What is “special” about the ethics of gene transfer trials? To many, the answer is “nothing.” Indeed, many gene transfer researchers resent what they perceive as an unusually high bar for initiating human studies of gene transfer.
The March 2008 issue of Molecular Therapy contains an excellent article by ethicist Nancy King and gene transfer researcher Odile Cohen-Haguenauer that attempts to answer this question. They argue that gene transfer is subject to high degrees of uncertainty, and that a trial’s knowledge environment can change rapidly. Though the authors shy from branding gene transfer as “unique” or “distinctive,” they also seem to suggest that scientific uncertainty, and a number of other considerations, call out for a different model for thinking about translational research ethics.
I couldn’t agree more. (photo credit: his noodly appendage 2005, Alberto Boccioni 1913)
@Manual{stream2008-162,
title = {Unique Forms of Discontinuity},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = apr,
day = 8,
url = {http://www.translationalethics.com/2008/04/08/unique-forms-of-discontinuity/}
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MLA
Jonathan Kimmelman. "Unique Forms of Discontinuity" Web blog post. STREAM research. 08 Apr 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/04/08/unique-forms-of-discontinuity/>
APA
Jonathan Kimmelman. (2008, Apr 08). Unique Forms of Discontinuity [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/08/unique-forms-of-discontinuity/
In the next issue of the journal Haemophilia, two researchers, Katherine Ponder and Alok Srivistava, take me to task for an article I recently published on the ethics of hemophilia gene transfer trials. My article discusses the little noticed phenomenon of researchers at elite medical centers in the U.S. recruiting trial subjects in Brazil and India for Phase 1 studies.
Ponder and Srivastava make two basic arguments in defense of the practice: 1- they represent a good therapeutic option for persons living in low and middle-income countries (LMICs) who can’t afford standard of care of high-income countries, and 2- we needn’t worry about exploitation at all, because such studies might produce medical applications that can be used in LMICs.
Could be. But the latter argument strikes me as logical and doubtful as any generic ethical claim, such as “We needn’t worry about safety in gene transfer trials, because gene transfer can be safe.” At any rate, look for a full response to their letter in an upcoming issue of Haemophilia. (photo credit: wallyg 2008– Rothko No.25/28).
@Manual{stream2008-163,
title = {Seeing Red},
journal = {STREAM research},
author = {Jonathan Kimmelman},
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url = {http://www.translationalethics.com/2008/04/04/seeing-red/}
}
MLA
Jonathan Kimmelman. "Seeing Red" Web blog post. STREAM research. 04 Apr 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/04/04/seeing-red/>
APA
Jonathan Kimmelman. (2008, Apr 04). Seeing Red [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/04/seeing-red/
A month ago or so, I wrote about a new gene-based strategy against disease: RNAi. Recall that in 2006, Andrew Fire and Craig Mello won Nobel Prizes in Medicine for the discovery of RNAi.
The idea of using RNAi in therapeutic applications would be to administer these small genetic sequences to “knock down” the activity of certain, aberrant genes. Because they function on the basis of genetic complementation, RNAi therapies should be highly specific. Such specificity is key for limiting side effects, which are often caused when drugs stray to the wrong target.
As with almost all novel technologies (and, in particular, genetic ones), researchers will not have an EZ-Pass in attempting to translate RNAi to the clinic. In a recent issue of Nature (and a corresponding news story by Andrew Pollack in the NYTimes on April 2), researchers reported that any sequence consisting of 21 or so nucleotides could trigger a physiological effect (angiogenesis inhibition) in mice through a generic mechanism, the “Toll-like Receptor 3” pathway. The study is particularly troubling, because it suggests that RNAi (or, at least certain types of RNAi) might be prone to worrisome side-effects.
According to Pollack, at least five such drugs are presently being tested in human beings. (photo credit: pbo31, 2005)
@Manual{stream2008-164,
title = {For Whom the Cell Tolls?},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = apr,
day = 3,
url = {http://www.translationalethics.com/2008/04/03/for-whom-the-cell-tolls/}
}
MLA
Jonathan Kimmelman. "For Whom the Cell Tolls?" Web blog post. STREAM research. 03 Apr 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/04/03/for-whom-the-cell-tolls/>
APA
Jonathan Kimmelman. (2008, Apr 03). For Whom the Cell Tolls? [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/03/for-whom-the-cell-tolls/
March 26 NYTimes and Washington Post ran stories about a “summit meeting” of HIV vaccine researchers at the NIH. According to the reports, the meeting was prompted by a widely publicized study in which a highly promising Merck HIV vaccine candidate proved ineffective in a large placebo controlled study. Even more disturbing is an analysis indicating that the vaccine might have increased seroconversion rates in volunteers who received the vaccine.
Interestingly, news reports have not tagged this as a setback for gene transfer– perhaps because it does not involve genetic modification of a recipient’s tissues. But the vaccine involved strategies– namely, genetically modified adenoviruses– that conventionally fall under the rubric of gene transfer. This counts as yet another reminder of the profound uncertainties and complexities surrounding gene transfer translational research. Over the next week, I’ll continue my commentary on this event. (photo credit: ciao chow 2007)
@Manual{stream2008-165,
title = {Low Summit: Setbacks in HIV Vaccine Research},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
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day = 27,
url = {http://www.translationalethics.com/2008/03/27/low-summit-setbacks-in-hiv-vaccine-research/}
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MLA
Jonathan Kimmelman. "Low Summit: Setbacks in HIV Vaccine Research" Web blog post. STREAM research. 27 Mar 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/03/27/low-summit-setbacks-in-hiv-vaccine-research/>
APA
Jonathan Kimmelman. (2008, Mar 27). Low Summit: Setbacks in HIV Vaccine Research [Web log post]. Retrieved from http://www.translationalethics.com/2008/03/27/low-summit-setbacks-in-hiv-vaccine-research/
On March 14th, the Guardian reported on a recent advance using gene transfer against a degenerative brain condition called spinalcerebellar ataxia. The condition belongs to a class of diseases that also includes Huntington’s disease, and as the report indicates, the study could prove useful for many other degenerative brain disorders.
The lede begins “Scientists are a step closer to curing a severe inherited brain-wasting disease using gene therapy.” Without diminishing the value of the study, readers should interpret the story with caution. Among the limitations of studies like these, two stand out. First, perhaps more than any single class of diseases, those involving neurodegenerative diseases have the highest failure rate in terms of preclinical findings translating into clinical applications. Second, most brain degenerative diseases involve multiple brain regions. But most gene transfer strategies, while thinking globally, target locally. As such, they seem unlikely to halt progression of disease in regions of the brain that are not specifically targeted. (photo credit: moon rhythm 2006)
@Manual{stream2008-166,
title = {Misfolding Proteins, MisLede-ing Headlines?},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = mar,
day = 25,
url = {http://www.translationalethics.com/2008/03/25/misfolding-proteins-mislede-ing-headlines/}
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MLA
Jonathan Kimmelman. "Misfolding Proteins, MisLede-ing Headlines?" Web blog post. STREAM research. 25 Mar 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/03/25/misfolding-proteins-mislede-ing-headlines/>
APA
Jonathan Kimmelman. (2008, Mar 25). Misfolding Proteins, MisLede-ing Headlines? [Web log post]. Retrieved from http://www.translationalethics.com/2008/03/25/misfolding-proteins-mislede-ing-headlines/
…At any rate, the NEJM article describes four bills as having been introduced in the U.S. Congress in 2007 to expedite approval of follow-on protein products. None reached the floor. The article cheerfully concludes “despite failures of the bills… [they] collectively represent important first steps that should help stimulate further discourse… and signal an end to the de facto permanent patent that a recombinant protein therapeutic currently enjoys.” In the meantime, its a hard knock life for persons with ultra-rare disorders. (photo credit: dishevld 2007)
@Manual{stream2008-167,
title = {Little Orphan Ending},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = mar,
day = 21,
url = {http://www.translationalethics.com/2008/03/21/little-orphan-ending/}
}
MLA
Jonathan Kimmelman. "Little Orphan Ending" Web blog post. STREAM research. 21 Mar 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/03/21/little-orphan-ending/>
APA
Jonathan Kimmelman. (2008, Mar 21). Little Orphan Ending [Web log post]. Retrieved from http://www.translationalethics.com/2008/03/21/little-orphan-ending/
…Another reason why drugs like Cerezyme are so expensive is because it is very difficult for generic drug companies to license follow-on (that is, generic) drugs under existing drug regulations. In the March 17 issue of New England Journal of Medicine, two Boston-based researchers review the legal and regulatory environment for generic protein-drugs.
Under the Hatch-Waxman Act, drug manufacturers can market generic versions of a drug provided a sponsor can show bioequivalence. But because of a quirk in the history of drug regulation, products regulated as biologicals can not follow the conventional path to generic approval. The biotechnology industry opposes licensure on the basis of bioequivalence, arguing that “the process is the product.” Does this sound familiar to anyone? It might be a plausible position: different manufacturing processes can alter protein folding or post-translational modifications, which in turn can affect immunogenicity and pharmacokinetics. But it directly contradicts the biotechnology industry’s position that GM foods should be regulated as products, not processes. (photo credit: Steelepop 2006)
@Manual{stream2008-168,
title = {A Fruity Defense?},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = mar,
day = 20,
url = {http://www.translationalethics.com/2008/03/20/a-fruity-defense/}
}
MLA
Jonathan Kimmelman. "A Fruity Defense?" Web blog post. STREAM research. 20 Mar 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/03/20/a-fruity-defense/>
APA
Jonathan Kimmelman. (2008, Mar 20). A Fruity Defense? [Web log post]. Retrieved from http://www.translationalethics.com/2008/03/20/a-fruity-defense/
Why is Cerezyme so expensive? One reason is that it targets an ultra-rare disease. Drug companies generally avoid developing products for such “orphan diseases” because there is little consumer demand. To spur development of orphan drugs, the U.S. and other countries have enacted legislation granting market exclusivity (in the U.S., seven years) for orphan drug products.
Gene transfer products aimed at genetic diseases will likely have orphan disease status, which should prompt us to think carefully about how access to this promising technology platform will be e(i)nsured. (photo credit: klynslis, 2007)
@Manual{stream2008-169,
title = {The Cost of Orphan Upkeep},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = mar,
day = 19,
url = {http://www.translationalethics.com/2008/03/19/the-cost-of-orphan-upkeep/}
}
MLA
Jonathan Kimmelman. "The Cost of Orphan Upkeep" Web blog post. STREAM research. 19 Mar 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/03/19/the-cost-of-orphan-upkeep/>
APA
Jonathan Kimmelman. (2008, Mar 19). The Cost of Orphan Upkeep [Web log post]. Retrieved from http://www.translationalethics.com/2008/03/19/the-cost-of-orphan-upkeep/
…the other NYTimes article on Cerezyme concerned Genzyme’s cultivation of relationships with the small Gaucher’s disease population. The article described Genzyme as employing a staff of 50 to help patients negotiate insurance coverage for their products. Genzyme has also established treatment centers and built a stable of Gaucher’s specialists. Said one Gaucher’s specialist, Genzyme has “monopoloized the disease itself, not just the medicine.” (image credit: George Cruikshank, c. 1837)
@Manual{stream2008-170,
title = {Wardens of the Orphanage},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = mar,
day = 18,
url = {http://www.translationalethics.com/2008/03/18/wardens-of-the-orphanage/}
}
MLA
Jonathan Kimmelman. "Wardens of the Orphanage" Web blog post. STREAM research. 18 Mar 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/03/18/wardens-of-the-orphanage/>
APA
Jonathan Kimmelman. (2008, Mar 18). Wardens of the Orphanage [Web log post]. Retrieved from http://www.translationalethics.com/2008/03/18/wardens-of-the-orphanage/
On March 16, the NYTimes ran two stories on Cerezyme, an expensive protein-based drug used to treat a rare genetic disorder, Gaucher’s disease. Both articles covered issues that might be emblematic of those that will be encountered when gene transfer applications are commercialized.
One article described uncertainties clinicians face in establishing the appropriate dose for Cerezyme. At $350K/year to treat a typical adult, lowering doses can have important economic benefits for patients. But with the drug licensed at a particular dose level, reliable clinical evidence on response at lower dose is not available. And Genzyme isn’t about to run trials testing whether Gaucher’s patients can get away with less of their product. Similar issues are raised by the treatment of wet age-related macular degeneration (AMD), where some ophthalmologists use Avastin off-label at a fraction of the cost of Lucentis, which is licensed for AMD. So are Gaucher’s physicians practicing substandard medicine by considering their patients’ pocketbooks, or are they treating the whole patient instead of the disease? (photocredit: banner from Genzyme website (www.cerezyme.com/home)
@Manual{stream2008-171,
title = {Cutting Recombinant Protein Pills?},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = mar,
day = 17,
url = {http://www.translationalethics.com/2008/03/17/cutting-recombinant-protein-pills/}
}
MLA
Jonathan Kimmelman. "Cutting Recombinant Protein Pills?" Web blog post. STREAM research. 17 Mar 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/03/17/cutting-recombinant-protein-pills/>
APA
Jonathan Kimmelman. (2008, Mar 17). Cutting Recombinant Protein Pills? [Web log post]. Retrieved from http://www.translationalethics.com/2008/03/17/cutting-recombinant-protein-pills/
What is “special” about the ethics of gene transfer trials? To many, the answer is “nothing.” Indeed, many gene transfer researchers resent what they perceive as an unusually high bar for initiating human studies of gene transfer.
