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)

2008 May 27 | Leave a comment | Tags:

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. 10 Jan 2025. <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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Goodbye, Helsinki

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According to recent news reports, the U.S. FDA recently decided to abandon its endorsement of the Declaration of Helsinki when sponsors submit clinical trial data obtained overseas.


The Declaration of Helsinki (DoH)- which was first adopted in 1964- is the World Medical Association’s statement on ethical requirements for human experimentation.  According to an editorial in Nature (22 May 2008), 85 countries have endorsed the DoH.

The FDA had long ago began distancing itself from the DoH when it refused to endorse revisions to the statement that followed controversies over the use of placebos in HIV mother-to-child transmission studies.  But the FDA has now opted to slam shut a door it had, for years, left ajar.

Helsinki is an imperfect document.  Certain paragraphs– particularly those involving international research– have continued to provoke heated debate.  But it is arguably the most influential, multilateral statement on ethical human experimentation, and it speaks clearly to considerations of justice when high income countries pursue trials in resource-poor settings.

Shame on FDA, and the U.S. government, for favoring parochial interests over international policy and, indeed, human rights. (photo credit: sobergeorge 2007)

2008 May 23 | Leave a comment | Tags:

BibTeX

@Manual{stream2008-153,
    title = {Goodbye, Helsinki},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 23,
    url = {http://www.translationalethics.com/2008/05/23/goodbye-helsinki/}
}

MLA

Jonathan Kimmelman. "Goodbye, Helsinki" Web blog post. STREAM research. 23 May 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/05/23/goodbye-helsinki/>

APA

Jonathan Kimmelman. (2008, May 23). Goodbye, Helsinki [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/23/goodbye-helsinki/

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Kid Time for LCA gene transfer?

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(…continued from previous posts).  The promising results, and the surge of expectation they generated, will be used by the investigators and many advocates for the blind to defend pursuing the remainder of the study in children.  After all, children stand a better chance of benefiting, because their retinas have not yet degenerated.


Traditionally, bioethicists have frowned on pursuing studies in children that could otherwise be done in adults, because children are unable to provide valid consent.  Given that the primary objective of the study is safety, and that a sample size of 3 (or, combining the two studies, 6) and a follow-up of less than a year is minimally meaningful in terms of projecting safety, many bioethicists would question the prudence of continuing the study in pediatric populations.

The third volunteer in the Moorfield study was not an adult.  A report in Science magazine (2 May 2008) indicates that the Philadelphia team will test the agent next in an eight-year-old.
(photo credit: kiddocone 1998) 

2008 May 15 | 2 comments | Tags:

BibTeX

@Manual{stream2008-154,
    title = {Kid Time for LCA gene transfer?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 15,
    url = {http://www.translationalethics.com/2008/05/15/kid-time-for-lca-gene-transfer/}
}

MLA

Jonathan Kimmelman. "Kid Time for LCA gene transfer?" Web blog post. STREAM research. 15 May 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/05/15/kid-time-for-lca-gene-transfer/>

APA

Jonathan Kimmelman. (2008, May 15). Kid Time for LCA gene transfer? [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/15/kid-time-for-lca-gene-transfer/

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Imprinting Expectation

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(…continued from previous post)  Whatever the ambiguity and severe limitations in terms of sample size and interpretability, the NEJM studies have unleashed a torrent of expectation. Accoding to the U.K. Guardian, “an 18-year-old man… has amazed doctors by navigating a maze…” and the technique “represented a ‘huge advance.'”


The Washington Post’s Rick Weiss was harshly critical of Targeted Genetics when a volunteer died in a study involving AAV vectors and arthritis. Those who view Weiss as sour on gene transfer should consider his enthusiastic coverage of the LCA results.  The lede states unequivocally that three volunteers “regained modest amounts of vision,” and describes the results as “something short of miraculous.”

In Canada, the Globe and Mail’s Hayley Mick reports on a Canadian undergoing a similar procedure in Florida (their results are unpublished). “Within weeks, the patients who took part [in the Penn and U.K.] trials reported varying degrees of vision improvement.”

Per usual, all three present a human drama narrative– which is certain to amplify expectations further– naming (and in some cases, photographing) two volunteers: Dale Turner and Steven Howarth. (to be continued… photo credit: GiantsFanatic 2007)

2008 May 6 | Leave a comment | Tags:

BibTeX

@Manual{stream2008-155,
    title = {Imprinting Expectation},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 6,
    url = {http://www.translationalethics.com/2008/05/06/imprinting-expectation/}
}

MLA

Jonathan Kimmelman. "Imprinting Expectation" Web blog post. STREAM research. 06 May 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/05/06/imprinting-expectation/>

APA

Jonathan Kimmelman. (2008, May 06). Imprinting Expectation [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/06/imprinting-expectation/

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Seeing Light?

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…continued from previous post:  So did the researchers make the blind see?  Any suggestion that vision has been restored is premature. The authors of both reports acknowledge that measures of vision are subjective and visual improvements might reflect a placebo effect. What can be said– at least of the U.S. study– is that the pupil reflex is behaving as if the eye (and brain) are responding to visual stimuli better than before the experiment.


Many will view these two studies as confirmation of the promise of gene transfer– as evidence that gene transfer, in the words of one leader in the field, “has turned a corner.” Though I understand the sentiment and view these results as encouraging, I also worry about the way these modest findings are being amplified into a signal event. (to be continued… photo credit: daniel y go, 2008)

2008 May 2 | Leave a comment | Tags:

BibTeX

@Manual{stream2008-156,
    title = {Seeing Light?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 2,
    url = {http://www.translationalethics.com/2008/05/02/seeing-light/}
}

MLA

Jonathan Kimmelman. "Seeing Light?" Web blog post. STREAM research. 02 May 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/05/02/seeing-light/>

APA

Jonathan Kimmelman. (2008, May 02). Seeing Light? [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/02/seeing-light/

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Safety First: Two Gene Transfer Studies Against Blindness

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...continued from previous post:  The preclinical studies supporting these human trials are about as good as it ever gets in translational research: numerous large animals (dogs) were treated effectively, and their vision in treated eyes seems to have been restored out to as much as eight years.


The NEJM papers report delivering nearly identical vectors to one eye of volunteers with Leber’s Congenital Amaurosis type 2 (LCA2). The U.K. group did not observe any clinically “significant improvement in visual acuity,” though one of the three volunteers showed some improved retinal function. The U.S. group (based at the University of Pennsylvania) shows significant improvement using an ostensibly objective measure– the pupillary light reflex. The authors also claim all three volunteers had improved visual acuity.

Importantly, neither group reported any adverse events attributable to the gene transfer product.  No immune response to the transgene was detected in sera.  Immune response to vector was detected in only one instance– and only transiently. Importantly, no vector was detected outside the eye. Thus, the vector does not appear to present any really big, extremely common, and almost immediate safety concerns.  All good. (to be continued… photo credit: lu lacerda 2007)

2008 May 1 | Leave a comment | Tags:

BibTeX

@Manual{stream2008-157,
    title = {Safety First: Two Gene Transfer Studies Against Blindness},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 1,
    url = {http://www.translationalethics.com/2008/05/01/safety-first-two-gene-transfer-studies-against-blindness/}
}

MLA

Jonathan Kimmelman. "Safety First: Two Gene Transfer Studies Against Blindness" Web blog post. STREAM research. 01 May 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/05/01/safety-first-two-gene-transfer-studies-against-blindness/>

APA

Jonathan Kimmelman. (2008, May 01). Safety First: Two Gene Transfer Studies Against Blindness [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/01/safety-first-two-gene-transfer-studies-against-blindness/

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Envisioning Gene Transfer: Report on Congenital Blindness Studies

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This week, the New England Journal of Medicine published two preliminary trial reports using gene transfer against a rare form of congenital blindness– Leber’s Congenital Amaurosis type 2.  Since Jean Bennett and coworkers at the University of Pennsylvania reported in 2001 successfully correcting visual deficiencies in dogs afflicted with a nearly identical genetic condition, the field of gene transfer has been atwitter with anticipation of these results.


In the next few posts, I will comment on the studies, the science, the ethics, and the reporting of the LCA studies. (photo credit: chrisphoto, optomap retina scan, 2005)

| Leave a comment | Tags:

BibTeX

@Manual{stream2008-158,
    title = {Envisioning Gene Transfer: Report on Congenital Blindness Studies},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 1,
    url = {http://www.translationalethics.com/2008/05/01/envisioning-gene-transfer-report-on-congenital-blindness-studies/}
}

MLA

Jonathan Kimmelman. "Envisioning Gene Transfer: Report on Congenital Blindness Studies" Web blog post. STREAM research. 01 May 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/05/01/envisioning-gene-transfer-report-on-congenital-blindness-studies/>

APA

Jonathan Kimmelman. (2008, May 01). Envisioning Gene Transfer: Report on Congenital Blindness Studies [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/01/envisioning-gene-transfer-report-on-congenital-blindness-studies/

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More Grey Matter: Parkinson’s Disease Gene Transfer

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Ceregene published long awaited results of its phase 1 gene transfer study of a Parkinson’s disease treatment in the May issue of Lancet Neurology. The open-label study involved two dose levels. After one year of observation, the authors report no major adverse events relating to the study product, CERE-120 (importantly, no neutralizing antibodies against the transgene product were observed).


The authors also report some hints of efficacy. For example, various motor functions appear improved over the course of the study. As the authors point out, however, the study was uncontrolled, and the road to effective neuroprotection strategies in Parkinson’s disease is littered with casualties. And there are many reasons to greet these results with caution. First, imaging performed in concert with the study is not consistent with a therapeutic effect. Second, a major concern with studies like this is whether they produce symptomatic treatment, or whether they actually stem neurodegeneration. Disentangling the two presents an extraordinary scientific and biostatistical problem. Third, a relationship between dose and response does not seem to have been observed.

Still, the case for proceeding to phase 2 studies- to this observer at least- looks credible (photo credit: brunsdon 2007)

2008 April 25 | Leave a comment | Tags:

BibTeX

@Manual{stream2008-159,
    title = {More Grey Matter: Parkinson’s Disease Gene Transfer},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = apr,
    day = 25,
    url = {http://www.translationalethics.com/2008/04/25/more-grey-matter-parkinsons-disease-gene-transfer/}
}

MLA

Jonathan Kimmelman. "More Grey Matter: Parkinson’s Disease Gene Transfer" Web blog post. STREAM research. 25 Apr 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/04/25/more-grey-matter-parkinsons-disease-gene-transfer/>

APA

Jonathan Kimmelman. (2008, Apr 25). More Grey Matter: Parkinson’s Disease Gene Transfer [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/25/more-grey-matter-parkinsons-disease-gene-transfer/

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Teddy’s Frowning

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This blog primarily covers the ethics of translational clinical trials. Products tested in such studies, should they progress towards licensure, will eventually fall under the oversight of drug regulatory agencies like the FDA. How prepared will the FDA be to protect the public once these highly complex interventions are introduced to clinical practice? And when they are tested in early phase trials, how much should IRBs be reassured by the fact that sponsors can show a letter of “no objection”?


The FDA has long been considered the world’s “gold standard” for the evaluation of drug safety and efficacy. But here is a list of NYTimes headlines over the last 6 months that suggest that standards at the agency have fallen.

Panel’s Bipartisan View: FDA is Underfinanced (April 16, 2008). Headline says it all

Drug Makers Near Old Goal: A Legal Shield (April 6, 2008). Reporting that, if the FDA screws up its review, courts are increasingly reluctant to allow injured parties to sue drug and device manufacturers.

Tainted Drugs Put Focus on the FDA (March 17, 2008).  FDA violated its own safety rules in not inspecting overseas drug manufacturing facilities.

Justices Shield Medical Devices from Lawsuits (February 21, 2008).  Reporting that the Supreme Court found that device manufacturers have immunity from tort litigation if the FDA approves them– even though FDA standards on device approval are notoriously weak.

FDA Seeks to Broaden Range of Use for Drugs (February 16, 2008).  Reporting on proposed FDA guidelines that, more or less, would allow drug makers to promote applications of their drugs that have not yet been reviewed or approved by the FDA.

FDA in Crisis: It Needs More Money and Talent (February 3, 2008).  Editorial.

Advisors Say FDA’s Flaws Put Lives at Risk (December 1, 2007).  Reporting that an FDA Science Board report stated that “FDA’s inability to keep up with scientific advances means that American lives are at risk.”

FDA Tests on Devices Scrutinized (October 23, 2007).  Reporting on a letter from Congressman Waxman to the FDA questioning the rigor of their review of a Medtronic implantable defibrillator. (photocredit: sluggerwv 2008, though probably lifted from someone else)

2008 April 17 | Leave a comment | Tags:

BibTeX

@Manual{stream2008-160,
    title = {Teddy’s Frowning},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = apr,
    day = 17,
    url = {http://www.translationalethics.com/2008/04/17/teddys-frowning/}
}

MLA

Jonathan Kimmelman. "Teddy’s Frowning" Web blog post. STREAM research. 17 Apr 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/04/17/teddys-frowning/>

APA

Jonathan Kimmelman. (2008, Apr 17). Teddy’s Frowning [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/17/teddys-frowning/

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Is Embryonic Stem Cell Research Fully Developed?

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As reported by Monya Baker in the April 10 issue of Nature (and Alicia Mundy in Wall Street Journal, April 11), FDA is convening a public hearing on the safety of therapies derived from embryonic stem cells as I write this blog entry. (Note: for info on the meeting, visit http://www.fda.gov/OHRMS/  DOCKETS/98fr/E7-24629.htm)


As yet, (reputable) researchers have not yet administered embryo-derived tissues to human beings. For several years, however, Geron has talked about a trial involving volunteers with spinal chord injury. The Nature report says that Geron intends to submit their IND this summer.

I (and others) have previously warned about too hasty a move into human clinical trials.  There are several concerns: 1- will embryo-derived tissues develop into cancers? 2- how will we assay this risk preclinically?  3-how will human volunteers be monitored? 4-embryo derived tissues are heterogeneous. What kinds of purity standards should be expected?  Each of these questions is incredibly complex, dividing into numerous sub-questions.

Let’s hope that researchers avoid some of the mistakes made in the field of gene transfer– and that the FDA plays a more proactive role in establishing appropriate guidelines. One troubling difference between this field and gene transfer is that initial studies of the latter took place in public settings.  Expect that embryonic stem cell tissue transplantation studies will largely take place beyond the gaze of the public. (photo credit: uiruriamu 2007)

2008 April 11 | Leave a comment | Tags:

BibTeX

@Manual{stream2008-161,
    title = {Is Embryonic Stem Cell Research Fully Developed?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = apr,
    day = 11,
    url = {http://www.translationalethics.com/2008/04/11/is-embryonic-stem-cell-research-fully-developed/}
}

MLA

Jonathan Kimmelman. "Is Embryonic Stem Cell Research Fully Developed?" Web blog post. STREAM research. 11 Apr 2008. Web. 10 Jan 2025. <http://www.translationalethics.com/2008/04/11/is-embryonic-stem-cell-research-fully-developed/>

APA

Jonathan Kimmelman. (2008, Apr 11). Is Embryonic Stem Cell Research Fully Developed? [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/11/is-embryonic-stem-cell-research-fully-developed/

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