety and efficacy of the treatment were not established, and regulatory approval was not obtained from Italian authorities. Following the pattern of other clinics that sell unproven stem cell therapy (eg the X-Cell Center), online patient testimonials became a key tool in selling hope to desperate and frustrated patients.

Following media reports of the miracle treatment, Torino magistrate Raffaele Guariniello in 2009 investigated claims made by the Stamina Foundation and concluded the treatments could be ‘dangerous to public health’. The closing of local operations forced the Foundation to move from San Marino to Trieste before re-establishing its operation at a public hospital in Brescia. The clinicians using the Stamina method on patients (including many children) justified their use of the ‘treatment’ by invoking the ‘hospital exemption’ clause for unproven treatments that is permitted under EU regulations and allows the use of experimental therapies on a case-by-case basis under strict conditions.

In May 2012, another investigation of the treatment was undertaken, this time by Agenzia Italiana del Farmaco (AIFA), the Italian Medicines Agency and by Carabinieri NAS (Unit for Health Protection). Following AIFA’s investigation of the Stamina Foundation a number of irregularities were identified:

• Ethics committee approvals had been based on inadequate information.
• Cells were prepared within a GLP lab intended for the handling of haematopoietic stem cells for transplant (Bianco, 2013) and not in a GMP-lab authorized for more than minimal manipulation of mesenchymal stem cells for clinical use.
• There were irregularities in the storage and documentation of cells confiscated by Carabinieri NAS (Unit for Health Protection).
• There were no published clinical data nor detailed protocols or patient follow-up.

As a result, the AIFA shut down the laboratory, effectively banning the Stamina method.

Following this ban, many Italian citizens upset at being denied this ‘miracle’ treatment engaged in legal challenges in the hope of obtaining treatment for themselves or their sick children. Patient protests were held across Italy, such as the 'March of the Sick’ by pro-Stamina advocates. At the Rome protest patient activists held large banners, such as one proclaiming:

Pretendiamo l’accesso alle cure compassionevoli con il metodo stamina / We claim access to compassionate care with the stamina method. (author's translation)

The Stamina debate was widely covered in the media, with popular satirical news program Le Iene (The Hyenas), and other celebrities and some politicians, coming out in support of activists and calling for the ban on the Stamina therapy to be overturned.

Anti-Stamina advocates were also active. An open letter signed by 13 stem cell scientists, for example, sought to highlight concerns about the safety and efficacy of the Stamina therapy and warned the Italian Health Minister of the dangers of facilitating ongoing access to unfounded treatment.

On the 20 May 2013, in response to the significant public outcry by patient activists and pro-Stamina advocates, Italy’s Parliament, first the Chamber of Deputies and later the Senate agreed to overturn the ban on the Stamina therapy and allow compassionate use, with some strict conditions. A clinical trial of the Stamina therapy was ordered and €3 million of funding allocated. It was also stated that the Stamina therapy could be given to the 36 patients already receiving it at the hospital in Brescia, It was also ordered that the stem cells must adhere to good manufacturing practice standards (Margottini, 2013a).

Then in July 2013 the new Minister of Health, Beatrice Lorenzin, ordered the Stamina Foundation to release its scientific data and treatment protocols for examination by a "committee of scientific experts to assess if the Stamina method was safe and effective enough to enter human trials" (Margottini, 2013b). On 12 September the committee rejected the scientific basis of the Stamina therapy and would not let it proceed to clinical trial. Concerns included the lack of detail about how the MSC were differentiated into neural stem cells; and the lack of quality controls regarding the cells, and consequently the lack of safeguards and evidence as to the efficacy of the treatment (Margottini, 2013b). While the impartiality of the expert scientific committee was questioned in a subsequent legal challenge, a second panel of experts convened in 2014 again recommended that the trial of the Stamina method not proceed (Margottini, 2014). Yet, despite the concerns raised about the lack of scientific justification and emerging allegations of criminal conduct involving fraud by those promoting the therapy (Margottini, 2014), patients continued to seek access to the treatment until March 2015, when Davide Vannoni, found guilty, negotiated a suspended sentence with the Torino Court on the condition that he would not treat patients.

Enter the European Court of Human Rights

In May 2014 an application (Durisotto vs Italy no 62804/13) was made to the European Court of Human Rights to obtain access to the Stamina therapy on compassionate use grounds. Mr Durisotto, an Italian citizen, sought treatment for his daughter who had suffered from metachromatic leukodystrophy (MLD), a neurodegenerative condition, since adolescence. In April 2013, Mr Durisotto had requested in the Italian courts access to the Stamina therapy for compassionate use for his daughter, in the absence of other treatment options (Rial-Sebbag and Blasimme, 2014). The Italian court initially granted his request, but following the Government’s subsequent ban on the Stamina therapy it reversed its decision. Mr Durisotto appealed to the European Court of Human Rights claiming infringement of several articles of the European Convention of Human Rights namely Article 2 (a right to life), Article 8 (right to respect for private life) and Article 14 (prohibition of discrimination) (Rial-Sebbag and Blasimme, 2014). Therefore Durisotto vs Italy sought to establish if compassionate use of an unproven therapy could be granted according to the principles of the European Convention of Human Rights (Rial-Sebbag and Blasimme, 2014).

The European Court of Human Rights declared Mr Durisotto’s application for access on compassionate grounds inadmissible, drawing on the findings from the expert scientific committees that there was no scientific basis for the Stamina therapy. Furthermore the Court found it was not discriminatory to prohibit access to the Stamina method on compassionate grounds, as prohibiting access to the therapy "possessed a legitimate aim of protecting health" (ECHR, 2015).

The right to life?

Pro-Stamina activists have long asserted a ‘right to life’ ethos – often using the slogan Sì a Stamina, sì alla vita/ Yes to Stamina, yes to life - in their campaign for compassionate access to the therapy.

Invoking a human rights discourse to facilitate access experimental and unproven therapies is not new. In the USA during the 1980s AIDS activist Ron Woodroof appealed to human rights in order to seek to experimental HIV treatment zidovudine (AZT) and to change FDA regulation concerning access to these experimental HIV drugs – a story immortalised in the film Dallas Buyers Club. More recently in the USA, the so called ‘right to try’ movement has sought to establish democratic principles within state law to mandate access to experimental and unproven treatments in an effort to promote constitutional change (Adriance, 2014). The fight to recognise a ‘right to try’ has become a political movement to not only extend access to life saving drugs such as the antiviral Brincidofovir by Chimerix to treat cases of the Ebola virus, but also to reform FDA procedures, such as fast tracking access to life saving pharmaceuticals and allow for greater patient input into the clinical trials framework. These issues are being discussed in the 21^st Century Cures Act currently under consideration (Adriance, 2014).

The debate about patient access to unproven and untested treatments politicises human rights. By this we mean that the language and discourse of human rights becomes a political tactic in order to advance rights based upon the blurring of legal rights with particular moral and ethical positions. Patients and their families and friends invoke the ‘right to life’ to gain compassionate access to experimental and unproven treatments. But as illustrated by the European Court of Human Rights, the counter argument of the ‘right to protect life’, which seeks to maintain the boundary between legal and moral rights, must be considered. What we can observe in this example is a politics of life – how life simultaneously shapes and is shaped by the political choices and the moral economies of contemporary societies (Fassin, 2009:49). The politics of life seeks to highlight the meaning and values we give to life, rather than the power over life in determining the sort of life people may or may not live (Fassin, 2009:49).

Patient access to unproven stem cell treatments is a human rights issue, but the nature of those ‘human rights’ can be contested, as the Stamina case illustrates. Patients may invoke ‘human rights’ to gain access to unproven stem cell treatments. But we must first uphold ‘human rights’ and ‘do no harm’. We need to allow stem cell technologies and other experimental treatments time to develop and prove their efficacy before they are made widely available, and certainly before they are sold and marketed to the public.

References 

• Abbot, A. (2013) Stem-cell ruling riles researchers. Nature 495(7442), 418-9.
• Adriance, S. (2014). Fighting for the" Right to Try" Unapproved Drugs: Law as Persuasion. Yale Law Journal Forum, 124, 148-148 (subscription may be required)
• Bianco et. al (2013). Regulation of stem cell therapies under attack in Europe: for whom the bell tolls. The EMBO Journal, 32, 1489-1495
• European Court of Human Rights (ECHR) (2015) Health Factsheet (PDF)  
• Fassin, D. (2009). Another politics of life is possible. Theory, Culture & Society, 26(5), 44-60 (subscription may be required).
• Margottini, L. (2013a) Italian parliament orders €3 million trial of disputed therapy. Science 340 (6136):1028 (subscription may be required).
• Margottini, L. (2013b) Italy blocks use of controversial stem cell therapy. Science News 11 October. 
• Margottini, L. (2014) Final chapter in Italian stem cell controversy? Science News 7 October.
• Munsie, M. & Pera, M. (2014). Regulatory Loophole Enables Unproven Autologous Cell Therapies to Thrive in Australia. Stem Cells and Development, 23(S1), 34-38.
• Rial-Sebbag, E., & Blasimme, A. (2014). The European Court of Human Rights’ Ruling on Unproven Stem Cell Therapies: A Missed Opportunity?. Stem Cells and Development, 23(S1), 39-43.

Acknowledgements

• Authored by Casimir MacGregor, Alan Petersen and Megan Munsie
• Thanks to Gianni Munizza, Stefania Bettinelli and Michele De Luca for reviewing this article
• Courtroom, European Court of Human Rights by Adrian Grycuk (Own work) [CC BY-SA 3.0 pl], via Wikimedia Commons
• Edited by Kate Doherty

This composite article was predominantly written by Megan Munsie and Casimir McGregor, University of Melbourne. It was edited by Kate Doherty and Jan Barfoot. It was reviewed by Phil Rossall, Research Manager (Knowledge Management) Age UK and Fellow, University of Edinburgh (Knowledge Exchange).