tag:blogger.com,1999:blog-55970084240044740792024-03-05T14:35:10.007-05:00Lost in TranslationJonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.comBlogger129125tag:blogger.com,1999:blog-5597008424004474079.post-87654998725971528922012-10-04T15:04:00.004-04:002012-10-04T15:04:56.611-04:00Missing Reports: Research Biopsy in Cancer Trials<div class="separator" style="clear: both; text-align: center;">
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A growing number of drug trials are collecting tissue to
determine whether the drug hits its molecular target.<span style="mso-spacerun: yes;">
</span>These studies are called “pharmacodynamics.”<span style="mso-spacerun: yes;"> </span>And in cancer, many pharmacodynamics studies
involve collection of tumor tissue through biopsies.<span style="mso-spacerun: yes;"> </span>These procedures are painful, and
are performed solely to answer scientific questions.<span style="mso-spacerun: yes;"> </span>That is, they generally have no diagnostic or
clinical value.<span style="mso-spacerun: yes;"> </span>As such, some commentators worry
about their ethics.<o:p></o:p></div>
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<br /></div>
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In a recent issue of <a href="http://www.ncbi.nlm.nih.gov/pubmed/22912391">Clinical Cancer Research</a>, my Master’s
student Gina Freeman and I report on publication practices for
pharmacodynamics studies involving tumor biopsy.<span style="mso-spacerun: yes;"> </span>The basic idea is this: the ethical
justification for such invasive research procedures rests on a claim that they
are scientifically valuable.<span style="mso-spacerun: yes;"> </span>However, if
they are never published, it is harder to argue that they have a sound scientific justification.<span style="mso-spacerun: yes;"> So we set out to determine how frequently results are published, and reasons why some results are never reported. </span>Briefly, we found that a third of promised
analyses are not published- which is more or less in line with the frequency of
nonpublication for trials in general.<span style="mso-spacerun: yes;"> </span>We
also find that researchers who perform pharmacodynamics studies regard
reporting quality as fair to poor, and many perceive the most common reason for
nonpublication to be “strategic considerations” (as in: result does not fit the
narrative of the overall trial).<o:p></o:p></div>
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<br /></div>
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Does our article support a definitive statement about the
ethics of research biopsy in cancer trials?<span style="mso-spacerun: yes;">
</span>No.<span style="mso-spacerun: yes;"> </span>But it does point to a number
of ways that the ethical justification can be strengthened- and questions
clinical investigators and ethics boards should be asking when designing and/or reviewing protocols involving research biopsy. (graphic: <a href="http://www.flickr.com/photos/cole007/5997558927/lightbox/">cole007</a> 2011)<o:p></o:p></div>
<!--EndFragment-->Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com1tag:blogger.com,1999:blog-5597008424004474079.post-53281380511359484312012-08-20T18:50:00.003-04:002012-08-20T18:50:49.232-04:00Targeted Cancer Drugs: The "Price of Progress"?<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgFFZ_hinK61YGt9eZbm3nEzEO7UJ3hULKI8_BOhxn6wm0l1uRsNlDcghjvd1JCPLi_KKJZBpmloywmaAepO2Rcz7qWwisd2zN_7_SNcKjdG-i81wtuhP6CFE8PpSKgmRze1ktAwvbtLMo/s1600/3668600906_b56f9f2469.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="227" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgFFZ_hinK61YGt9eZbm3nEzEO7UJ3hULKI8_BOhxn6wm0l1uRsNlDcghjvd1JCPLi_KKJZBpmloywmaAepO2Rcz7qWwisd2zN_7_SNcKjdG-i81wtuhP6CFE8PpSKgmRze1ktAwvbtLMo/s320/3668600906_b56f9f2469.jpg" width="320" /></a></div>
<br />
<span class="Apple-style-span" style="font-size: x-large;">S</span>o here is the party line on the newest generation of cancer drugs. Unlike older generation drugs, which are generalized poisons, newer cancer drugs hone in on very specific molecular targets. Because of this specificity, they have fewer "off-target" effects, and hence fewer side effects.<br />
<br />
In the current issue of <i>Journal of Clinical Oncology</i>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/22802313">Niraula et al</a> offer a more nuanced picture of newer cancer drugs and safety. In it, they used meta-analytic techniques to compare rates of life-threatening side effects for patients receiving new cancer drugs against patients receiving standard of care. Briefly, they report that newer cancer drugs were associated with significantly greater probability of experiencing a life threatening toxicity. In short, new cancer drugs may have resulted in better clinical outcomes like survival, but at the cost of greater toxicity. How can this be? According to the report's authors, one possible explanation is the fact that many newer cancer drugs require prolonged exposure to new drug, resulting in greater risk of cumulative toxicity.<br />
<br />
A few other tidbits. Safety reporting in cancer drugs is very problematic. The authors found 8% randomized trials in their sample made no mention of drug-related mortality(!). Only 34% of trials reported the proportion of patients experiencing at least one life-threatening toxicity. Journal editors and referees have a lot of demands on their attention, but when it comes to safety reporting at least, they are asleep at the switch.<br />
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What makes this study particularly interesting is the way the authors combined results of trials testing a variety of different style interventions. Through studies like this, we get an aerial view of where things are headed in cancer drug development, and provide a basis for assessing whether the field is achieving its goals. (photo credit: <a href="http://www.flickr.com/photos/teflon/3668600906/">Martin Deutsch</a> 2009)Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com3tag:blogger.com,1999:blog-5597008424004474079.post-35028470537187604452012-05-02T14:34:00.000-04:002012-05-02T14:34:24.544-04:00Registration of Trials: A Census<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjeUlOhNZ8_SrOmvRivFr873BCBK8tgM0ebpV0-UJtiYVH4jm8cAWtid9tWzekno6w2g0i0AS6PJ71xu5t2lQpRsWmPv1BOTcjqmXZHrXRktqqWTHJfNh7IK4bV-T_fBUbOtJtUJhaUtWg/s1600/3111378165_220041e064_b.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjeUlOhNZ8_SrOmvRivFr873BCBK8tgM0ebpV0-UJtiYVH4jm8cAWtid9tWzekno6w2g0i0AS6PJ71xu5t2lQpRsWmPv1BOTcjqmXZHrXRktqqWTHJfNh7IK4bV-T_fBUbOtJtUJhaUtWg/s320/3111378165_220041e064_b.jpg" width="248" /></a></div>
Apologies to the millions of avid followers of Lost in Translation for the long haitus. In response to an international petition campaign, with several Nobelist signatories, I am cautiously restarting this blog with the aim of (monthly??) blogposts on troubles and turmoil in clinical translation.<br />
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We lead off with an article in this week's <a href="http://jama.ama-assn.org/content/307/17/1838.full">JAMA, led by Robert Califf</a>, which provides a census of the clinical research enterprise through an analysis of registered trials at clinicaltrials.gov. As with many such surveys of clinicaltrials.gov, the picture w/ respect to registry compliance ain't pretty. Some particularly troubling highlights: the proportion of trials that were registered AFTER beginning enrollment was 52% between Oct 2007 and Sept 2010, and 6.8% of trials do not report their primary purpose (as required). <br />
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More generally, Califf et al finds 62% of registered trials are drug trials (the remainder involve procedures, diet, etc.); 63% involve North American research sites; 32% are industry sponsored; 15% are phase 3.<br />
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There are some interesting tidbits buried here. For instance, many commentators are critical of phase 4 studies- viewing many such studies as trials aimed primarily at marketing (phase 4 trials test drugs that have already received regulatory approval for marketing). Califf et al find that phase 4 studies are significantly less likely to report using blinding compared with phase 3.<br />
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The commentary by Dickersin and Rennie makes for a riveting read for those interested in the broader clinical research enterprise. (photo credit: <a href="http://www.flickr.com/photos/davidclow/3111378165/">D. Clow 2008</a>)Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-38030815053159536012011-03-21T14:31:00.008-04:002011-03-21T14:53:13.049-04:00Tea Leaves: Predicting Risk and Benefit in Translation<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEis51XDPwxCGXEBYtuxTPoODGR_LegwdoQR_4nANqSLUxKwtSW0e3IWaAWqt5dG6J7od7h3rP-A0C17xSib43DSHixw3s1eQV3pJ8pS9tnnQFlsVqu5vVemYXLT17iAp2YxP508OlYy5SE/s1600/5212293643_39201797ea.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 257px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEis51XDPwxCGXEBYtuxTPoODGR_LegwdoQR_4nANqSLUxKwtSW0e3IWaAWqt5dG6J7od7h3rP-A0C17xSib43DSHixw3s1eQV3pJ8pS9tnnQFlsVqu5vVemYXLT17iAp2YxP508OlYy5SE/s320/5212293643_39201797ea.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5586602926879208562" /></a><br /><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">E</span><span class="Apple-style-span" style="font-size:small;">very early phase trial begins with a series of predictions: that a new drug will show clinical utility down to road, that risks to study volunteers will be manageable, and perhaps, that patients in trials will benefit. Make a bad prediction here, and people potentially get hurt and resources wasted. So how good a job do we do with these predictions?</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Hard to know, but given the high rate of failure in clinical translation, there are grounds for believing that various stakeholders go into early phase trials with an excess of optimism. In the current issue of <i>PLoS Medicine</i>, </span></span><a href="http://www.hss.cmu.edu/philosophy/faculty-london.php"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Alex London</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> and I posit two problems with the way decision-makers make predictions in early phase trials. First, they underattend frequent and systematic flaws in the preclinical evidence base. Secondly, they draw on an overly narrow evidence base (what we call "evidential conservatism") that obscures an assessment of whether preclinical studies in a given research area are a reliable indicator of agent promise.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">As an open access journal, readers are invited to view our article </span></span><a href="http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001010"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">here</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">. The article has garnered a decent amount of press- digestible summaries can also be found at the </span></span><a href="http://www.the-scientist.com/news/display/58042/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Scientist</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> and </span></span><a href="http://www.post-gazette.com/pg/11073/1131841-114.stm"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Pittsburgh Gazette</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">. Also check out a </span></span><a href="http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001011"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">commentary</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> commissioned by the journal editors. (</span><span class="Apple-style-span" style="font-size:x-small;">photo credit: </span></span><a href="http://www.flickr.com/photos/canopic/5212293643/sizes/m/in/photostream/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">canopic</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;"> 2010</span><span class="Apple-style-span" style="font-size:small;">)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com2tag:blogger.com,1999:blog-5597008424004474079.post-63328158901717883192011-02-08T20:24:00.007-05:002011-02-26T23:08:51.241-05:00Dirty Windows of Drug Development<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiYusfR9egG7GCDomyMw7lL1lYNp_RUwK5icrbfpLBaRyMGWaEslFz3XofzcrgaZuaxl44FysvrCxTKItO5K2jhxqQStBMVHVR2mPYQ3OOu4k1UjwUUvpDPiNrujKY7huqbmEytsQ0y72E/s1600/841879262_d90e689dde.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 240px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiYusfR9egG7GCDomyMw7lL1lYNp_RUwK5icrbfpLBaRyMGWaEslFz3XofzcrgaZuaxl44FysvrCxTKItO5K2jhxqQStBMVHVR2mPYQ3OOu4k1UjwUUvpDPiNrujKY7huqbmEytsQ0y72E/s320/841879262_d90e689dde.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5571494848110937570" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">T</span><span class="Apple-style-span" style="font-size:small;">hink of clinical trial data as a window on the efficacy and safety of a drug. Think of data protection and trade secrecy as soot. The above picture? This is the public view on drug safety and efficacy.</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">According to a recent report in </span></span><i><a href="http://www.nature.com/nbt/journal/v29/n2/full/nbt0211-98.html"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Nature Biotechnology</span></span></a></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> (Feb 2011), medicine may be getting some soapy water and a squeegee, thanks to several policy initiatives at drug regulatory authorities. In Europe, the main drug regulatory authority, EMA, recently issued a policy that will make publicly available "full clinical trial reports"-- even for drugs that are not approved for licensure.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">The reforms roughly parallel a series of proposed policies at FDA under the </span></span><a href="http://www.fda.gov/AboutFDA/Transparency/TransparencyInitiative/default.htm"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">FDA Transparency Initiative</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">. Among the </span></span><a href="http://www.fda.gov/downloads/AboutFDA/Transparency/PublicDisclosure/GlossaryofAcronymsandAbbreviations/UCM212110.pdf"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">proposed items</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> that would be publicly accessible: when an application has been submitted to the agency (or withdrawn); whether a significant safety issue triggered withdrawal, and reasons why the agency turned down an application.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Disclosure of such information carries some risk. Contrary to common belief, information disclosure does not level all power and influence, as some parties are better equipped to aggregate, analyze, and act on information. No doubt, such transparency will be used by various parties to harangue FDA for otherwise enlightened regulatory decisions.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">However, what the public sees of safety and efficacy information- to mix metaphors- is merely the tip of the iceberg. The <i>Nature Biotechnology</i> report, for example, describes the case of Pfizer's SSRI drug Edronax. Published trials included data on 1600 patients, but in actuality, trials involved 4600 patients. When complete data sets were obtained and reviewed, the drug turned out to be no better than placebo, and possibly unsafe (read more <a href="http://www.ncbi.nlm.nih.gov/pubmed/20940209">here</a>). [[Yet one more reason to wonder what Canadian Institute of Health Research was thinking when it appointed <a href="http://www.cihr-irsc.gc.ca/e/40472.html">Medical Director of Pfizer Canada</a> to its Governing Council.)]]</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Any transparency reforms would provide a much better basis for a) circumventing ethically suspect information practices so that healthcare systems can assess the totality of evidence on drug safety and efficacy, and b) getting a better understanding of the drug development process- warts and all. (</span><span class="Apple-style-span" style="font-size:x-small;">photo credit: </span></span><a href="http://www.flickr.com/photos/lulutoo/841879262/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">Lulu Vision</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;"> 2007</span><span class="Apple-style-span" style="font-size:small;">). </span></span></div><div><div><br /></div><div><br /></div></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com1tag:blogger.com,1999:blog-5597008424004474079.post-62877832302327091302010-12-20T12:16:00.005-05:002010-12-20T12:56:55.597-05:00More Gray Matter: Parkinson's Disease and Gene Transfer<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglf-Lb525ah7QOzH1hpUaediY7yr66vlgKMHlPOIWZss3EKVK9F9GN8uZ3lyAOykNQN-GTQcEdRKkhAdMoLc_ZzntkQdjNiRANuAOyOlbvigjaXNlEPcKMdPYw96jZ7rMO4d5QWjTuZ18/s1600/2052759598_103c2ee5a0_b.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 240px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglf-Lb525ah7QOzH1hpUaediY7yr66vlgKMHlPOIWZss3EKVK9F9GN8uZ3lyAOykNQN-GTQcEdRKkhAdMoLc_ZzntkQdjNiRANuAOyOlbvigjaXNlEPcKMdPYw96jZ7rMO4d5QWjTuZ18/s320/2052759598_103c2ee5a0_b.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5552815136935821826" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">S</span><span class="Apple-style-span" style="font-size:small;">everal groups are pursuing gene transfer strategies against Parkinson's disease. No small task, because for these approaches to work, investigators have to deliver vectors deep inside the brain using surgery. I have previously written that early phase studies using surgical delivery press the boundaries of acceptable risk, because patients can generally manage their disease adequately- though far from completely- with dopamine replacement, and study participation entails nontrivial surgical risks (by my calculations, about 0.5% chance of mortality, depending on the approach).</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">In the December issue of <i><a href="http://www.ncbi.nlm.nih.gov/pubmed/20970382">Lancet Neurology</a></i>, Marks et al report results of a phase 2, sham controlled trial of CERE-120. The results were negative. That is, for the main measure in the study, improvement in symptoms at 12 months, patients receiving CERE-120 did not do significantly better than patients receiving sham. On the other hand, the product did not raise any major safety issues, apart from a hemorrhage during surgery in one patient.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">The team performing the study has emphasized several "positive" outcomes. For one, patients receiving CERE-120 generally responded better than patients in the sham arm (though not significantly better- that is, differences may be attributable to chance). And on a secondary endpoint- response at 18 months- patients receiving CERE-120 did indeed perform significantly better. So did Ceregene score against Parkinson's disease? In an accompanying commentary, French Neurologist Alim Benabid says "the findings... provide the first clinical evidence of a clinical benefit of gene therapy in Parkinson's disease."</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">I ain't no neurologist, but I say: hold on a minute. When researchers start trials, they pick primary endpoints based on where they think they are most likely to succeed. In this case, the researchers picked improvement at 12 months, rather than at 18 months. From the looks of it, they backed the wrong horse- patients did significantly better at 18 rather than 12 months. What does this tell us? Success in a secondary endpoint might have occurred by chance, and the fact that researchers were unsuccessful on their primary endpoint indicates that they do not yet understand enough about their system to pick the "right" endpoints. So I see this as symptomatic of scientific uncertainty rather than a glimpse of medical destiny. [[One other issue to consider: it is possible that surgery itself (rather than gene transfer) may have caused symptomatic improvements.]]</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">The study was well reported and provides, yet again, evidence of the utility of sham comparator arms in studies involving Parkinson's disease. One disappointing feature, however, is that the authors did not report whether patients or clinicians could correctly guess their treatment allocation just prior to unblinding. Without this, it is difficult to exclude the possibility that any difference between groups- even at 18 months- was due to "placebo effect." (</span><span class="Apple-style-span" style="font-size:x-small;">photo credit: </span></span><a href="http://www.flickr.com/photos/vin60/2052759598/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">Vin6</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">, 2007</span><span class="Apple-style-span" style="font-size:small;">)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-82823214850548175862010-11-29T09:38:00.003-05:002010-11-29T09:45:49.470-05:00Icarus, again: Adversity in another Gene Transfer Trial<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg8zYcbLradrXgjo9jeOQnsN9OxmtSYS5vL62BcLAqPximx398XZjWHm7Vk0BUmOLbkh_wzx9MFt7wRfB8_soYiUvqdFNAzhzgSuKbLW_toBa9ss-doO8Y3zwWN7mYkb4qY7tvvYdOggdA/s1600/4182423736_11f12ecaaf.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 217px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg8zYcbLradrXgjo9jeOQnsN9OxmtSYS5vL62BcLAqPximx398XZjWHm7Vk0BUmOLbkh_wzx9MFt7wRfB8_soYiUvqdFNAzhzgSuKbLW_toBa9ss-doO8Y3zwWN7mYkb4qY7tvvYdOggdA/s320/4182423736_11f12ecaaf.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5544981221445165058" /></a> <!--StartFragment--> <p class="MsoNormal"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">Two weeks ago brought good news and bad news for gene transfer. First the good news. <i>New England Journal of Medicine</i><a href="http://www.nejm.org/doi/pdf/10.1056/NEJMoa1003548"> beatified a new gene transfer strategy</a> for Wiskott-Aldrich Syndrome (WAS). WAS is a primary immunodeficiency that primarily affects boys. It is thus in the same family of disorders that have been, in varying degrees, successfully addressed using retroviral gene transfer. Like other immunodeficiencies, this represents relatively low hanging fruit for an approach like gene transfer, because scientists can access and target stem cells, and because corrected cells should be at a selective advantage for survival compared with uncorrected cells.<o:p></o:p></span></span></p> <p class="MsoNormal"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">The NEJM article reported clinical, functional, and molecular outcomes for two boys in a trial based in Germany. Briefly the two boys were given a type of chemotherapy (in order to make space for genetically corrected cells), and then transplanted with “corrected” blood stem cells. The corrected blood stem cells contained a viral vector similar to those used in previous gene transfer trials of primary immune deficiency. The team saw: 1) stable levels of genetically corrected stem cells that expressed the WAS protein (indicating the genetically modified cells “took,” and produced WAS; 2) recovery of the function of a variety of immune cells; 3) reduction of disease symptoms, including improvement of eczema, and reduced severity of infections.</span></span></p> <p class="MsoNormal"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">The article exhaustively ruled out events that have occurred in other, similar gene transfer trials in which children developed leukemias from the vector. Now the bad news. The same day <i>NEJM</i> published the results, American Society of Gene and Cell Therapy (the largest professional society devoted to gene transfer) released a statement saying that the German team <a href="http://www.mh-hannover.de/46.html?&no_cache=1&L=1&tx_ttnews%5Btt_news%5D=1798&tx_ttnews%5BbackPid%5D=45&cHash=5f110f2bc3">just announced</a> “</span></span><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">a serious adverse event in a gene therapy trial for Wiskott-Aldrich syndrome (WAS)”- one of the ten children in the German trial developed a leukemia.<o:p></o:p></span></span></p> <p class="MsoNormal"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">And so continues the saga of gene transfer: three steps forward, one back.</span></span><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"> (<span class="Apple-style-span" style="font-size: x-small;">photo credit: </span></span></span><a href="http://www.flickr.com/photos/theredphotographies/4182423736/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">vk-red</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;"> 2009</span>)</span></span></p>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-11160525815238184692010-09-20T17:25:00.006-04:002010-09-20T18:06:19.930-04:00Are Trials Necessary?<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgBaO1Y8rR-nTWr6ItRGl8MuYG-h1gzKhYPMAisK_kX68azdGsVBIIhhU4-IW19m3Szn_0p5blTLlZslDhD7-96dm_6SQu0n_L9Q1UkvBOrLZ3VlJ5OuwFRSPK-_nHhQhwrpuSq1nmsmtc/s1600/3059963173_0c62ca4297.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 213px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgBaO1Y8rR-nTWr6ItRGl8MuYG-h1gzKhYPMAisK_kX68azdGsVBIIhhU4-IW19m3Szn_0p5blTLlZslDhD7-96dm_6SQu0n_L9Q1UkvBOrLZ3VlJ5OuwFRSPK-_nHhQhwrpuSq1nmsmtc/s320/3059963173_0c62ca4297.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5519109959524803906" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">T</span><span class="Apple-style-span" style="font-size:small;">oday's </span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">New York Times</span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> ran a heartbreaking </span></span><a href="http://www.nytimes.com/2010/09/19/health/research/19trial.html"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">story</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> by Amy Harmon about two cousins who developed melanoma. One was entered into a cancer clinical trial and received the investigational drug PLX4032. The other was ineligible for the trial, and therefore unable to access the experimental drug. Guess which cousin died?</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">The article is one in a series of Harmon articles that seems to raise questions about whether rules governing drug testing and research are depriving desperately ill patients timely access to curative therapy. In this article, the narrative takes aim at two practices: 1- the practice of including control groups within trials, and randomly determining that some patients will receive standard care that is widely regarded as inadequate; 2- excluding patient access to drugs that have not yet demonstrated unequivocal therapeutic advantage.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">As with many of my blog entries, I preface this one by saying that I am not a cancer doc, and therefore not in a position to evaluate whether PLX4032 is the wonder drug this story makes it out to be. I also preface my comment on this article by acknowledging the incredible pain and anxiety that patients suffer when denied access to a trial, or when denied access to a preferred drug within a trial. These disclaimers aside, I found the tenor of this article very problematic.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">First, the reason investigators randomly determine treatment choice in trials is because, at the outside of a well designed trial, there is genuine uncertainty about whether the new drug is better, the same, or worse than the (inadequate) standard treatment. Many doctors participate in trials because they fervently believe the new regimen is better than the standard one. But the evidence shows, again and again, that on average, new drugs outperform old ones in a small portion of instances (maybe around 15-20%). It is just as likely that new drugs will underperform standard treatments- making patients sicker perhaps, or failing to deliver as much punch. So one concern about the article is the premise that doctor's personal beliefs about which cancer drug will perform better in a randomized controlled trial carries some moral weight. The evidence shows doctors in the aggregate haven't a clue- which is why functional healthcare systems run trials.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">A second troubling premise here is that there is no harm to allowing public consumption of drugs that are not yet validated in rigorous clinical trials. CEOs of many pharmaceutical companies perhaps may share this view. But the historical record shows otherwise: in fact, many patients are severely harmed when drugs are introduced into clinical use before they have been established as safe and effective. Perhaps a few readers out there may be familiar with thalidomide? Or </span></span><a href="http://www.us.oup.com/us/catalog/general/subject/Medicine/PublicHealth/~~/dmlldz11c2EmY2k9OTc4MDE5NTE4Nzc2Mg=="><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">autologous bone marrow transplantation</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> for breast cancer? Ever considered the price tag on these new cancer drugs, and do you want your government or insurance company purchasing a potentially useless drug?</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Still, article zeros in on an ethical tension that is very difficult to eradicate from clinical research. Patients want- and are entitled- to be treated as individuals. Physicians also prefer to treat patients as individuals. Clinical trials, however require that patients be treated as tokens of larger populations- that they be treated, in a sense, as "stand ins" for future patients. Randomization has not been shown to deprive patients of access to life preserving drugs. However, it does rob patients of fulfilling their desire to be treated as individuals and to exercise personal choice. And this is one of the reasons why the field of research ethics is endlessly fascinating, important, and nettlesome. (</span><span class="Apple-style-span" style="font-size:x-small;">photo credit: </span></span><a href="http://www.flickr.com/photos/qchristopher/3059963173/sizes/m/in/photostream/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">travelingMango</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;"> 2008</span><span class="Apple-style-span" style="font-size:small;">).</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com5tag:blogger.com,1999:blog-5597008424004474079.post-27222992733962350852010-08-04T17:48:00.008-04:002010-08-05T16:51:45.802-04:00Embryonic Stem Cell Trials Start Development<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjaviQoU0XNx9ugjT_kNlyXuRFDlSS-hHAb4t5OBVlnHSZuSiPetirLQ4ox6eFXdkjf2SRkunQABCa2szSaJdzp6vFueoX30tcOwdFoNtx0oPcfZYx6YroE4DeniIyQfw7LnUCPmWJy22o/s1600/4671848479_62c0dea636_b.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 238px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjaviQoU0XNx9ugjT_kNlyXuRFDlSS-hHAb4t5OBVlnHSZuSiPetirLQ4ox6eFXdkjf2SRkunQABCa2szSaJdzp6vFueoX30tcOwdFoNtx0oPcfZYx6YroE4DeniIyQfw7LnUCPmWJy22o/s320/4671848479_62c0dea636_b.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5501675366985407138" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-large;">S</span></span><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">o, FDA has </span></span><a href="http://prescriptions.blogs.nytimes.com/2010/07/30/f-d-a-clears-way-for-embryonic-stem-cell-trial-using-patients/?scp=2&sq=geron&st=cse"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">lifted a hold</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> on the first ever clinical trial testing cells derived from human embyonic stem cells. The study- based in California and sponsored by the biotechnology company Geron (view press release </span></span><a href="http://www.geron.com/investors/factsheet/pressview.aspx?id=1229"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">here</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">)- will administer cells derived from human embryos ("neural support cells") to ten patients with recent spinal cord injury with the primary aim of demonstrating safety. The same study had been initiated last year- but halted after safety concerns arose in rodent tests. According to news reports, Geron was able to deliver a clean package of studies to FDA. And so- roughly 20 years since the first ever gene transfer study, we now have the first ever human trial of embryo stem cell derived tissue.</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Circumstances surrounding this study show all the signs of repeating phenomena surrounding other, highly publicized first in human trials. My book picks up on these signs as harbingers of challenge. Take, for example, the way the initiation of the study itself is seen as a milestone- as a visible sign of medical progress. This presents a regulatory decision as a stand in for study results; it confuses desire with results. And so, I worry when people like Alan Trounson, president of California Institute of Regenerative Medicine, say things like "I think it's a very important milestone for the whole industry... It's very important that they get on and treat the patients...." I also worry when I hear that share prices in Geron rose by 17% on news of the decision- as if permission to study a product is evidence of the product's promise.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">The New York Times article reports that Advanced Cell Technology is seeking permission to test another embryonic stem cell derived tissue in human beings- this time for an eye condition. Approval of Geron's trial will surely blaze a path for the latter- though the ethical justification for proceeding in such research may prove more difficult than for spinal cord injury</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="line-height: 22px; "><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">(</span></span><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">photo credit: </span></span><a href="http://www.flickr.com/photos/artsy_avenue/4671848479/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">Brennan G. Wills</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">, 2010</span></span><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">)</span></span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-77126426576792434352010-06-17T11:05:00.009-04:002010-06-17T11:39:29.395-04:00Information: Stem Cell Tourism Redux (part 1)<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgxjdt1qX8wbvmnXYqOMtFiW2y89u8iYsx3SXsDzzZPN4IhWstV7qhEoEAHfIWuwdkylfz_jGh3bGnjZxUFx99Lyk4QU5OvnTb2gXd30A59yPLPHIhiLWvm-p0Manx8Zxg8ACXPxJUHlqM/s1600/Tourism.jpg"><img style="display: block; margin: 0px auto 10px; text-align: center; cursor: pointer; width: 239px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgxjdt1qX8wbvmnXYqOMtFiW2y89u8iYsx3SXsDzzZPN4IhWstV7qhEoEAHfIWuwdkylfz_jGh3bGnjZxUFx99Lyk4QU5OvnTb2gXd30A59yPLPHIhiLWvm-p0Manx8Zxg8ACXPxJUHlqM/s320/Tourism.jpg" alt="" id="BLOGGER_PHOTO_ID_5483759301372684434" border="0" /></a><span style="font-size:85%;"><span style=";font-family:times new roman;font-size:100%;" ><span style="font-size:180%;">T</span>he current issue of </span><span style="font-style: italic;font-family:times new roman;font-size:100%;" >Kennedy Institute of Ethics Journal</span><span style=";font-family:times new roman;font-size:100%;" > contains the </span><span style="font-size:100%;"><a style="font-family: times new roman;" href="http://www.ncbi.nlm.nih.gov/pubmed/20506693">first installment</a></span><span style=";font-family:times new roman;font-size:100%;" > 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). </span><span style="font-size:100%;"><br /><br /></span><span style=";font-family:times new roman;font-size:100%;" >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. </span><span style="font-size:100%;"><br /><br /></span><span style=";font-family:times new roman;font-size:100%;" >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."</span><span style="font-size:100%;"><br /><br /></span><span style=";font-family:times new roman;font-size:100%;" >There is an intriguing theme in this article that ties in with my recent </span><span style="font-size:100%;"><a style="font-family: times new roman;" href="http://lostintranslationethics.blogspot.com/2010/05/conditions-of-collaboration-protecting.html"><span style="font-style: italic;">Science</span></a></span><span style="font-family:times new roman;"><span style="font-family:times new roman;"><span style="font-size:100%;"> 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...</span> </span><span style="font-size:78%;">(photo credit: </span></span><span style="font-size:78%;"><a style="font-family: times new roman;" href="http://www.flickr.com/photos/clearhop/108430037/">Alex McGibbon</a><span style="font-family:times new roman;">, (courtesy </span><a style="font-family: times new roman;" href="http://www.banksy.co.uk/">Banksy</a><span style="font-family:times new roman;">), 2006)</span></span></span>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-80647820628875495472010-05-26T16:54:00.002-04:002010-05-26T17:36:56.940-04:00ASGCT, cont': Results on Fetal Tissue for Battens Presented<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjRUcj5Kr8una0ps290f7Z7YG2tlXn9306TDyyjFjNjktf3Lw__0AQAXoCfrLVCMll2NRAKiZYIH6b_uxxxNYRTY0IGZhyphenhyphenj9MYE0vtuV-twc1fF5zPnCgL2TuSboc8fv0erUzotmPVfJCQ/s1600/subcortical.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 313px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjRUcj5Kr8una0ps290f7Z7YG2tlXn9306TDyyjFjNjktf3Lw__0AQAXoCfrLVCMll2NRAKiZYIH6b_uxxxNYRTY0IGZhyphenhyphenj9MYE0vtuV-twc1fF5zPnCgL2TuSboc8fv0erUzotmPVfJCQ/s320/subcortical.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5475685469110121250" /></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-large;">R</span>obert Steiner, co-principal investigator in a fetal cell transplantation study involving the rare, fatal hereditary disease </span></span><span class="Apple-style-span" style="color: rgb(63, 63, 63); font-weight: bold; line-height: 14px; -webkit-border-horizontal-spacing: 2px; -webkit-border-vertical-spacing: 2px; "><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="color:#000000;"><span class="Apple-style-span" style="font-weight: normal;">Neuronal Ceroid Lipofuscinosis</span></span> </span></span></span><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">(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.</span></span><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">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).</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">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 </span></span><a href="http://www.drugs.com/clinical_trials/stemcells-inc-announces-positive-phase-batten-trial-results-7496.html"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">press release</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">, "</span></span><span class="Apple-style-span" style="line-height: 14px; "><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">By permitting the autopsy, the family allowed the researchers to learn very important details that will potentially benefit future patients</span></span><span class="Apple-style-span" style="line-height: normal; "><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">."</span></span></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="line-height: 14px; "><span class="Apple-style-span" style="line-height: normal; "><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">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. (<span class="Apple-style-span" style="font-size: x-small;">photo credit: </span></span></span><a href="http://www.flickr.com/photos/dopamineharper/3520892409/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">dopamineharper</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;"> 2009</span>)</span></span></span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-77697290199340683292010-05-25T10:35:00.006-04:002010-06-01T22:19:50.606-04:00ASGCT, continued: Eyes on Stage<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgkzFxDxVynTR6SQETaIIhTuxRmOQ8ir699dSOV-cMLRA4ygLJ_afwe9x5noBA1z6C3LFpY0Fmf2nBh_BuJET_W2obvR0zwaOXsdYMU9gGIei5d06-r_34Fig_H2dAh7Ksd10rkperVuyE/s1600/eye.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 245px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgkzFxDxVynTR6SQETaIIhTuxRmOQ8ir699dSOV-cMLRA4ygLJ_afwe9x5noBA1z6C3LFpY0Fmf2nBh_BuJET_W2obvR0zwaOXsdYMU9gGIei5d06-r_34Fig_H2dAh7Ksd10rkperVuyE/s320/eye.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5475216605983156786" /></a><span class="Apple-style-span" style="font-size:x-large;"><span class="Apple-style-span" style="font-family:'times new roman';">P</span></span><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">redictably, 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."</span></span><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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 <i>with</i> 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.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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. </span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman', serif;"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">Spectacular research, to be sure. But it makes for spectacle science as well. <span class="Apple-style-span" style="font-size:x-small;">(photo credit: </span></span></span><a href="http://www.flickr.com/photos/strangejourney/3197907475/in/photostream/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">strangejourney</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;"> 2009)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-3262040917129228802010-05-22T09:26:00.003-04:002010-05-22T09:40:08.365-04:00ASGCT in Washington DC<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEit9M_Auu05rp7F0zb8Rp9bautAseEvqp-s8GLhmh0BbuMGrfdN7rvB6QXOo9Pm9Kp6S_UHkKzrdZXA3i_umuzg8ogapIoYBY-QedTVKUdA-x4YXS8OfxttPPgihclIsQ60CiLl7F3HmaE/s1600/515588510_4798ab85cc.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 240px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEit9M_Auu05rp7F0zb8Rp9bautAseEvqp-s8GLhmh0BbuMGrfdN7rvB6QXOo9Pm9Kp6S_UHkKzrdZXA3i_umuzg8ogapIoYBY-QedTVKUdA-x4YXS8OfxttPPgihclIsQ60CiLl7F3HmaE/s320/515588510_4798ab85cc.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5474085641757187634" /></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-large;">A</span>nother 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... <span class="Apple-style-span" style="font-size: x-small;">(photo credit: </span></span></span><a href="http://www.flickr.com/photos/afagen/515588510/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">afagan</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;"> 2007)</span> </span></span>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-30990044396863600612010-05-17T22:11:00.006-04:002010-06-01T22:16:33.632-04:00Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhooOfYah4d6LZDTFEE7fXaPs3iYdNKi46XE8oTanEIqLZ4dvzhNSYyE7PjzNgEWSwLTitWuyuWhKVCeM_YxEBFlGhPIDdD0RmqLhd178-olsbOwR6JHmVLpzJj-dlgepWX5n66Q4ehme4/s1600/3260568768_9e98dfafdd.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 240px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhooOfYah4d6LZDTFEE7fXaPs3iYdNKi46XE8oTanEIqLZ4dvzhNSYyE7PjzNgEWSwLTitWuyuWhKVCeM_YxEBFlGhPIDdD0RmqLhd178-olsbOwR6JHmVLpzJj-dlgepWX5n66Q4ehme4/s320/3260568768_9e98dfafdd.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5472427161910303650" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">S</span><span class="Apple-style-span" style="font-size:small;">o 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 </span></span><a href="http://www.hss.cmu.edu/philosophy/faculty-london.php"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Alex John London</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> and </span></span><a href="http://ink.primate.wisc.edu/~emborg/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Marina Emborg</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> in a piece appearing in </span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><a href="http://www.sciencemag.org/cgi/content/summary/328/5980/829">Science</a> <span class="Apple-style-span" style="font-style: normal;">[a publicly accessible version of the essay is available at </span><a href="http://www.scienceprogress.org/2010/06/clinical-trials-and-the-common-good/">Science Progress</a><span class="Apple-style-span" style="font-style: normal;">]</span></span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">. 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.</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">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).</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">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. </span><span class="Apple-style-span" style="font-size:x-small;"> (photo credit: McKillaboy, </span></span><a href="http://www.flickr.com/photos/mckillaboy/3260568768/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">Cataglyphis velox 22</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">, 2009)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-28547378311044447442010-05-11T13:35:00.005-04:002010-05-11T14:17:03.131-04:00Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjac7BgcU4Px3uEUekBiIqJ-nCPqz4-dC9HBRqBTDoOTt8oSkd6XvJI-UzKEe3RtGvmRqrCnjkV-dA7MkBUwDfU2lMup66HG4yRwrc_9v-jDZ0ImAJQNsmgA-Iga7ZiWh4jwAnBFvWw92s/s1600/filing+cabinet.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 221px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjac7BgcU4Px3uEUekBiIqJ-nCPqz4-dC9HBRqBTDoOTt8oSkd6XvJI-UzKEe3RtGvmRqrCnjkV-dA7MkBUwDfU2lMup66HG4yRwrc_9v-jDZ0ImAJQNsmgA-Iga7ZiWh4jwAnBFvWw92s/s320/filing+cabinet.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5470067717813209730" /></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">M</span>uch 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, </span></span><a href="http://www.nature.com/nature/journal/v429/n6992/full/429589a.html"><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">back in 2004</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">, 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, </span></span><a href="http://www.wma.net/en/30publications/10policies/b3/index.html"><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">World Medical Association</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">, and others to require researchers to register clinical trials before they enroll any patients.</span></span><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">Yet important gaps remain. In the March 2010 issue of <i>PLoS Biology</i>, Emily S. Sena and coauthors provide </span></span><a href="http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000344"><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">the most detailed analysis yet</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"> 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: "w</span></span><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">e estimate that for the interventions described here, experiments involving some 3,600 animals have remained unpublished. We consider this practice to be unethical."</span></span></div><div><span class="Apple-style-span" style="color:#303030;"><span class="Apple-style-span" style="line-height: 21px; "><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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. </span></span><span class="Apple-style-span" style="color: rgb(0, 0, 0); line-height: normal; "><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">(<span class="Apple-style-span" style="font-size:x-small;">photo credit: </span></span></span><a href="http://www.flickr.com/photos/amyallcock/3392347918/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">amy allcock</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;"> 2009</span>)</span></span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-24862193074755499402010-04-22T10:24:00.008-04:002010-04-24T19:34:52.953-04:00CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiazwkL-OuddofOOyrDiNvZ1xI0lmUjtYKkFV43KpGnR_eLCywG0_XnVrard9voT0zl-wKgbMeYZ8ot5FQDZGIo9f7ZKnoC-iLCDSaORVVvaW4tr-YD4bh1ZWNIiti0CeVlQN0FrNYRraQ/s1600/2590380482_ee31fa2030.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 213px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiazwkL-OuddofOOyrDiNvZ1xI0lmUjtYKkFV43KpGnR_eLCywG0_XnVrard9voT0zl-wKgbMeYZ8ot5FQDZGIo9f7ZKnoC-iLCDSaORVVvaW4tr-YD4bh1ZWNIiti0CeVlQN0FrNYRraQ/s320/2590380482_ee31fa2030.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5462967944890678850" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">T</span><span class="Apple-style-span" style="font-size:small;">his month's issue of </span></span><i><a href="http://www.nature.com/mt/journal/v18/n4/index.html"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Molecular Therapy</span></span></a></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">- 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 </span></span><a href="http://www.ncbi.nlm.nih.gov/pubmed/20179677"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">one</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> case, the authors attribute death to the gene transfer; in the </span></span><a href="http://www.ncbi.nlm.nih.gov/pubmed/20357779"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">other</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">, the authors categorize the death as possibly related to the gene transfer (the latter was previously described at ASGT in 2009).</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">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:</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">1- </span></span><b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Unpredictability</span></span></b><b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">:</span></span></b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> 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.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">2-</span></span><b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Where's the Toxicology</span></span></b><b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">?</span></span></b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> 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?</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">3-</span></span><b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Did Investigators Give Preclinical Studies Their Best Shot at Producing Similar Toxicity?</span></span></b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> 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 </span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">and</span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> immunosuppressive drugs.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">4- </span></span><b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Ple</span></span></b><b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">ase: No More Gratuitous Appeals to the Integrity of the Investigators</span></span></b><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">. An </span></span><a href="http://www.nature.com/mt/journal/v18/n4/pdf/mt201042a.pdf"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">editorial</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> by a leading expert on CARs accompanies the reports in </span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Molecular Therapy </span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">and</span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> </span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">provides 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 </span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">supposed</span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> 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. </span><span class="Apple-style-span" style="font-size:x-small;">(photo credit: </span></span><a href="http://www.flickr.com/photos/nifmus/2590380482/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">Steve Kay</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;"> 2008)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-60328851285816104152010-04-20T18:57:00.005-04:002010-04-20T21:05:53.144-04:00Testing Testing...: Personal Medicine, Breast Cancer, and Policy<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhC6rmuqTbDLM07lNBFE4KTddoEqefVmGs-JvHy0R0h3ouGlDQu9PwXJ_d-p8sueLRIfnh3StzNiKN1ps0PNxyyhAi-mYmgFvtwvKt5tdbj0ZeGLB7WBgxZAS5Nz3x-jlVC1dRLda6IhRE/s1600/4024368125_6cee3d572d.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 249px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhC6rmuqTbDLM07lNBFE4KTddoEqefVmGs-JvHy0R0h3ouGlDQu9PwXJ_d-p8sueLRIfnh3StzNiKN1ps0PNxyyhAi-mYmgFvtwvKt5tdbj0ZeGLB7WBgxZAS5Nz3x-jlVC1dRLda6IhRE/s320/4024368125_6cee3d572d.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5462358054464381746" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">P</span><span class="Apple-style-span" style="font-size:small;">ersonalized 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. </span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Some may see HER2 testing as foreshadowing a perfect future in which treatment decisions are coupled to molecular diagnostics. But Gina Kolata in the <i><a href="http://www.nytimes.com/2010/04/20/health/research/20cancer.html?ref=health">New York Times</a></i> 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.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"></span></span></div><span><span><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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!) <span class="Apple-style-span" style="font-size:x-small;">(photo credit: crafty dame, breast cancer cells, 2009)</span></span></span></span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"></span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-14973927523419087972010-04-16T15:16:00.011-04:002010-04-16T22:26:24.617-04:00Teaching Kills Blogging: Somewhat Recent Developments...<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEii7xFHW5Xs9jhXBlV-ty-3o6rQPL0iJPGM5bv3WPVfKujB_itIgnvuvn8aXHPKgsbZCGVLEvsXoLh-ARyvEv0IxvmaJyjRwUhGWNlzQdiLWPRdUa1RGx3cxjTegWlgssiisAX-ypXkm4M/s1600/2398616138_1aa8572ee8.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 240px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEii7xFHW5Xs9jhXBlV-ty-3o6rQPL0iJPGM5bv3WPVfKujB_itIgnvuvn8aXHPKgsbZCGVLEvsXoLh-ARyvEv0IxvmaJyjRwUhGWNlzQdiLWPRdUa1RGx3cxjTegWlgssiisAX-ypXkm4M/s320/2398616138_1aa8572ee8.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5460816705080557234" /></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">D</span>ear 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:</span></span><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">• <b>Obama picks members for his Bioethics advisory panel</b>: White house recently announced membership of its "</span></span><a href="http://www.whitehouse.gov/the-press-office/president-obama-announces-more-key-administration-posts-4-7-10"><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">Presidential Commission for the Study of Bioethical Issues</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">." 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).</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">• <b>Health care reform (+ Translational Research) passes in the U.S</b>.: 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).</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">• <b>Gene Patents Voided</b>: Following an ACLU challenge, a U.S. District Court Judge <a href="http://www.genomicslawreport.com/index.php/2010/03/30/pigs-fly-federal-court-invalidates-myriads-patent-claims/">threw out Myriad Genetics' patent</a> on BRCA1 and BRCA2 (genes associated with hereditary breast cancer; the company markets a $3K per pop test for mutations in the genes) by </span></span><a href="http://www.genomicslawreport.com/wp-content/uploads/2010/03/Myriad-SJ-Opinion.pdf"><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">ruling</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"> 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. <span class="Apple-style-span" style="font-size:x-small;">(photo credit: </span></span></span><a href="http://www.flickr.com/photos/nagada2/2398616138/in/photostream/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">aurelian s</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;"> 2008)</span></span></div><div><br /></div><div><br /></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-55625230554311174122010-03-08T18:06:00.002-05:002010-03-08T18:38:23.715-05:00Ark, Troubled Waters, and Rainbows for Gene Transfer<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg7zMOaiS4om-mjp3cwBIGe8hUe2nHQvd80mh5D2fmSfsMwQqNHeN7nh2F9fgwUBDtM4n_mIFFFflIAMWjEwqX1xXljoVfRO3rSDjiidVzRi06sLFkdV63x_d2LOT_4OQzPHg-Wxlu_FeU/s1600-h/ark+occhiovivo07.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 215px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg7zMOaiS4om-mjp3cwBIGe8hUe2nHQvd80mh5D2fmSfsMwQqNHeN7nh2F9fgwUBDtM4n_mIFFFflIAMWjEwqX1xXljoVfRO3rSDjiidVzRi06sLFkdV63x_d2LOT_4OQzPHg-Wxlu_FeU/s320/ark+occhiovivo07.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5446403610665662226" /></a><span class="Apple-style-span" style="font-size: x-large;"><span class="Apple-style-span" style="font-family:'times new roman';">T</span></span><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">his morning I awoke to a </span></span><a href="http://www.npr.org/templates/story/story.php?storyId=124355459"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">news report</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;"> 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.</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">Coincidentally, the just released March issue of </span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">Nature Biotechnology</span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;"> 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 </span></span><a href="http://www.londonstockexchange.com/exchange/prices-and-news/news/market-news/market-news-detail.html?announcementId=10316999"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">here</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">). Recall that, last June, </span></span><a href="http://lostintranslationethics.blogspot.com/2009/05/asgt-in-san-diego.html"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">I described</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;"> 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). </span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">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 </span></span><i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">Nature Biotechnology</span></span></i><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">, 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: </span></span><a href="http://www.flickr.com/photos/occhiovivo/350441273/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;">Occhiovivo</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: small;"> 2007)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-15066751073716729912010-02-26T11:55:00.004-05:002010-02-26T18:43:04.932-05:00Canada Human Research Ethics Policies: Take 2<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjQEsuy1JqesyNdWW4aD3mA5kFwN1nwsvhks5ShTyU1tXk2b35OANkBWrh3vAt22S-bkUcuIrQ5G1WLLn3Hj5L84n2hQz2ZOtsoxZrRpBCL8zTZhy0Kqo2WME_sDUkjcd6M3Xt5geViGiw/s1600-h/canada.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 240px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjQEsuy1JqesyNdWW4aD3mA5kFwN1nwsvhks5ShTyU1tXk2b35OANkBWrh3vAt22S-bkUcuIrQ5G1WLLn3Hj5L84n2hQz2ZOtsoxZrRpBCL8zTZhy0Kqo2WME_sDUkjcd6M3Xt5geViGiw/s320/canada.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5442599910026973410" /></a><span class="Apple-style-span" style="font-size:x-large;"><span class="Apple-style-span" style="font-family:'times new roman';">I</span></span><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">n the Vancouver Olympics, Canada is tied for the most gold medals as of this writing. Will Canada also "own the podium" when it comes to providing a clear and effective voice for ethical human research?</span></span><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">Recall that, in a <a href="http://lostintranslationethics.blogspot.com/2008/12/northern-lights-canada-and-new.html">previous post</a>, I mentioned that Canada was presently undertaking a major overhaul of its main research ethics policy- the Tricouncil Policy Statement. After issuing an intital draft, the panel charged with revising the document (PRE) released a second draft. In a few days, the comment period closes for this second draft. The policy will then be revised again and finalized.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">I will be submitting comments on the new version, along with my research collaborators. Here are a few important problems that carry over from the previous version:</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><b>1)</b> The draft, like the old version, does not quite get the foundations for research ethics right. As a consequence, principles like respect for persons or justice are made subservient to beneficence. This is not an obscure philosophical point: it sends a message to investigators and research ethics committees that these other principles matter less.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><b>2)</b> The application of justice in studies involving economically or socially disadvantaged populations is somewhat muddled. The draft defines justice in terms of what it is not, or what researchers should not do, rather than providing an affirmative description of what justice entails. Consider what it would mean if the application of "respect for persons" merely meant that researchers should avoid enrolling patients who did not consent, or that researchers should refrain from studies if risks are unacceptable.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><b>3)</b> The language on undue inducement has problems: The TCPS language implies that concerns about undue inducement arise out of a concern for risk (see point 1 above). It doesn't. It is unethical to pay individuals to override certain moral commitments (in government, we call this bribery), even in the absence of risk to the individual.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><b>4)</b> The chapter on clinical trials sends conflicting messages, and seems to imply that it is ok for doctors and institutions to put patients at medical disadvantage by enrolling them in research. Hard to imagine, if this is accepted, how conscientious doctors could ever participate in research, much less refer their patients to studies. Of particular concern, the chapter on clinical trials seems like it is trying to accommodate the unethical standards established by the International Council on Harmonization's Good Clinical Practice.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">I hope the panel can correct these (and other) flaws, while preserving the many qualities contained in the proposed revisions. (</span></span><span class="Apple-style-span" style="font-size:x-small;"><span class="Apple-style-span" style="font-family:'times new roman';">photo credit: </span></span><a href="http://www.flickr.com/photos/pmorgan/2096795/"><span class="Apple-style-span" style="font-size:x-small;"><span class="Apple-style-span" style="font-family:'times new roman';">pmorgan</span></span></a><span class="Apple-style-span" style="font-size:x-small;"><span class="Apple-style-span" style="font-family:'times new roman';"> 2004</span></span><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com1tag:blogger.com,1999:blog-5597008424004474079.post-54571793096831430882010-02-26T11:21:00.005-05:002010-02-26T18:39:17.045-05:00Transplanting Autoimmune Research<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXw44X4-o79sKXsboH1GqyFh1w2av-K37Xw-wGXnPtM3kPmFSlR701rUu5DT1BhsOl-idqY3bcFE2NWhc4om71ERUwuaL3tSIdtWF8c2xu-qjTpclyoUVAxs7Lr0WvBQZCeAq0J1gzMEI/s1600-h/marrow.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 239px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXw44X4-o79sKXsboH1GqyFh1w2av-K37Xw-wGXnPtM3kPmFSlR701rUu5DT1BhsOl-idqY3bcFE2NWhc4om71ERUwuaL3tSIdtWF8c2xu-qjTpclyoUVAxs7Lr0WvBQZCeAq0J1gzMEI/s320/marrow.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5442588388396599730" /></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">W</span>hat'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 <i>Science</i> ("<a href="http://www.sciencemag.org/cgi/content/short/327/5967/772">Replacing an Immune System Gone Haywire</a>").</span></span><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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. (</span></span><span class="Apple-style-span" style="font-size:x-small;"><span class="Apple-style-span" style="font-family:'times new roman';">photo credit: Wellcome Images, </span></span><a href="http://www.flickr.com/photos/wellcomeimages/4013247483/"><span class="Apple-style-span" style="font-size:x-small;"><span class="Apple-style-span" style="font-family:'times new roman';">Compact Bone</span></span></a><span class="Apple-style-span" style="font-size:x-small;"><span class="Apple-style-span" style="font-family:'times new roman';">, 2009</span></span><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-25006100963896516962010-02-13T22:50:00.004-05:002010-02-14T09:12:46.622-05:00Cooperation and Medical Research<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi7u5euv09Neq9uyk7GDjXH4Mf9okI0jPN22zcbQamH1n-MssThUAsthn9WltwdS2RX-U0QwJ-DAhVmHn7v3HcODqh_d3NGawL2b_5wQiDOngiJPEanRdZnPz8uVZB4zPcL71OhPoMtDNM/s1600-h/cooperation.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 221px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi7u5euv09Neq9uyk7GDjXH4Mf9okI0jPN22zcbQamH1n-MssThUAsthn9WltwdS2RX-U0QwJ-DAhVmHn7v3HcODqh_d3NGawL2b_5wQiDOngiJPEanRdZnPz8uVZB4zPcL71OhPoMtDNM/s320/cooperation.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5437941599132418850" /></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-large;">W</span>hy 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 </span></span><i><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><a href="http://www.ncbi.nlm.nih.gov/pubmed/19394741?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=7">Social Science and Medicine</a>. </span></span></i><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">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.</span></span><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">Using interviews from three different clinical studies, Dixon-Woods and Tarrant identify five recurring themes:</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">1- </span></span><b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">Research as Moral Act:</span></span></b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"> 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</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">2- </span></span><b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">Research as Risk:</span></span></b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"> 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)</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">3- </span></span><b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">Trust in Regulation:</span></span></b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"> 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</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">4- </span></span><b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">Signals of Trustworthiness:</span></span></b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"> 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."</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">5- </span></span><b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">Trust of Professions</span></span></b><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">: 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</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">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. (<span class="Apple-style-span" style="font-size: x-small;">photocredit: </span></span></span><a href="http://www.flickr.com/photos/klashback/2201236621/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">Lucas</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;"> 2008</span>)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com2tag:blogger.com,1999:blog-5597008424004474079.post-64015369169816952822009-12-29T15:20:00.005-05:002009-12-29T16:48:44.461-05:00Annus Mirabilis for Gene Transfer<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEilsVCWweQndwx1Lzp1hitQ4dXUFjSceiTOvLeQid0AAwrf0jwjCX9aoAWoWuqdvmuZiSOIWMOCH41L_DYZtBTGdJylO9_VlRpPSlvUDJpiUsnZ04aPmou2luH2pN2F1iwroHu6gRbv-ks/s1600-h/4102494217_e17b404359.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 310px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEilsVCWweQndwx1Lzp1hitQ4dXUFjSceiTOvLeQid0AAwrf0jwjCX9aoAWoWuqdvmuZiSOIWMOCH41L_DYZtBTGdJylO9_VlRpPSlvUDJpiUsnZ04aPmou2luH2pN2F1iwroHu6gRbv-ks/s320/4102494217_e17b404359.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5420755960770582882" /></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-large;">T</span>ime to review the year 2009 for cutting edge clinical research. For the field of gene transfer, it has been an </span></span><i><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">annus mirabilis</span></span></i><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">: 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:</span></span><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">• in March 2009, Italian researchers reported major clinical improvement in eight of ten children participating in a gene transfer study involving ADA-SCID. [</span></span><a href="http://lostintranslationethics.blogspot.com/2009/03/departing-milano-stazione-ada-scid-and.html"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">discussed here</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">]</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">• in June 2009, researchers at Penn / Scheie Eye Institute reported very encouraging outcomes in three children with hereditary blindness, including evidence of visual recovery. [</span></span><a href="http://lostintranslationethics.blogspot.com/2009_05_01_archive.html"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">discussed here</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">]</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">• 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 </span></span><a href="http://blogs.sciencemag.org/scienceinsider/2009/09/massive-aids-va.html"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">here</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"> and </span></span><a href="http://www3.niaid.nih.gov/news/newsreleases/2009/ThaiVaxStudy.htm"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">here</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">].</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">• in November 2009, researchers at Paris-Necker reported very encouraging outcomes in two children with adreno leukodystrophy who received a vector derived from lentiviruses [</span></span><a href="http://lostintranslationethics.blogspot.com/2009/11/more-on-lentis-gene-transfer-and.html"><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">discussed here</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">]</span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';">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. (<span class="Apple-style-span" style="font-size: x-small;">photo credit: </span></span></span><a href="http://www.flickr.com/photos/xlup/4102494217/in/set-72157621914785745/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;">Xavier Luque</span></span></a><span class="Apple-style-span" style="font-size: small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-small;"> 2009</span>)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-67500595740536047862009-12-04T17:20:00.005-05:002009-12-05T10:21:36.911-05:00Finding Skew: Informed Consent and Bias in Clinical Trials<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjEZOgv5i3fYQDrqIOKBxJSk-2-VNfceyxqVmZLmBNdVdM0uKY43Ju_DIPCLM3DmraZ3Gn1inORA8FxCwkeHt6oVfd-E3lslmA5fLnSmLGeYGVfVp6odDxcaNdFBSdsfnVTGVoMUcOsalg/s1600-h/skew.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 320px; height: 150px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjEZOgv5i3fYQDrqIOKBxJSk-2-VNfceyxqVmZLmBNdVdM0uKY43Ju_DIPCLM3DmraZ3Gn1inORA8FxCwkeHt6oVfd-E3lslmA5fLnSmLGeYGVfVp6odDxcaNdFBSdsfnVTGVoMUcOsalg/s320/skew.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5411509887758822514" /></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size: x-large;">C</span>linical 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.</span></span><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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 (</span></span><i><a href="http://eurjhf.oxfordjournals.org/content/vol11/issue11/"><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">Eur J Heart Failure</span></span></a></i><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">; also reported in the December </span></span><a href="http://www.nature.com/nm/journal/v15/n12/pdf/nm1209-1338c.pdf"><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">issue</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"> of </span></span><i><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">Nature Medicine</span></span></i><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">). 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.</span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><br /></span></span></div><div><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';">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. (<span class="Apple-style-span" style="font-size:x-small;">photo credit: funkandjazz, </span></span></span><a href="http://www.flickr.com/photos/phunk/665586786/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">Skew</span></span></a><span class="Apple-style-span" style="font-size:small;"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">, 2007</span>)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com0tag:blogger.com,1999:blog-5597008424004474079.post-83706643197234563542009-11-24T11:10:00.008-05:002009-11-26T17:34:16.705-05:00Expectation is a Vascular Condition: Thoughts on Media Coverage of "Liberation Procedures" for Multiple Sclerosis<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTRAOzto8n4zDeZL4K98lV42-TceNNB3XNJ3qML9inz5Dm2HlpVDWcuxRJ8r_X6JEqs65qTTdkAvb9JC_dKwhcwIoA6-1JqlJC_ZImmEqYVfAUkAfr-UzQaIzEphmvY6eQWWV90POFZJ0/s1600/vascular.jpg"><img style="display:block; margin:0px auto 10px; text-align:center;cursor:pointer; cursor:hand;width: 238px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTRAOzto8n4zDeZL4K98lV42-TceNNB3XNJ3qML9inz5Dm2HlpVDWcuxRJ8r_X6JEqs65qTTdkAvb9JC_dKwhcwIoA6-1JqlJC_ZImmEqYVfAUkAfr-UzQaIzEphmvY6eQWWV90POFZJ0/s320/vascular.jpg" border="0" alt="" id="BLOGGER_PHOTO_ID_5407703647225860818" /></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-large;">D</span><span class="Apple-style-span" style="font-size:small;">isclaimer 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.</span></span><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">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.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Finally, a point of clarification: my comments below concern the quality and consequences of media coverage, not the merits of the medical procedure discussed.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Here is the background: on November 20, the <i>Globe and Mail</i> ran a </span></span><a href="http://www.theglobeandmail.com/news/national/researchers-labour-of-love-leads-to-ms-breakthrough/article1372414/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">feature</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> 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.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">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." </span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">As observed on the excellent NPR program <i>On the Media</i>, </span></span><a href="http://www.onthemedia.org/transcripts/2009/11/13/01"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">media coverage of medical research and breakthroughs</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> "</span></span><span class="Apple-style-span" style="line-height: 15px; "><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">overflow 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.</span></span><span class="Apple-style-span" style="line-height: normal; "><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">" (Schwitzer, by the way, runs an excellent </span></span><a href="http://blog.lib.umn.edu/schwitz/healthnews/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">blog</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> on health news coverage).</span></span></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">Here are some concerns I had about the <i>Globe and Mail</i> story:</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">• 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.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">• 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.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">• 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..."?</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman', serif;"><span class="Apple-style-span" style="font-size:small;">• 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?).</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman', serif;"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">• 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."</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">• 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.</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">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 <i>Globe and Mail</i> </span></span><a href="http://www.theglobeandmail.com/news/national/ms-group-to-fund-research-into-liberation-procedure/article1374954/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">reports</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"> 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."</span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;"><br /></span></span></div><div><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:small;">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? (</span><span class="Apple-style-span" style="font-size:x-small;">photo credit: xbloodsin, </span></span><a href="http://www.flickr.com/photos/xbloodsin/3123900680/"><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">sepulcrum</span></span></a><span class="Apple-style-span" style="font-family:'times new roman';"><span class="Apple-style-span" style="font-size:x-small;">, 2008</span><span class="Apple-style-span" style="font-size:small;">)</span></span></div>Jonathan Kimmelmanhttp://www.blogger.com/profile/04735338453860941287noreply@blogger.com9