Transplanting Autoimmune Research

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What’s the difference between testing a typical small molecule drug, and testing a novel cell therapy strategy? And where might the latter raise ethical challenges that the former doesn’t? These questions are extensively discussed in my book, and given human drama in a recent story by Jennifer Couzin-Frankel in the Feb 12, 2010 issue of Science (“Replacing an Immune System Gone Haywire“).


Couzin-Frankel describes the numerous difficulties that researchers have faced in attempting to validate autologous bone marrow transplantation for the treatment of (often nonlethal but highly debilitating) autoimmune disorders like type 1 diabetes, Crohn’s disease, and multiple sclerosis. The idea of this procedure is to “reset” the immune system by purging patients of their bone marrow cells, and then returning healthy bone marrow to them. The approach has shown some promise for certain autoimmune disorders. However, response is highly variable and unpredictable, and validating and applying bone marrow transplantation for autoimmune disorders is beset by numerous ethical and logistical difficulties.

A major one is the risk-benefit balance: bone marrow transplantation requires exposing patients to the dangers of the transplantation procedure (6.6% mortality in one report of lupus patients). And yet, the procedures appear to work better in patients whose disease is not yet advanced. Testing the procedure therefore requires recruiting more or less healthy, at risk patients (sometimes children) into studies that expose them to serious risk of mortality. Clinicians understandably balk at referring their patients to such studies, making recruitment very difficult.

A second challenge is funding: many of these approaches involve using the patient’s own bone marrow cells. There is nothing to patent– and hence, little commercial interest in bone marrow transplantation for autoimmune disorders. This deprives this promising line of research needed resources.

And all this creates the perfect storm for a series of ethical challenges not directly addressed in this article (but covered in my book and articles): the siting of such studies in low and middle-income settings. Prohibitive costs, plus extreme difficulty recruiting patients who are otherwise eligible for somewhat effective and extremely expensive monoclonal antibody therapies, makes the siting of such trials in economically disadvantaged settings very attractive. This gives rise to what I have elsewhere called “expedient” justification for recruitment. Not surprisingly, then, one of the first trials of the procedure was performed in Brazil, and the article closes by mentioning that ongoing trials involving high-income country researchers are recruiting from São Paulo, Prague, China, and Argentina. This is good news if people in those settings have a reasonable prospect of having widespread and affordable access to bone marrow transplantation once it becomes validated. But it is troubling indeed if people in these countries will be bearing considerable burdens for the sake of knowledge benefits that will primarily (or most expeditiously) accrue to patients in high-income settings. (photo credit: Wellcome Images, Compact Bone, 2009)

BibTeX

@Manual{stream2010-72,
    title = {Transplanting Autoimmune Research},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = feb,
    day = 26,
    url = {http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/}
}

MLA

Jonathan Kimmelman. "Transplanting Autoimmune Research" Web blog post. STREAM research. 26 Feb 2010. Web. 20 Nov 2017. <http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/>

APA

Jonathan Kimmelman. (2010, Feb 26). Transplanting Autoimmune Research [Web log post]. Retrieved from http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/


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. 20 Nov 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. 20 Nov 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/


Soft Cells and C-Sections

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The American Society of Gene Therapy is renaming itself: “American Society of Gene and Cell Therapy” (membership has yet to finalize the name change.”  The European Society of Gene Therapy has already done so: “European Society of Gene and Cell Therapy.”


Why is gene transfer going cellular? The publicly stated reasons are two fold. First is a recognition that gene transfer has always involved “cell transfer.” For instance, ADA-SCID and X-SCID protocols– for that matter, all ex vivo protocols– involve modifying cells outside the body, and returning them to the volunteer.

A second reason is to have a more “inclusive” society, and an “expanded membership base.” I suspect this partly reflects a concern that cell-types might affiliate with groups like ISCT (International Society of Cell Therapy), which has a “gene therapy” committee, or perhaps also ISSCR (International Society of Stem Cell Research).

Of course, this raises the question of what ASGCT means by “CT.” Does the society intend “American Society of Gene AND Cell Therapy,” or is it “OR Cell Therapy (which would include protocols that do not involve genetic modification). I can’t help but wonder what the realignment will mean for gene transfer. Since its founding, “gene transfer” has represented a kind of “invisible college” – an international network of collaborations and co-citations with a common set of concerns. Does renaming represent the demise of the gene transfer invisible college, as “genes” are absorbed under the more powerful social category of “cells?”  Or does it represent a promising extension of the network? Is this simply a reflection that in the first decade of the 21st century, “cells” are, in terms of scientific capital, what “genes” were to the 1990s? (photo credit: I like 2008)

BibTeX

@Manual{stream2008-117,
    title = {Soft Cells and C-Sections},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = dec,
    day = 10,
    url = {http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/}
}

MLA

Jonathan Kimmelman. "Soft Cells and C-Sections" Web blog post. STREAM research. 10 Dec 2008. Web. 20 Nov 2017. <http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/>

APA

Jonathan Kimmelman. (2008, Dec 10). Soft Cells and C-Sections [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/


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