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 = {https://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/}
}

MLA

Jonathan Kimmelman. "Transplanting Autoimmune Research" Web blog post. STREAM research. 26 Feb 2010. Web. 28 Mar 2024. <https://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/>

APA

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


Cooperation and Medical Research

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Why do patients cooperate with medical researchers? So asks sociologists Mary Dixon-Woods and Carolyn Grant in a study analysis appearing in the June 2009 issue of Social Science and Medicine. You might think the answer is simple: they think they will benefit; they want to contribute to medical knowledge; or, they trust researchers who invite them. These are the simple and pat answers that have dominated the research ethics literature until now. However, Dixon-Woods and Tarrant probe deeper by asking why it is that patients feel safe and justified in joining research studies.


Using interviews from three different clinical studies, Dixon-Woods and Tarrant identify five recurring themes:

1- Research as Moral Act: Volunteers perceive participation as a moral act: they are willing to participate and cooperate only insofar as they are “able to defend the moral character” of their actions

2- Research as Risk: There was an awareness of risk and research scandals, and volunteers perceived a need to defend their choice to enter a study (rather than feeling like the choice was an obvious one that needed no explanation)

3- Trust in Regulation: Volunteers perceived that the research enterprise was regulated- that transgression of errant researchers would be “subject to punishment,” though they had no familiarity at all with specific oversight structures

4- Signals of Trustworthiness: Participants sought “cues” and “signals” as to the values and trustworthiness of researchers. Informed consent, for example, was taken less as a substantive process than as a signal of the researcher’s openness and integrity. Participants had strong expectations that researchers and affiliated institutions shared values of cooperation. And they saw the healthcare setting and affiliation of research personnel as “signaling” a kind of trustworthiness.”

5- Trust of Professions: Building on item 4, participants made “swift” judgments about the trustworthiness of research personnel- not so much on the basis of their personal characteristics as their affiliation with trusted professions and institutions

The report helpfully contextualizes these findings within a broad sociological literature on giving, cooperation, and trust. Though the authors shy from offering specific prescription, two key themes emerge: oversight systems should focus on meeting these expectations; and regulation (whether external or internal to the profession), far from impeding research, creates social conditions in which patients can feel comfortable bearing risks imposed by strangers for the sake of strangers. (photocredit: Lucas 2008)

BibTeX

@Manual{stream2010-73,
    title = {Cooperation and Medical Research},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = feb,
    day = 14,
    url = {https://www.translationalethics.com/2010/02/14/cooperation-and-medical-research/}
}

MLA

Jonathan Kimmelman. "Cooperation and Medical Research" Web blog post. STREAM research. 14 Feb 2010. Web. 28 Mar 2024. <https://www.translationalethics.com/2010/02/14/cooperation-and-medical-research/>

APA

Jonathan Kimmelman. (2010, Feb 14). Cooperation and Medical Research [Web log post]. Retrieved from https://www.translationalethics.com/2010/02/14/cooperation-and-medical-research/


Hypothesis Generator

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Is good medical research directed at testing hypotheses? Or is there a competing model of good medical research that sees hypothesis generating research as a valuable end? In an intriguing essay appearing in the August 21, 2009 issue of Cell, Maureen O’Malley and co-authors show how current funding mechanisms at agencies like NIH and NSF center their model of scientific merit around the testing of hypotheses (e.g. does molecule X cause phenomenon Y? does drug A outperform drug B?). However, as the authors (and others) point out, many areas of research are not based on such “tightly bounded spheres of inquiry.” They suggest that a “more complete representation of the iterative, interdisciplinary, and multidimensional relationships between various modes of scientific investigation could improve funding agency guidelines.”

The questions presented by this article have particular relevance for translational clinical research. As I argue in my book, the traditional clinical trial apparatus–and corresponding discourse on research ethics– is overwhelmingly directed towards the type of hypothesis testing typified by the randomized controlled trial. However, many early phase studies involve a large component of hypothesis generating research as well. The challenge for O’Malley et al’s argument– and mine– is

(photo credit: Gouldy99, 2008)

BibTeX

@Manual{stream2010-74,
    title = {Hypothesis Generator},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = feb,
    day = 9,
    url = {https://www.translationalethics.com/2010/02/09/hypothesis-generator/}
}

MLA

Jonathan Kimmelman. "Hypothesis Generator" Web blog post. STREAM research. 09 Feb 2010. Web. 28 Mar 2024. <https://www.translationalethics.com/2010/02/09/hypothesis-generator/>

APA

Jonathan Kimmelman. (2010, Feb 09). Hypothesis Generator [Web log post]. Retrieved from https://www.translationalethics.com/2010/02/09/hypothesis-generator/


Annus Mirabilis for Gene Transfer

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Time to review the year 2009 for cutting edge clinical research. For the field of gene transfer, it has been an annus mirabilis: a year that has seen very encouraging results in a wide variety of human clinical studies, as well as preclinical studies. Indeed, I regret that this blog has only been able to cover a few of the former, and very little of the latter. Here are a few highlights from clinical studies:


• in March 2009, Italian researchers reported major clinical improvement in eight of ten children participating in a gene transfer study involving ADA-SCID. [discussed here]

• in June 2009, researchers at Penn / Scheie Eye Institute reported very encouraging outcomes in three children with hereditary blindness, including evidence of visual recovery. [discussed here]

• in September 2009, researchers reported “marginal effectiveness” in preventing HIV infection for a gene transfer-based vaccine. These findings from this trial (the “RV144 trial”) were unexpected after abysmal trial results involving a related strategy (the STEP trials). These are the first encouraging results from any HIV vaccine study conducted to date. [described here and here].

• in November 2009, researchers at Paris-Necker reported very encouraging outcomes in two children with adreno leukodystrophy who received a vector derived from lentiviruses [discussed here]

The decade began with a series of very inauspicious clinical outcomes in gene transfer, and a sharp abatement in the volume of clinical testing. The decade ends with several highly encouraging results from well designed and executed clinical trials. (photo credit: Xavier Luque 2009)

BibTeX

@Manual{stream2009-75,
    title = {Annus Mirabilis for Gene Transfer},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = dec,
    day = 29,
    url = {https://www.translationalethics.com/2009/12/29/annus-mirabilis-for-gene-transfer/}
}

MLA

Jonathan Kimmelman. "Annus Mirabilis for Gene Transfer" Web blog post. STREAM research. 29 Dec 2009. Web. 28 Mar 2024. <https://www.translationalethics.com/2009/12/29/annus-mirabilis-for-gene-transfer/>

APA

Jonathan Kimmelman. (2009, Dec 29). Annus Mirabilis for Gene Transfer [Web log post]. Retrieved from https://www.translationalethics.com/2009/12/29/annus-mirabilis-for-gene-transfer/


Finding Skew: Informed Consent and Bias in Clinical Trials

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Clinical researchers have long claimed that patients who enter clinical trials are better off medically than those who don’t. I’m open to the notion that patients might derive personal meaning from trial participation, but I’ve always been dubious of the suggestion that trial participation in itself is therapeutically beneficial–above and beyond drugs received– in part because this has never been demonstrated in a convincing way. I’ve also worried about the way the “trial effect” has been occasionally mobilized to recruit patients, or to apologize for studies of dubious design. Last, I’ve worried about the ethical implications of the prospect that, in order to receive top quality care, patients should be enrolling in (or have access to) clinical trials.


One reason I have been skeptical of the “trial effect” is that trials do not enroll a random sample of patients. Ethical research requires informed consent, and if patients who consent to trials have different characteristics than those who decline, it seems plausible that they will have different medical courses. UK researchers led by Andrew Clark recently put this thesis to the test (Eur J Heart Failure; also reported in the December issue of Nature Medicine). In their study, they asked a large sample of patients whether they were willing to enter a clinical trial. They then followed the clinical course of patients who declined, and compared them with patients who consented to participation but were never enrolled in a clinical trial. They found that patients who accepted enrollment had better clinical outcomes- even when factors like age, other sicknesses, or drug use.

The finding raises a number of interesting questions about tensions between study validity and informed consent. It does not suggest that we should relax consent standards to reduce bias- though some may be tempted to view the study in this way. It does, however, raise questions about how findings in clinical trials should be interpreted when applying them in real clinical settings. And it provides another problem for those who are attached to the position that trial participation is, in itself, therapeutic. (photo credit: funkandjazz, Skew, 2007)

BibTeX

@Manual{stream2009-76,
    title = {Finding Skew: Informed Consent and Bias in Clinical Trials},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = dec,
    day = 4,
    url = {https://www.translationalethics.com/2009/12/04/finding-skew-informed-consent-and-bias-in-clinical-trials/}
}

MLA

Jonathan Kimmelman. "Finding Skew: Informed Consent and Bias in Clinical Trials" Web blog post. STREAM research. 04 Dec 2009. Web. 28 Mar 2024. <https://www.translationalethics.com/2009/12/04/finding-skew-informed-consent-and-bias-in-clinical-trials/>

APA

Jonathan Kimmelman. (2009, Dec 04). Finding Skew: Informed Consent and Bias in Clinical Trials [Web log post]. Retrieved from https://www.translationalethics.com/2009/12/04/finding-skew-informed-consent-and-bias-in-clinical-trials/


Expectation is a Vascular Condition: Thoughts on Media Coverage of "Liberation Procedures" for Multiple Sclerosis

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Disclaimer to all readers: I am not expert in multiple sclerosis. I am not intimately familiar with recent research findings on a novel surgical treatment (“liberation procedure”) for multiple sclerosis that have received wide coverage in the Canadian media.


Now here are my “claimers:” recent media accounts of this novel approach border on the irresponsible, and point to serious problems with the way many media outlets cover translational clinical research. My second “claimer” is that such media coverage has important consequences for patients and the research community.

Finally, a point of clarification: my comments below concern the quality and consequences of media coverage, not the merits of the medical procedure discussed.

Here is the background: on November 20, the Globe and Mail ran a feature by veteran reporters André Picard and Avis Favaro titled “Researcher’s labor of love leads to MS breakthrough.” The story described a novel theory of an Italian researcher, Paolo Zamboni, that MS “is not, as widely believed, an autoimmune condition, but a vascular disease. More radically still, [an] experimental surgery offers hope that MS… can be cured and even largely prevented.” Said Dr. Zamboni, “I am confident that this could be a revolution for the research and diagnosis of multiple sclerosis.” The news story then describes an Italian study that performed the surgical procedure in 65 patients; the patients saw their disease virtually eradicated.

Like practically every other news article of this species, the reporters do two things. First, they truck out a few patients to proclaim the miracle cure (said one: “I don’t remember what it’s like to have MS”). Second, to establish credibility, the reporters throw in the perfunctory killjoy comments of a few scientists: “skeptics warn the evidence is too scant and speculative.”

As observed on the excellent NPR program On the Media, media coverage of medical research and breakthroughsoverflow with optimism and excitement, offering hope for millions.” According to long-time media analyst Gary Schwitzer, “What they don’t overflow with is accuracy, context and journalistic responsibility.” (Schwitzer, by the way, runs an excellent blog on health news coverage).

Here are some concerns I had about the Globe and Mail story:

• the story reports on clinical research findings. The story did not say, however, that the results have not been published and subjected to peer review.

• the story did not say whether the studies were well-designed: was there a control or placebo arm, for example? the story did not mention that placebo responses can be especially high in the setting of surgical interventions. Nor did it mention that placebo responses are often high in the context of remitting diseases like MS.

• the story wrapped logical fallacies within emotive proclamations. For example, what, precisely, could it possibly mean to say “I am confident this could be a revolution…”?

• the story was not linked in any way to any particular event. Usually reports like this follow from major scientific publications, or presentations at medical conferences. This story, however, is “free floating”- which makes it much more difficult to contextualize (why is it being reported now? how well have the findings been vetted? how did the researchers capture the attention of journalists?).

• the story contains statements that are deeply suspicious. One example is that Zamboni claims MS is not an autoimmune condition. Here is the very first line in the abstract of Professor Zamboni’s most recent publication: “Multiple sclerosis is primarily an autoimmune disorder of unknown origin.”

• the story did not address the correlation and causation problem. The story (and Zamboni) claim that vascular malformations cause MS symptoms, because the researcher discovered that many MS patients have “malformed or blocked” veins draining the brain. But an alternative explanation would be that malformations or blockages are themselves caused by MS- that they are symptomatic rather than causal. Any news coverage of correlation should always address the issue of cause.

And the consequences? Do a google search yourself on the procedure (CCVSI) to find out how much chatter there is among expectant patients, who (judging from discussions) are wondering whether they can travel to Italy to receive the “treatment.” And today, the Globe and Mail reports that the MS Society of Canada- portrayed as sourpuss nabobs of negativism in the previous article- will now fund CCVSI “with significant research dollars” in response to “the overwhelming public response to the media stories.”

Surely, more research, more trials, more basic science is needed. If indeed this approach is a promising as reported, it should be subject to rigorous clinical testing. But can anyone seriously argue that media coverage of this low quality should set the research agenda and decide how scarce research resources are allocated? (photo credit: xbloodsin, sepulcrum, 2008)

BibTeX

@Manual{stream2009-77,
    title = {Expectation is a Vascular Condition: Thoughts on Media Coverage of "Liberation Procedures" for Multiple Sclerosis},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 24,
    url = {https://www.translationalethics.com/2009/11/24/expectation-is-a-vascular-condition-thoughts-on-media-coverage-of-liberation-procedures-for-multiple-sclerosis/}
}

MLA

Jonathan Kimmelman. "Expectation is a Vascular Condition: Thoughts on Media Coverage of "Liberation Procedures" for Multiple Sclerosis" Web blog post. STREAM research. 24 Nov 2009. Web. 28 Mar 2024. <https://www.translationalethics.com/2009/11/24/expectation-is-a-vascular-condition-thoughts-on-media-coverage-of-liberation-procedures-for-multiple-sclerosis/>

APA

Jonathan Kimmelman. (2009, Nov 24). Expectation is a Vascular Condition: Thoughts on Media Coverage of "Liberation Procedures" for Multiple Sclerosis [Web log post]. Retrieved from https://www.translationalethics.com/2009/11/24/expectation-is-a-vascular-condition-thoughts-on-media-coverage-of-liberation-procedures-for-multiple-sclerosis/


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 = {https://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. 28 Mar 2024. <https://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 https://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 = {https://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. 28 Mar 2024. <https://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 https://www.translationalethics.com/2009/11/12/gene-transfer-and-adrenoleukodystrophy-there-will-always-be-paris/


California Dreamin: CIRM Announces New Stem Cell Awards

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California’s Institute for Regenerative Medicine just announced a series of large funding awards to fund translational research initiatives involving (mostly) stem cells. The projects funded are telling with respect to what was funded, and what they will attempt to achieve.


First, notwithstanding a press release containing the words “bringing stem cell therapies to the clinic,” several projects are really dressed up gene transfer studies. Thus, one team will use gene transfer in hematopoietic stem cells for sickle cell anemia; another two will use gene transfer to stem cells for treating brain malignancies; another RNAi for HIV. All this is only further evidence that the field of stem cells is devouring gene transfer. Other projects are aimed more at getting “stem cells out of the clinic” by using small molecules or monoclonal antibodies to destroy stem cells causing malignancies.

Second is the sweeping ambition. As it stands today, only one clinical trial involving embryonic stem cell-derived tissues has been initiated. The projects funded under these awards are “explicitly expected to result in a filing with the FDA to begin a clinical trial.” Given that these projects are funded for four years, CIRM seems to be banking on the prospect of at least a few of these initiating phase 1 trials within five years. Four of these proposals involve goals of implanting embryo-derived tissues, and two of these involve non-lethal conditions–macular degeneration and type I diabetes (technically, other awarded projects involve nonlethal, though extremely morbid conditions). Another involves implantation of embryo-derived tissues for Amyotrophic Lateral Sclerosis. It will be interesting to see how many of these meet their translational objectives, and how investigators will navigate the ethical, regulatory, and social complexity of initiating clinical testing. (photo credit: Michael Ransburg, 2008)

BibTeX

@Manual{stream2009-80,
    title = {California Dreamin: CIRM Announces New Stem Cell Awards},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 5,
    url = {https://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/}
}

MLA

Jonathan Kimmelman. "California Dreamin: CIRM Announces New Stem Cell Awards" Web blog post. STREAM research. 05 Nov 2009. Web. 28 Mar 2024. <https://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/>

APA

Jonathan Kimmelman. (2009, Nov 05). California Dreamin: CIRM Announces New Stem Cell Awards [Web log post]. Retrieved from https://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/


The Need for Speed: GAO Reports on Accelerated Approval

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Several blog posts ago, I wrote about the policy of accelerated approval (briefly, a mechanism whereby new drugs can be approved for sale by the FDA before definitive evidence of efficacy and safety are available). In that post, I reported on a recent paper where the authors claimed that, all things considered, accelerated approval enabled patients to get quicker access to life saving drugs without major adverse impacts on patient safety.


Last week, the Government Accounting Office issued a report on the subject that took a less favorable view of the program. Rules require that companies receiving accelerated approval for new drugs complete post-marketing studies confirming their efficacy. The GAO investigated the frequency with which companies fail to submit post-marketing trial data. They found that over a third of FDA-required post-marketing studies aimed at confirming efficacy had not yet been completed. Many of these studies might be incomplete because accelerated approval was only recently granted, and it can take as long as five years to complete requested studies. Disturbingly, however, the report found that a quarter of these studies had been incomplete for over five years; other studies have been completed but not yet reviewed by the agency. The figures are worse for other types of post-marketing studies requested by the agency.

The “poster boy” drug singled out in the GAO report is the hypertension drug Proamatine, which earned Shire Pharmaceuticals $257M since it was approved under accelerated approval 13 years ago. Apparently, the drug has not been subject to adequate confirmatory testing in all this time, though FDA has issued warning letters to the company over its promotion practices.

The report saves its criticism for the FDA, which it says has not reviewed sponsors’ submissions in a timely manner, does not adequately monitor progress of post-marketing studies, and has neither specified conditions under which it would exercise its authority to withdraw drugs from market, nor has it ever exercised its authority to do so. But isn’t some criticism also warranted for companies exploiting FDA’s deficiencies? (photo credit: lindsay kay photography 2009)

BibTeX

@Manual{stream2009-81,
    title = {The Need for Speed: GAO Reports on Accelerated Approval},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 2,
    url = {https://www.translationalethics.com/2009/11/02/the-need-for-speed-gao-reports-on-accelerated-approval/}
}

MLA

Jonathan Kimmelman. "The Need for Speed: GAO Reports on Accelerated Approval" Web blog post. STREAM research. 02 Nov 2009. Web. 28 Mar 2024. <https://www.translationalethics.com/2009/11/02/the-need-for-speed-gao-reports-on-accelerated-approval/>

APA

Jonathan Kimmelman. (2009, Nov 02). The Need for Speed: GAO Reports on Accelerated Approval [Web log post]. Retrieved from https://www.translationalethics.com/2009/11/02/the-need-for-speed-gao-reports-on-accelerated-approval/


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