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)
Jonathan Kimmelman. "Information: Stem Cell Tourism Redux (part 1)" Web blog post. STREAM research. 17 Jun 2010. Web. 20 Apr 2024. <https://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 https://www.translationalethics.com/2010/06/17/information-stem-cell-tourism-redux-part-1/
Robert Steiner, co-principal investigator in a fetal cell transplantation study involving the rare, fatal hereditary disease Neuronal Ceroid Lipofuscinosis(also known as Batten disease), presented results of a now completed phase 1 study. According to Steiner, the study involved the highest ever dose of stem cells delivered to the human brain. The trial involved six children with infantile and late-infantile forms of the disease.
Elsewhere, this safety study has been reported as “positive”- in the sense that there were no unexpected, stem cell related complications. Which is not to say the protocol was a picnic: the study involved (if I understood the presentation correctly) 14 trajectories to the brain, and an extended regime of immunosuppression that caused 23 adverse events. Steiner reported that none of the patients showed a clinical response- which is what one would expect in patients with such advanced forms of disease (hopefully, the research team conveyed the unexpectedness of clinical benefits to parents when they obtained informed consent).
Steiner also reported that, when one of the patients died due to natural course of illness, the family permitted the team to perform an autopsy. The autopsy ruled out the cell transplantation as a cause of mortality, and established that the tissues engrafted successfully. In the words of a press release, “By permitting the autopsy, the family allowed the researchers to learn very important details that will potentially benefit future patients.”
Did the research team use the autopsy to determine whether the transplanted cells were expressing the therapeutic gene? If so, was the gene product taken up by surrounding tissues? Answering these questions would be key to maximizing the scientific value of the study, and thus redeeming the risks of surgery, immunosuppression, stem cell transplantation, and the many follow-up visits required of patients participating in the study. But from what I heard, the brain is in the hands of the company, and it is unclear whether they have performed these studies (and if so, whether the results will be reported). Let’s hope the family’s permission for autopsy allows the researchers to learn still more. (photo credit: dopamineharper 2009)
@Manual{stream2010-62,
title = {ASGCT, cont’: Results on Fetal Tissue for Battens Presented},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2010,
month = may,
day = 26,
url = {https://www.translationalethics.com/2010/05/26/asgct-cont-results-on-fetal-tissue-for-battens-presented/}
}
MLA
Jonathan Kimmelman. "ASGCT, cont’: Results on Fetal Tissue for Battens Presented" Web blog post. STREAM research. 26 May 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/05/26/asgct-cont-results-on-fetal-tissue-for-battens-presented/>
APA
Jonathan Kimmelman. (2010, May 26). ASGCT, cont’: Results on Fetal Tissue for Battens Presented [Web log post]. Retrieved from https://www.translationalethics.com/2010/05/26/asgct-cont-results-on-fetal-tissue-for-battens-presented/
Predictably, the big presidential symposium at ASGCT reserved a slot for Jean Bennett, who led one of the three teams that have tested a gene transfer strategy for a rare genetic form of blindness, Leber’s Congenital Amaurosis (LCA). Unpredictably, however, Bennett trotted out one of her “treated” patients, Cory Haas, along with his two parents, who sat up on the podium as Bennett went through her 45 minute presentation, which was titled “An Aye for Gene Therapy.”
First, let me say that Bennett’s results- as well as those of the other teams- continue to be very encouraging. In adults whose retinal tissues have degenerated, the approach has not restored vision, but it has also not raised any major safety concerns (apart from a surgical complication in one patient). In younger patients, the approach has shown safety with restoration of vision, and Bennett this time presented various functional data, along with neuroimaging data consistent with restoration of vision. And nothing that follows detracts from all the credit she and her team deserve for their smarts, scientific rigor, perseverance, and clinical accomplishments. Second, the family has agreed to go public, and this was not their first time on display. No doubt, they feel that putting themselves on display like his helps bring visibility to this important research. As well, they have their own battles to fight: only one eye has been corrected, and perhaps they feel that going public like this may help nudge regulatory authorities to clear the investigators to apply gene transfer to the second eye.
Nevertheless, I found Bennett’s exhibition of her subject, and his parents, a case of poor judgment. And judging from one or two conversations with others in attendance, I was not alone. In my book, I warn against the perils of putting patients on display. It performs a rhetorical function that tends to neutralize critical thinking and indulge sentimentality. I found it particularly problematic that this would occur at a major scientific address: if there were skeptical questions to be asked (as there typically are at scientific meetings), who would dare ask them in front of a child and his parents? At any rate, Bennett used a short question and answer period following her talk by asking Corey and his parents a series of Diane Sawyer-like questions: “are you glad you joined the study?” “what was the most difficult part?” “do you have any questions?” She then elicited a round of applause “for the patients” from the >500 assembled attendees. Was the Q and A scripted? Was this a kind of victory lap for Bennett? Who knows.
Spectacular research, to be sure. But it makes for spectacle science as well. (photo credit: strangejourney 2009)
@Manual{stream2010-63,
title = {ASGCT, continued: Eyes on Stage},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2010,
month = may,
day = 25,
url = {https://www.translationalethics.com/2010/05/25/asgct-continued-eyes-on-stage/}
}
MLA
Jonathan Kimmelman. "ASGCT, continued: Eyes on Stage" Web blog post. STREAM research. 25 May 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/05/25/asgct-continued-eyes-on-stage/>
APA
Jonathan Kimmelman. (2010, May 25). ASGCT, continued: Eyes on Stage [Web log post]. Retrieved from https://www.translationalethics.com/2010/05/25/asgct-continued-eyes-on-stage/
Another year, another annual meeting of the American Society of Gene Therapy- now rechristened American Society of Gene AND CELL Therapy. The meeting ends today, and I am way behind in posts. There have been, to my knowledge, no startling new revelations about high impact trials or disastrous adverse events. The studies of Leber’s Congenital Amaurosis- a rare genetic disorder causing blindness- continue to dazzle, with several groups presenting results showing consistent safety and functional recovery- especially in younger patients. The ADA-SCID data continue to show very encouraging results without any indication of the safety problems encountered using similar vectors. Same goes for the adrenoleukodystrophy study- now three children have received a lentivirus-based cell intervention. Again- no evidence that delivered cells are expanding in a way that would raise concerns about a malignancy, and the disease course for children appears to be significantly improved. Off, now, to catch a session on a new product for another genetic disease- LPL deficiency- which (by the title of the session) has been submitted for regulatory licensure. To be continued, with some ethical commentary… (photo credit: afagan 2007)
@Manual{stream2010-64,
title = {ASGCT in Washington DC},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2010,
month = may,
day = 22,
url = {https://www.translationalethics.com/2010/05/22/asgct-in-washington-dc/}
}
MLA
Jonathan Kimmelman. "ASGCT in Washington DC" Web blog post. STREAM research. 22 May 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/05/22/asgct-in-washington-dc/>
APA
Jonathan Kimmelman. (2010, May 22). ASGCT in Washington DC [Web log post]. Retrieved from https://www.translationalethics.com/2010/05/22/asgct-in-washington-dc/
So what does it take to keep medical research a well-oiled enterprise that efficiently and effectively delivers cures? Lots of cooperation–or so I argue, along with co-authors Alex John London and Marina Emborg in a piece appearing in Science[a publicly accessible version of the essay is available at Science Progress]. Unfortunately, we argue, the way or system of drug development currently thinks about the ethics of clinical research does not presently place sufficient emphasis on the conditions necessary to sustain this cooperation.
Right now, oversight of clinical research is focused almost exclusively on protecting the personal interests of human subjects by obtaining valid informed consent and ensuring that risks are reasonable in relation to benefits. We suggest that this ostensibly private transaction between investigators and patient-volunteers has a public dimension in at least three ways. First, such private transactions inevitably draw on public resources. Second, such transactions have externalities- adverse events occurring on one trial have potential to disrupt collaborations elsewhere in the research system. Third, lax oversight of such private transactions creates conditions where consumers have difficulty identifying (and hence rewarding) producers of high quality goods (namely, trials that are well designed).
We suggest that, when considering whether to initiate highly innovative clinical trials that draw on such public goods, proper oversight and analysis must take into consideration factors that lie beyond the personal interests of human volunteers. (photo credit: McKillaboy, Cataglyphis velox 22, 2009)
@Manual{stream2010-65,
title = {Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2010,
month = may,
day = 18,
url = {https://www.translationalethics.com/2010/05/18/conditions-of-collaboration-protecting-the-integrity-of-the-scientific-enterprise/}
}
MLA
Jonathan Kimmelman. "Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise" Web blog post. STREAM research. 18 May 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/05/18/conditions-of-collaboration-protecting-the-integrity-of-the-scientific-enterprise/>
APA
Jonathan Kimmelman. (2010, May 18). Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise [Web log post]. Retrieved from https://www.translationalethics.com/2010/05/18/conditions-of-collaboration-protecting-the-integrity-of-the-scientific-enterprise/
Much has already been said about Filing Cabinet syndrome in medical research: the tendency of researchers to publish exciting results from clinical trials, and to stash null or negative findings safely away from public view in a filing cabinet. Nonpublication distorts the medical literature, because it prevents medical practitioners from accessing negative information about drugs. Recall that, back in 2004, attorney-general Eliot Spitzer sued Glaxo Smithkline for suppressing trial results that showed elevated risk of suicide for adolescents taking the antidepressant drug Paxil; this and several similar episodes led FDA, major medical journals, World Health Organization, World Medical Association, and others to require researchers to register clinical trials before they enroll any patients.
Yet important gaps remain. In the March 2010 issue of PLoS Biology, Emily S. Sena and coauthors provide the most detailed analysis yet of one of these gaps: nonpublication of preclinical (animal) studies. They aggregated results of 16 systematic reviews of preclinical studies involving acute ischaemic stroke, and used statistical methods to estimate the degree of publication bias, and the likely effect of publication bias on measured disease responses. Among other things, they found that 16% of animal experiments were not published, leading to a 31% overstatement of efficacy. The authors note: “we estimate that for the interventions described here, experiments involving some 3,600 animals have remained unpublished. We consider this practice to be unethical.”
The authors urge that central registries of preclinical studies be established and maintained– a call that is not likely to go heeded anytime soon by companies that have much at stake in the secrecy in preclinical research. But their proposal ought to be taken seriously by anyone committed not only to respecting animals used in medical research, but also protecting the welfare of human beings who might enroll in possibly unwarranted clinical research. (photo credit: amy allcock 2009)
@Manual{stream2010-66,
title = {Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research},
journal = {STREAM research},
author = {Jonathan Kimmelman},
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url = {https://www.translationalethics.com/2010/05/11/filing-cabinet-syndrome-the-effect-of-nonpublication-of-preclinical-research/}
}
MLA
Jonathan Kimmelman. "Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research" Web blog post. STREAM research. 11 May 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/05/11/filing-cabinet-syndrome-the-effect-of-nonpublication-of-preclinical-research/>
APA
Jonathan Kimmelman. (2010, May 11). Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research [Web log post]. Retrieved from https://www.translationalethics.com/2010/05/11/filing-cabinet-syndrome-the-effect-of-nonpublication-of-preclinical-research/
This month’s issue of Molecular Therapy– the premium journal covering developments in gene transfer- reports two deaths in recent cancer gene transfer studies. Both studies involved a similar anti-cancer strategy, in which a patient’s T cells are genetically modified to mount a strong and sudden immune attack against the patient’s cancer (the particular genetic modification is known as “CAR,” for chimeric antigen receptors). Both were phase 1 studies. Both patients died from what looks like “cytokine storm”- the same phenomenon that caused life threatening toxicity in the Tegenero TGN1412 study in 2005. In one case, the authors attribute death to the gene transfer; in the other, the authors categorize the death as possibly related to the gene transfer (the latter was previously described at ASGT in 2009).
In all likelihood, these patients (or at least, one of the patients) will be the third or fourth death in gene transfer that is clearly attributable to gene transfer. Don’t expect too much public hand-wringing or media coverage, however: in both cases, the patients were adults and had terminal cancer. I have not made a careful study of these particular trials or the strategies they employ. So the following thoughts about these deaths should be read with caution:
1- Unpredictability: These deaths point, once again, to the unpredictability of strategies aimed at training the immune system to respond against tumors. Immune systems are notoriously difficult to model in animals, and as a result, every human study is essentially a shot in the dark. The authors of one of the reports sagely urge that phase 1 studies using similar strategies begin at low doses.
2-Where’s the Toxicology? Neither report mentions anything about observing similar toxicities in preclinical studies. Indeed, neither report even mentions preclinical toxicology studies. One wonders why: were they done? how were they done? what was observed? For example, both studies involved immunosuppression co-interventions aimed at enhancing the effects of the T-cells (in one case, administration of the drug cyclophosphamide; in the other, use of nonmyeloablative conditioning). Were toxicology studies performed in animals receiving these immunosuppression treatments?
3-Did Investigators Give Preclinical Studies Their Best Shot at Producing Similar Toxicity? Both phase 1 studies were supported by preclinical studies using mice that lacked functional immune systems. One has to wonder how useful it is to test immunotherapies in mice that lack properly functioning immune systems. From what I can tell, in neither the first nor the second case did investigators perform preclinical studies that simultaneously delivered modified T-cells and immunosuppressive drugs.
4- Please: No More Gratuitous Appeals to the Integrity of the Investigators. An editorial by a leading expert on CARs accompanies the reports in Molecular Therapy andprovides a very helpful summary and context of the events. It ends, however, with the statement “it is a great credit to all investigators involved that they have been so forthcoming in providing detailed reports of serious adverse events.” I heard similar sentiments expressed when one of the deaths was presented at a scientific meeting last year. True- the research team did provide an unusually extensive report and investigation, including autopsy. However, careful and public reporting of serious adverse events is exactly what researchers are supposed to do in phase 1 studies involving highly innovative approaches; praising them for coming forward with this kind of information is a bit like congratulating Canada every time it holds a democratic election. One has to wonder whether there is a reserve of trial deaths that are never investigated or reported. (photo credit: Steve Kay 2008)
@Manual{stream2010-67,
title = {CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2010,
month = apr,
day = 22,
url = {https://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/}
}
MLA
Jonathan Kimmelman. "CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy" Web blog post. STREAM research. 22 Apr 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/>
APA
Jonathan Kimmelman. (2010, Apr 22). CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy [Web log post]. Retrieved from https://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/
Personalized medicine is supposed to usher an era in which treatments are tailored to individuals. And HER2 testing has long been seen as heralding the promise of personalized medicine: tumors that test positive for an amplified HER2 gene are more likely to be responsive to drugs, like trastuzumab, that block the HER2 receptor.
Some may see HER2 testing as foreshadowing a perfect future in which treatment decisions are coupled to molecular diagnostics. But Gina Kolata in the New York Times instead tells a story of shadows. Like all medical tests, HER2 testing is error prone: some tumors test positive when they are in fact negative, and others test negative when they are in fact positive. And some results are just plain ambiguous, with parts of the tumor being positive and other parts being negative. Kolata describes the challenges that women and their physicians confront when interpreting test results.
Most troubling in this story is the role, or lack thereof, played by regulatory agencies like the FDA. Quoting Kolata: “there is a proliferation of laboratories offering tests without F.D.A. oversight. But, for now, the agency has no specific plan to regulate the tests, in part because of lack of money.” If FDA is not prepared to regulate tests because of resource constraints, and prescription decisions are likely to be increasingly coupled to diagnostic tests, it logically follows that FDA is not prepared to regulate the approval and use of newer generation, test-based drugs. In other words, FDA seems unable to establish the validity of labeling indications for drugs that rely on diagnostic tests. This can’t be a good thing for patients, physicians, or third party payers (but is great for the makers of drugs and diagnostics, who thrive in this kind of clinical and regulatory uncertainty!) (photo credit: crafty dame, breast cancer cells, 2009)
@Manual{stream2010-68,
title = {Testing Testing…: Personal Medicine, Breast Cancer, and Policy},
journal = {STREAM research},
author = {Jonathan Kimmelman},
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month = apr,
day = 20,
url = {https://www.translationalethics.com/2010/04/20/testing-testing-personal-medicine-breast-cancer-and-policy/}
}
MLA
Jonathan Kimmelman. "Testing Testing…: Personal Medicine, Breast Cancer, and Policy" Web blog post. STREAM research. 20 Apr 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/04/20/testing-testing-personal-medicine-breast-cancer-and-policy/>
APA
Jonathan Kimmelman. (2010, Apr 20). Testing Testing…: Personal Medicine, Breast Cancer, and Policy [Web log post]. Retrieved from https://www.translationalethics.com/2010/04/20/testing-testing-personal-medicine-breast-cancer-and-policy/
Dear Faithful Readers: Teaching has cut my blogging to a trickle, though the teaching has now begun to taper off. My silence is not for want of major developments in the last two months. Among a few highlights:
• Obama picks members for his Bioethics advisory panel: White house recently announced membership of its “Presidential Commission for the Study of Bioethical Issues.” The group is smaller than past Presidential panels. Its membership is lean on working bioethicists (3 or 4 who clearly fit the classic definition– all others scientists, clinicians, federal employees, university administrators, or a disease advocate).
• Health care reform (+ Translational Research) passes in the U.S.: Among the intriguing elements here is the relationship between reform and biomedical research. When Clinton proposed healthcare reform in the 1990s, there was much consternation in the research community that this would spell a retreat from investment in basic research. Indeed, failure to enact reform propelled a massive expansion of the NIH budget through the 1990s. This time around, healthcare reform has specifically integrated basic research. The law includes language creating a “Cures Acceleration Network” that would fund up to $15M/year in translational research (though the budget will depend on direct appropriation from Congress, and there is no certainty that it will be funded).
• Gene Patents Voided: Following an ACLU challenge, a U.S. District Court Judge threw out Myriad Genetics’ patent on BRCA1 and BRCA2 (genes associated with hereditary breast cancer; the company markets a $3K per pop test for mutations in the genes) by ruling that the genes are “products of nature.” Products of nature are not patentable, though products purified from nature (e.g. enzymes, wood chemicals, etc.) are. The logic behind the decisions is that genes are better thought of as information rather than as chemicals, and that information extracted from the natural entities does not have distinct properties in the way that chemicals do. If ever there were a demonstration of the power of metaphors; suffice it to say, biotechnology companies will appeal. (photo credit: aurelian s 2008)
This morning I awoke to a news report by National Public Radio’s Joe Palca on promising developments in gene transfer. In it, Palca provided a good account of the field’s travails, as well as some encouraging developments in the last few years. The story ended with the prediction that the coming “months and years” would bring landings for more common disorders like AIDS and cancer.
Coincidentally, the just released March issue of Nature Biotechnology ran a report on a front-runner for gene transfer commercialization: biotechnology company Ark Therapeutics gene transfer gliobastoma product Cerepro. The application for licensure of this product in Europe was unsuccessful (press release here). Recall that, last June, I described what seemed like unimpressive results from a phase 3 trial that were reported at an annual meeting of the American Society of Gene Therapy. Apparently, European drug regulators weren’t impressed either (they cited flaws in trial design, including a small sample size and unconcealed allocation; Ark has asked the agency to re-examine their application).
But for those awaiting the first commercialization of a gene transfer product in a country with a robust drug regulatory system, there is still some indication that the rains may be subsiding: according to the report in Nature Biotechnology, Amsterdam Molecular Therapeutics has filed with EMEA for marketing authorization of their AAV product for a rare hereditary disorder, LPL deficiency; the company will soon file in Canada as well (the disorder is more prevalent in Quebec) (photo credit: Occhiovivo 2007)
@Manual{stream2010-70,
title = {Ark, Troubled Waters, and Rainbows for Gene Transfer},
journal = {STREAM research},
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url = {https://www.translationalethics.com/2010/03/08/ark-troubled-waters-and-rainbows-for-gene-transfer/}
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MLA
Jonathan Kimmelman. "Ark, Troubled Waters, and Rainbows for Gene Transfer" Web blog post. STREAM research. 08 Mar 2010. Web. 20 Apr 2024. <https://www.translationalethics.com/2010/03/08/ark-troubled-waters-and-rainbows-for-gene-transfer/>
APA
Jonathan Kimmelman. (2010, Mar 08). Ark, Troubled Waters, and Rainbows for Gene Transfer [Web log post]. Retrieved from https://www.translationalethics.com/2010/03/08/ark-troubled-waters-and-rainbows-for-gene-transfer/
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). 
