Information: Stem Cell Tourism Redux (part 1)

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The current issue of Kennedy Institute of Ethics Journal contains the first installment in a two part series on the ethics of stem cell tourism, by long time stem cell watcher Cynthia Cohen and Peter Cohen. The Cohens pull together a large body of news reports and internet posts on Russian and Indian private clinics offering stem cell interventions to foreign patients (who travel to these clinics because they cannot receive the nonvalidated interventions in their native countries).

They provide a very critical view of these clinics and the practice of offering nonvalidated stem cell interventions to large numbers of patients outside of clinical trials- a view that readers of this blog will recognize as one that I share: “those who travel to other countries for stem cell treatments enter into a sort of medical Russian roulette.” I would add: they pay large sums to shady characters for the privilege.

The back end of the article takes issue with commentators who have offered a quasi-defense of stem cell tourism, viewing stem cell development as analogous to surgical innovation. These commentators have thus defended the idea of offering stem cells outside the trial context. According to the Cohens, these commentators “do not explain in what respects these interventions resemble surgical procedures and do not furnish reasons why clinical trials are not possible for them.”

There is an intriguing theme in this article that ties in with my recent Science article. Namely, the Cohens are careful to point out that there are many legitimate stem cell scientists in Russia and India that have called on their governments to regulate stem cell clinics because their activities harm the reputation of unaffiliated stem cell researchers in the same country. More on how stem cell scientists have attempted to draw boundaries between their own work and that of these clinics in my next post… (photo credit: Alex McGibbon, (courtesy Banksy), 2006)

BibTeX

@Manual{stream2010-61,
    title = {Information: Stem Cell Tourism Redux (part 1)},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = jun,
    day = 17,
    url = {http://www.translationalethics.com/2010/06/17/information-stem-cell-tourism-redux-part-1/}
}

MLA

Jonathan Kimmelman. "Information: Stem Cell Tourism Redux (part 1)" Web blog post. STREAM research. 17 Jun 2010. Web. 21 Sep 2017. <http://www.translationalethics.com/2010/06/17/information-stem-cell-tourism-redux-part-1/>

APA

Jonathan Kimmelman. (2010, Jun 17). Information: Stem Cell Tourism Redux (part 1) [Web log post]. Retrieved from http://www.translationalethics.com/2010/06/17/information-stem-cell-tourism-redux-part-1/


More on Lenti’s, Gene Transfer and Adrenoleukodystrophy

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(…continued from the previous post). There are several features that make the recent Adrenoleukodystrophy (ALD) gene transfer study noteworthy.


1- A New Viral Vector Debuts: this is the first successful application of HIV-derived viruses in gene transfer (lentiviruses). These vectors have various advantages over retroviruses used in other protocols. One is that, in theory, at least, they are supposed to be safer. Previous trials of the same team (different disease) involving retroviruses triggered leukemia-like disorders in several volunteers. In this study, the authors do not detect any evidence that cells are poised to cause a malignancy. However, in a post this summer, I noted that another trial involving thalessemia and lentiviruses did, indeed, detect clonal enrichment. And the ALD study enrolled only two patients- if there were going to be safety problems detected, they’d need to be massive to be detected in so small a sample of patients. Thus, despite the encouraging findings in the ALD study, the safety of lentiviral gene transfer remains to be firmly established.

2- Prior Animal and Clinical Experience are Successfully Integrated: here is one instance where favorable clinical outcomes were achieved on the basis of limited preclinical evidence. Specifically, the authors previously tested their approach in mice, but because rodents do not develop the same pathology as human beings, they were uncertain whether the gene correction would be sufficient to correct the disorder in human patients. These animal studies were bootstrapped with extensive experience with bone marrow transplantation in children with ALD. Rarely is this transition from rodents into clinical applications so successful. All the more surprising- this is occurring within the realm of central nervous system disorders, which have a particularly high rate of failed drug development.

3- Patients in the Service of Science: This study will no doubt be perceived as a story of “science in the service of patients:” a team of clinicians applying cutting edge discoveries to do the best they can for their patients. But it is as much- perhaps more- a story of patients in the service of science. The study is notable for how well it used the occasion of ALD to make more fundamental discoveries. For example, in a “Perspective” piece that accompanies the published trial, Luigi Naldini describes this as what “may be a first glimpse of live [generation of new blood and immune cells at the level of DNA].” Naldini also notes how the study developed and applied new techniques for ruling out clonal dominance that “will likely become a gold standard.” Also intriguing is the hint that this approach may be applicable for other disorders involving the central nervous system, and the finding that only a small amount of gene correction is needed to arrest the pathology. (photo credit: photobunny 2007)

BibTeX

@Manual{stream2009-78,
    title = {More on Lenti’s, Gene Transfer and Adrenoleukodystrophy},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 12,
    url = {http://www.translationalethics.com/2009/11/12/more-on-lentis-gene-transfer-and-adrenoleukodystrophy/}
}

MLA

Jonathan Kimmelman. "More on Lenti’s, Gene Transfer and Adrenoleukodystrophy" Web blog post. STREAM research. 12 Nov 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/11/12/more-on-lentis-gene-transfer-and-adrenoleukodystrophy/>

APA

Jonathan Kimmelman. (2009, Nov 12). More on Lenti’s, Gene Transfer and Adrenoleukodystrophy [Web log post]. Retrieved from http://www.translationalethics.com/2009/11/12/more-on-lentis-gene-transfer-and-adrenoleukodystrophy/


Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris

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Last week’s Science magazine reported what seems likely to count as one of gene transfer’s greatest clinical successes to date: stabilization of adrenoleukodystrophy in two boys receiving genetically modified blood stem cells. Preliminary results of this study had been presented at this summer’s American Society of Gene and Cell Therapy meeting.


Adrenoleukodystrophy (ALD) is a rare hereditary brain disorder in which a deficiency in a gene, ABCD1, causes degeneration of tissues (myelin) that insulate cells in the central nervous system. The disease is familiar to many because of its most famous patient, Lorenzo Odone, whose story was featured in the movie Lorenzo’s Oil. Untreated, ALD is invariably fatal.

Because myelin cells originate from blood stem cells, researchers had previously used bone marrow transplantation to successfully halt progression of demyelination in ALD patients. However, bone marrow transplantation has two severe limitations: many patients lack matched bone marrow donors; second, even when a matched donor is available, the procedure is burdensome and risky.

In this most recent study, researchers at Hôpital Necker in Paris transplanted genetically modified bone marrow cells into two Spanish boys who lacked matched bone marrow donors. The boys were also given myeloablative conditioning- a type of chemotherapy that increases the likelihood that genetically modified cells will repopulate the bone marrow. The Science report showed:

1- genetically modified cells did, indeed, survive and were maintained at stable levels for two years.
2- the modified cells expressed the therapeutic gene, ABCD1, again for two years.
3- brain demyelination was halted after 14 months- the timing is similar to what would occur for patients receiving bone marrow transplantation.
4- the two boys did not appear to decline on various measures of neurological or verbal tests, as would almost certainly have occurred with the natural course of ALD.
5- the authors did not detect “clonal dominance” in their modified cells– that is, evidence that genetically modified cells were poised to cause a malignancy.

In an accompanying editorial, Luigi Naldini calls this study a “Comeback for Gene Therapy,” describing it as a “long-sought rewarding achievement in the field of gene therapy.” In my next post, I will discuss some implications, interpretations, and other interesting dimensions of this very encouraging study (photo credit: tgif28, chalk graffiti at Hopital Necker, 2009)

BibTeX

@Manual{stream2009-79,
    title = {Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 12,
    url = {http://www.translationalethics.com/2009/11/12/gene-transfer-and-adrenoleukodystrophy-there-will-always-be-paris/}
}

MLA

Jonathan Kimmelman. "Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris" Web blog post. STREAM research. 12 Nov 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/11/12/gene-transfer-and-adrenoleukodystrophy-there-will-always-be-paris/>

APA

Jonathan Kimmelman. (2009, Nov 12). Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris [Web log post]. Retrieved from http://www.translationalethics.com/2009/11/12/gene-transfer-and-adrenoleukodystrophy-there-will-always-be-paris/


Quack You! Medical Tourism and Stem Cells

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In the September 2009 issue of Nature Biotechnology, Jane Qiu reports on a thriving trade in nonvalidated stem cell interventions for incurable illnesses (“Trading on Hope”). The article provides numerous examples of overseas clinics that cater primarily to North American and European clientele in offering pricey, unproven stem cell transplants for incurable conditions like spinal cord injury, Parkinson’s disease, and autism. Many of these clinics make extravagant claims in their promotion materials.


Encouragingly, policy makers are beginning to take notice. China, for example, has issued new regulations on clinical application of novel interventions; it requires licensing for clinics that provide unproven stem cells. India has issued guidelines on stem cell research and therapy. As noted previously in this blog, the scientific society ISSCR issued guidelines urging clinicians to offer nonvalidated stem cell interventions to patients only in the context of clinical trials designed to test safety and efficacy. Problem is (according to the article), guidelines are sporadically enforced, if that.

I think there is much more that governments and professional societies can and should do to stem this unethical conduct. Though most of these clinics are located outside of North American and Europe, some overseas clinics have reputable, North American / European scientists and clinicians on their advisory board or have partnerships with biotechnology companies that are based in North America / Europe. Examples include Stemedica (which includes several Stanford and UCSD faculty on its advisory board), and Theravitae (which has involved close collaboration with University of Pittsburgh clinicians), and Vescell (which includes Nobelist Aaron Ciechanover on its scientific advisory board). All of these companies offer stem cell interventions to large numbers of patients outside trials, and make claims that their interventions are effective when, in fact, they remain unproven.

1- Research ethics policies should condemn scientist-clinicians who travel or collaborate abroad in delivering nonvalidated, potentially risky interventions overseas outside the context of a clinical trial. Policies should state clearly the imperative of subjecting nonvalidated interventions to systematic study.
2- Institutions should not allow these clinics to trade on their reputations, and should sanction faculty members who are involved in such activities.
3- professional societies in medical fields (e.g. cardiology) and research areas (stem cells, gene transfer) should steward the standing and credibility of their research field by developing policies and standards that discourage inappropriate activities– through social pressure– by providing a benchmark against which the conduct of scientists and clinicians can be judged.

(photo credit: Insert Photographer Here, 2006)

BibTeX

@Manual{stream2009-84,
    title = {Quack You! Medical Tourism and Stem Cells},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = sep,
    day = 23,
    url = {http://www.translationalethics.com/2009/09/23/quack-you-medical-tourism-and-stem-cells/}
}

MLA

Jonathan Kimmelman. "Quack You! Medical Tourism and Stem Cells" Web blog post. STREAM research. 23 Sep 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/09/23/quack-you-medical-tourism-and-stem-cells/>

APA

Jonathan Kimmelman. (2009, Sep 23). Quack You! Medical Tourism and Stem Cells [Web log post]. Retrieved from http://www.translationalethics.com/2009/09/23/quack-you-medical-tourism-and-stem-cells/


Stems and Blossoms (part 2): Really Informed Consent

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There is a strain within the clinical and bioethics community that takes a minimal view of informed consent: investigators are supposed to provide requisite information to volunteers; if research subjects fail to comprehend this information, pity for them. This view brings to mind a memorable exchange between Inspector Clouseau and a hotel clerk (Clouseau: “does your dog bite?” Clerk: “No.”  Clouseau then extends a hand; the dog lunges at him.  “I thought you said your dog doesn’t bite.” Clerk: “Zat is not my dog.”)


The ISSCR guidelines take a bold stand on informed consent. “Investigators involved in clinical research must carefully assess whether participants understand the essential aspects of the study.”  The guidelines go on to state “ideally, the subject’s comprehension of information should be assessed through a written test or an oral quiz during the time of obtaining consent.” Once again, ISSCR shows vision here in going well beyond the legalistic conception of informed consent described above.

The ISSCR guidelines also urge researchers to:
• explain possible irreversibility of some toxicities
• describe the sources of stem cells
• inform patients that researchers “do not know whether they will work as hoped”

These laudable recommendations aside, I might have hoped for more guarded language about the therapeutic value of early phase studies. For one, the guidelines use mostly “therapeutic” language, for example, using the aspirational term “cell therapy” instead of the neutral term “cell transfer.” Second, the third item above logically means that the probability of benefit is less than 100%; experience tells us, however, that when interventions are highly novel, major therapeutic benefits for early phase trials are very improbable. (photo credit: Helen K, Stems, 2008)

BibTeX

@Manual{stream2008-114,
    title = {Stems and Blossoms (part 2): Really Informed Consent},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = dec,
    day = 30,
    url = {http://www.translationalethics.com/2008/12/30/stems-and-blossoms-part-2-really-informed-consent/}
}

MLA

Jonathan Kimmelman. "Stems and Blossoms (part 2): Really Informed Consent" Web blog post. STREAM research. 30 Dec 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/12/30/stems-and-blossoms-part-2-really-informed-consent/>

APA

Jonathan Kimmelman. (2008, Dec 30). Stems and Blossoms (part 2): Really Informed Consent [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/30/stems-and-blossoms-part-2-really-informed-consent/


Stems and Blossoms (part 1): Justice

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Shortly before I left for holiday, the International Society for Stem Cell Research (ISSCR) issued a policy paper, “Guidelines for the Clinical Translation of Stem Cells,” outlining ethical and scientific considerations for researchers designing translational trials involving stem cells (whether stem cell derived, adult, or embryonic).


In my opinion, the document wins the award for most forward thinking and comprehensive statement on the ethics of a translational enterprise. It shows that the stem cell research leadership has closely studied mistakes made by translational researchers in other highly innovative fields.  But the guidelines do more than look backwards; they proactively contemplate fairness and justice considerations as well.  Here are a few justice-related excerpts:

On responsiveness: “The ISSCR strongly discourages conduct of trials in a foreign country solely to benefit patients in the home country of the sponsoring agency. The test therapy, if approved, should realistically be expected to become available to the population participating in the clinical trial through existing health systems or those developed on a permanent basis in connection with the trial.”

On reasonable availability: “As far as possible, groups or individuals who participate in clinical stem cell research should be in a position to benefit from the results of this research.”

On diversity: “Stem cell collections with genetically diverse sources of cell lines should be established”

On access and licensing: “Commercial companies, subject to their financial capability, should offer affordable therapeutic interventions to persons living in resource-poor countries who would otherwise be wholly excluded from benefiting from that stem cell-based therapy. Academic and other institutions that are licensing stem cell therapeutics and diagnostic inventions should incorporate this requirement in their intellectual property license”

On review: “Regulatory and oversight agencies (local, national, and international) must explicitly include the consideration of social justice principles into their evaluations.”

On trial participation: “… the sponsor and principal investigator have an ethical responsibility to make good faith, reasonable efforts whenever possible to secure sufficient funding so that no person who meets eligibility criteria is prevented from being considered for enrollment because of his or her inability to cover the costs of the experimental treatment.”

In upcoming posts, I will comment on other aspects of the ISSCR guidelines. (photo credit: Helen K, Stems, 2008)

BibTeX

@Manual{stream2008-115,
    title = {Stems and Blossoms (part 1): Justice},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = dec,
    day = 28,
    url = {http://www.translationalethics.com/2008/12/28/stems-and-blossoms-part-1-justice/}
}

MLA

Jonathan Kimmelman. "Stems and Blossoms (part 1): Justice" Web blog post. STREAM research. 28 Dec 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/12/28/stems-and-blossoms-part-1-justice/>

APA

Jonathan Kimmelman. (2008, Dec 28). Stems and Blossoms (part 1): Justice [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/28/stems-and-blossoms-part-1-justice/


Sell Therapy, European Style

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Two side-by-side news reports in the August 21 issue of Nature spell more trouble for cell therapy in Europe. The first story follows on previous reports about Austrian urologist Hannes Strasser (see postings on Jul 23 and May 27, 2008). According to an Austrian government report, Strasser “failed to get appropriate approval for the trial from authorities… failed to adequately inform patients… [and used] poor study design.” Strasser’s university has banned him from seeing patients. Somewhat cryptically, the article mentions that “several of the hundreds of patients who have undergone the procedure by Strasser’s team… claim that they have had serious side effects.”  Are these attributable to the intervention?  We shall see.


About 600 kilometers to the Southeast, a Bulgarian deputy minister resigned after the European Union shut down a Sophia-based clinic that provides non-validated bone marrow therapy treatments for victims of spinal-cord trauma, stroke, and neurodegenerative diseases.  The minister reportedly has family members who “own two private companies” that perform the procedures. (photocredit: Eesti, Central Hali Market in Sophia, 2005)

BibTeX

@Manual{stream2008-139,
    title = {Sell Therapy, European Style},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = aug,
    day = 28,
    url = {http://www.translationalethics.com/2008/08/28/sell-therapy-european-style/}
}

MLA

Jonathan Kimmelman. "Sell Therapy, European Style" Web blog post. STREAM research. 28 Aug 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/08/28/sell-therapy-european-style/>

APA

Jonathan Kimmelman. (2008, Aug 28). Sell Therapy, European Style [Web log post]. Retrieved from http://www.translationalethics.com/2008/08/28/sell-therapy-european-style/


Stemming Medical Tourism (part 1)

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The July 17 issue of Nature reports that a patient participating in a Vienna-based cell transfer study for urinary incontinence won a lawsuit against the University Hospital in Innsbruck for not being “told… the procedure was experimental.”


The case was described in an earlier post in my blog (May 27, 2008: Bladder Trouble at the Frontier).  There are a number of cell transfer strategies that are being applied in clinics, despite absence of reliable data showing efficacy. This should worry conscientious investigators who are trying to shepherd this promising technology platform to clinical application.

Here’s one example: Bankok based company TheraVitae offers cell transfer to advanced heart patients. In future posts, I will explore concerns about an emerging overseas industry in non-validated therapeutics that 1- involve cutting edge therapies, and 2-involve investors, and scientists, whose countries of origin have not yet licensed such therapies for clinical application. (photo credit: Olivander 2006)

BibTeX

@Manual{stream2008-143,
    title = {Stemming Medical Tourism (part 1)},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = jul,
    day = 23,
    url = {http://www.translationalethics.com/2008/07/23/stemming-medical-tourism-part-1/}
}

MLA

Jonathan Kimmelman. "Stemming Medical Tourism (part 1)" Web blog post. STREAM research. 23 Jul 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/07/23/stemming-medical-tourism-part-1/>

APA

Jonathan Kimmelman. (2008, Jul 23). Stemming Medical Tourism (part 1) [Web log post]. Retrieved from http://www.translationalethics.com/2008/07/23/stemming-medical-tourism-part-1/


Bladder Trouble at the Frontier

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In the May 1, 2008 issue of Nature, Alison Abbott reports on fraud allegations against Austrian researcher Hannes Strasser for performing an adult stem cell trial for urinary incontinence without having his protocol reviewed by an ethics committee.


According to the story, the volunteers paid approximately $17K U.S. to enter the study. They also were not told the procedure was investigational. The researchers might also have lied to their ethics committee, as well as Lancet (where they published the results). There also appear to be questions about whether the promising results obtained by Strasser are reproducible.

Of course, the allegations have yet to be proven. But the story will sound familiar to anyone that has followed the history of gene transfer- and indeed any cutting edge research area. The allegations highlight a key point I make in my book: part of what makes risk assessment at the medical frontier difficult has to do with the mercurial individuals and institutions– and the unstable relationships among various interested parties– that surround high-risk, high-payoff research. These “social” components of risk need to be par of the equation when policy makers, ethicists, and others evaluate the ethics of a study. (photocredit: DisneyKrazie 2007)

BibTeX

@Manual{stream2008-152,
    title = {Bladder Trouble at the Frontier},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 27,
    url = {http://www.translationalethics.com/2008/05/27/bladder-trouble-at-the-frontier/}
}

MLA

Jonathan Kimmelman. "Bladder Trouble at the Frontier" Web blog post. STREAM research. 27 May 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/05/27/bladder-trouble-at-the-frontier/>

APA

Jonathan Kimmelman. (2008, May 27). Bladder Trouble at the Frontier [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/27/bladder-trouble-at-the-frontier/


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