{"id":62027,"date":"2015-12-09T13:49:15","date_gmt":"2015-12-09T18:49:15","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=62027"},"modified":"2015-12-10T12:46:09","modified_gmt":"2015-12-10T17:46:09","slug":"62027","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2015\/12\/09\/62027\/","title":{"rendered":"creative funding III &#038; some other things&#8230;"},"content":{"rendered":"<div align=\"justify\" class=\"small\">I know <a href=\"http:\/\/1boringoldman.com\/index.php\/2015\/12\/07\/creative-funding-i\/\">creative funding I&hellip;<\/a> and <a href=\"http:\/\/1boringoldman.com\/index.php\/2015\/12\/08\/creative-funding-ii\/\">creative funding II&hellip;<\/a> were probably as tedious to read as they were to write, but since they were not available on-line, I felt like I had to say what they were in order to talk about them. I&#8217;ve sort of slacked off of vetting Clinical Trials for a while. Total immersion in Study 329 for several years was enough for a while, but my habit has been to look at the big journals once a month to see what the RCT&nbsp; fairy has put under the pillow this time. And when I looked at the December <strong><font color=\"#004400\">American Journal of Psychiatry<\/font><\/strong>, there were two RCTs, each with an accompanying editorial blurb:<\/div>\n<blockquote>\n<div align=\"justify\"><strong><font color=\"#200020\">EDITORIALS<\/font><\/strong><\/div>\n<ul>\n<li>\n<div align=\"justify\"><strong><font color=\"#200020\">Pediatric Psychopharmacology Trials: Beyond Efficacy<\/font><\/strong> &#8211; by Graham J. Emslie, M.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#200020\">Adjunctive Ziprasidone in Major Depression and the Current Status of Adjunctive Atypical Antipsychotics<\/font><\/strong> &#8211; by J. Craig Nelson, M.D.<\/div>\n<\/li>\n<\/ul>\n<div align=\"justify\"><strong><font color=\"#200020\">REVIEWS AND OVERVIEWS<\/font><\/strong><\/div>\n<ul>\n<li>\n<div align=\"justify\">\n<div align=\"justify\"><strong><font color=\"#200020\">Extended-Release Guanfacine for Hyperactivity in Children With Autism Spectrum Disorder<\/font><\/strong> &#8211; by Lawrence Scahill, M.S.N., Ph.D., et al.<\/div>\n<\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#200020\">Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Efficacy Results From a Randomized, Double-Blind, Placebo-Controlled Study<\/font><\/strong> &#8211; by George I. Papakostas, M.D., et al.<\/div>\n<\/li>\n<\/ul>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">My initial reaction was that these were advertisements. I object to <font color=\"#200020\">advertisement RCTs<\/font> being funded with public funds. I object to the&nbsp; <strong><font color=\"#004400\">American Journal of Psychiatry<\/font><\/strong> publishing <font color=\"#200020\">advertisement RCTs<\/font>. But among the things I learned from my Study 329 experience is that <em><font color=\"#200020\">The Devil is in the Details<\/font><\/em> is a very wise saying indeed. And when I looked at the details of these articles and get beyond the two over-riding complaints above, these articles share a couple of things, but they are also very different. So, I&#8217;m going to live up to the <strong><font color=\"#200020\">boring<\/font><\/strong> in <font color=\"#200020\">1<\/font><strong><font color=\"#200020\">boring<\/font><\/strong><font color=\"#200020\">oldman<\/font> and linger for a while to look at some of those details.<\/div>\n<p align=\"justify\" class=\"small\">So first to <strong><font color=\"#200020\">Extended-Release Guanfacine for Hyperactivity in Children With Autism Spectrum Disorder<\/font><\/strong> &#8211; by <a href=\"http:\/\/www.ctsn.emory.edu\/faculty\/Scahill_Lawrence.html\" target=\"_blank\">Lawrence Scahill<\/a>, M.S.N., Ph.D., et al. I spent four or five years in my retirement volunteering at a local Child and Adolescent agency. I saw a number of special needs kids, including the Autistic Spectrum variety. Many of them do have the Attention\/Hyperactivity diathesis described here, and the question of medication was often in the wind. I had seen several kids on Tenex where it helped a lot and several where the side effect burden was prohibitive, so when I saw this article, I was drawn to it by interest. I wish they had done the study as proposed with a stimulant arm [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2015\/12\/08\/creative-funding-ii\/\" target=\"_blank\">creative funding II&hellip;<\/a>], but for unclear reasons, that didn&#8217;t happen. <\/p>\n<p align=\"justify\" class=\"small\">As I said, I thought their reporting was balanced and useful. My only complaints were that they used <strong><font color=\"#200020\">Extended-Release Guanfacine <\/font><\/strong>[<strong><font color=\"#200020\">Intuniv<\/font><\/strong>] and that Dr. Cahill is an adviser to <strong><em><font color=\"#990000\">Shire<\/font><\/em><\/strong> &#8211; but that&#8217;s no small complaint. The introduction of Extended Release products as a way of <em><font color=\"#200020\">extending<\/font><\/em> patents and profits is well known [Paxil, Seroquel, etc] and I think it&#8217;s &quot;dirty pool&quot; unless they have solid evidence that it&#8217;s better than the original [and they never do]. Likewise, this is a publicly funded study keyed to a commercial product [when there&#8217;s no reason to pick the ER product]. Either let Shire foot the bill, or do <strong><font color=\"#200020\">Guanfacine for Hyperactivity in Children With Autism Spectrum Disorder <\/font><\/strong>study. If the <em><font color=\"#200020\">why?<\/font><\/em> isn&#8217;t obvious, take a long look at this:<\/p>\n<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" align=\"center\" class=\"small\">\n<tr>\n<td align=\"center\" colspan=\"9\"><strong><font color=\"#200020\">Walmart Pharmacy [with goodRx card]<\/font><\/strong>                               <\/td>\n<\/tr>\n<tr>\n<td width=\"100\" align=\"center\"><strong><font color=\"#200020\">drug<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"5\">&nbsp;<\/td>\n<td width=\"35\" align=\"center\"><strong><font color=\"#200020\">size<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"5\">&nbsp;<\/td>\n<td width=\"50\" align=\"center\"><strong><font color=\"#200020\">price<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"5\">&nbsp;<\/td>\n<td width=\"50\" align=\"center\"><strong><font color=\"#200020\">quanity<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"5\">&nbsp;<\/td>\n<td width=\"60\" align=\"center\"><strong><font color=\"#200020\">unit cost<\/font><\/strong><\/td>\n<\/tr>\n<tr>\n<td>Tenex [Brand]                     <\/td>\n<td align=\"right\">1mg<\/td>\n<td align=\"right\">$79.77<\/td>\n<td align=\"center\">30<\/td>\n<td align=\"center\"><strong>$2.66<\/strong><\/td>\n<\/tr>\n<tr>\n<td>Guanfacine<\/td>\n<td align=\"right\">1mg<\/td>\n<td align=\"right\">$4.00<\/td>\n<td align=\"center\">30<\/td>\n<td align=\"center\"><strong><font color=\"#990000\">$0.13<\/font><\/strong><\/td>\n<\/tr>\n<tr>\n<td>Intuniv&reg;<\/td>\n<td align=\"right\">2mg<\/td>\n<td align=\"right\">$200.23<\/td>\n<td align=\"center\">30<\/td>\n<td align=\"center\"><strong><font color=\"#990000\">$6.67<\/font><\/strong><\/td>\n<\/tr>\n<tr valign=\"top\">\n<td>Guanfacine ER <sub>&sect;<\/sub><\/td>\n<td align=\"right\">2mg<\/td>\n<td align=\"right\">$31.62<\/td>\n<td align=\"center\">30<\/td>\n<td align=\"center\"><strong>$1.05<\/strong><\/td>\n<\/tr>\n<\/table>\n<div align=\"center\"><sup><font color=\"#200020\">&sect; not available when this study was conceived<\/font><\/sup><\/div>\n<p align=\"justify\" class=\"small\">Even if Shire had funded it, all Extended Release <em><font color=\"#200020\">extend-the-patent<\/font><\/em> studies should require the <em><font color=\"#200020\">non-extended-release<\/font><\/em> drug as a camparator. Except for that point [again, a big point], I think the study, particularly as originally described, was deserving of its public funding. As for Dr. Emslie&#8217;s editorial, he&#8217;s is a high volume KOL whose name is all over the industry-funded C&amp;A RCTS. In the commentary, he encourages more independently funded RCTs to look for more than efficacy, actually a reasonable point.             <\/p>\n<div align=\"justify\" class=\"small\">On the other hand, I can&#8217;t find any redemption for <strong><font color=\"#200020\">Ziprasidone Augmentation of Escitalopram for  Major Depressive Disorder: Efficacy Results From a Randomized,  Double-Blind, Placebo-Controlled Study<\/font><\/strong>. In the NIMH write-up, they say&#8230;<\/div>\n<blockquote>\n<div align=\"justify\"> If not found to  be either safe or effective, the results of this  proposed trial would  also be highly informative given the significant  proportion of TRD  patients who, despite <em><strong><font color=\"#990000\">the relative paucity of data from  independently-funded studies of rigorous design<\/font><\/strong><\/em>, are prescribed atypical  antipsychotic agents off-label&quot;&hellip;    <\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">&#8230; implying that this <em><font color=\"#200020\">independently-funded<\/font><\/em> [NIMH rather than industry] would be more bias-free, <em><font color=\"#200020\">more rigorous<\/font><\/em>. Yet all the MD Authors have <strong><em><font color=\"#990000\">Pfizer<\/font><\/em><\/strong> connections [COI]. It was conducted by the MGH RCT Network [essentially a CRO]. The <em>a priori<\/em> outcome variables [from clinicaltrials.gov] were odd. The declared primary barely made significance [and I questioned the statistical analysis which used baseline severity as a covariant]. And it failed one of two declared secondary outcome variables. The primary and both secondaries are all derived from the HAM-D, but give widely divergent signals. One would like to do an ANOVA on the raw scores, but they&#8217;re not available. In the write-up, other scales [QIDS-SR, CGI] were promoted to <em><font color=\"#200020\">secondaries<\/font><\/em>. So I can&#8217;t see that this study is any different from the usual industry-funded <em><font color=\"#200020\">exper&middot;o&middot;mmercial<\/font><\/em> other that the NIMH picked up the tab. Actually, the commentary had the more balanced interpretation of the outcome:        <\/div>\n<blockquote>\n<div align=\"justify\">The number needed to treat for ziprasidone was 7, which is similar to  the other atypicals; however, the 95% confidence interval for the number  needed to treat in this sample of 139 patients is very broad. As a  result, we should be very cautious about efficacy comparisons. The  relatively high rate of discontinuation due to adverse events is similar  to the rate for the 300 mg\/day dosage of extended-release quetiapine.  As with quetiapine, somnolence is the most frequent side effect of  ziprasidone. In this study, 34% of patients in the ziprasidone group  experienced somnolence or fatigue&#8230; On other parameters, the rate of  akathisia with ziprasidone was lower than with aripiprazole but greater  than with quetiapine or olanzapine.  Weight gain was less with ziprasidone than with olanzapine but greater  than with aripiprazole or quetiapine. The present study suggests that  adjunctive ziprasidone is effective in major depression, but it appears  to have a relatively high rate of discontinuation due to adverse events  and a high level of somnolence compared with other atypicals&#8230;<\/div>\n<\/blockquote>\n<p align=\"justify\" class=\"small\">And as for medication cost:<\/p>\n<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" align=\"center\" class=\"small\">\n<tr>\n<td align=\"center\" colspan=\"9\"><strong><font color=\"#200020\">Walmart [with goodRx card]<\/font><\/strong><\/td>\n<\/tr>\n<tr>\n<td width=\"90\" align=\"center\"><strong><font color=\"#200020\">drug<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"3\">&nbsp;<\/td>\n<td width=\"35\" align=\"center\"><strong><font color=\"#200020\">size<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"3\">&nbsp;<\/td>\n<td width=\"50\" align=\"center\"><strong><font color=\"#200020\">price<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"3\">&nbsp;<\/td>\n<td width=\"50\" align=\"center\"><strong><font color=\"#200020\">quanity<\/font><\/strong><\/td>\n<td width=\"10\" rowspan=\"3\">&nbsp;<\/td>\n<td width=\"60\" align=\"center\"><strong><font color=\"#200020\">unit cost<\/font><\/strong><\/td>\n<\/tr>\n<tr>\n<td>Geodon&reg;<\/td>\n<td align=\"right\">60mg<\/td>\n<td align=\"right\">$983.42<\/td>\n<td align=\"center\">60<\/td>\n<td align=\"center\"><strong><font color=\"#200020\">$16.39<\/font><\/strong><\/td>\n<\/tr>\n<tr>\n<td>Ziprasidone &sect;<\/td>\n<td align=\"right\">60mg<\/td>\n<td align=\"right\">$118.96<\/td>\n<td align=\"center\">60<\/td>\n<td align=\"center\"><strong><font color=\"#200020\">$&nbsp; 1.98<\/font><\/strong><\/td>\n<\/tr>\n<\/table>\n<div align=\"center\"><sup><font color=\"#200020\">&sect; not available when this study was conceived<\/font><\/sup><\/div>\n<p align=\"justify\" class=\"small\">Interestingly, the first author on this paper [<span class=\"contribDegrees\"><font color=\"#200020\"><span class=\"entryAuthor\">George I. Papakostas<\/span><\/font><\/span>] and the author of the commentary [<span class=\"contribDegrees\"><font color=\"#200020\"><span class=\"entryAuthor\">J. Craig Nelson<\/span><\/font><\/span>] were co-authors of a 2009 meta-analysis of the Atypical Antipsychotics as augmentation for <em><font color=\"#200020\">Treatment Resistant Depression<\/font><\/em> [<em><font color=\"#200020\">Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials<\/font><\/em> &#8211; <a target=\"_blank\" href=\"https:\/\/www.mainemed.com\/sites\/default\/files\/content\/Metanal%20Antipsy%20Depr_2009.pdf\">full text<\/a>].&nbsp; This figure is adapted from that meta-analysis [the NNT from this Geodon&reg; study was<strong><font color=\"#1d7fa3\"> 6.8 <\/font><\/strong>and the Odds Ratio was <strong><font color=\"#1d7fa3\">1.7<\/font><\/strong>]:     <\/p>\n<p align=\"center\" class=\"small\"><img decoding=\"async\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/aug-meta.gif\" \/><\/p>\n<p align=\"justify\" class=\"small\">There have been three additional Aripiprazole Studies since that meta-analysis [I couldn&#8217;t extract the values from the complicated Fava et al crossover study]. In addition, there are two recent positive  studies for brexpiprazole [cloned studies] [for an Abilify clone]&nbsp; recently approved by the FDA for augmentation in TRD [full text <a href=\"http:\/\/www.psychiatrist.com\/JCP\/article\/Pages\/2015\/v76n09\/v76n0932.aspx\" target=\"_blank\">here<\/a> and <a href=\"http:\/\/www.psychiatrist.com\/JCP\/article\/Pages\/2015\/v76n09\/v76n0931.aspx\" target=\"_blank\">here<\/a>]:<\/p>\n<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" align=\"center\" class=\"small\">\n<tr>\n<td align=\"center\" colspan=\"11\"><strong><font color=\"#200020\">Additional Aripiprazole Studies<\/font><\/strong><\/td>\n<\/tr>\n<tr>\n<td align=\"center\"><strong><font color=\"#200020\">Study<\/font><\/strong><\/td>\n<td width=\"10\" align=\"center\" rowspan=\"4\"><strong><font color=\"#200020\">&nbsp;<\/font><\/strong><\/td>\n<td align=\"center\"><strong><font color=\"#200020\">Treatment<\/font><\/strong><\/td>\n<td width=\"10\" align=\"center\" rowspan=\"3\"><strong><font color=\"#200020\">&nbsp;<\/font><\/strong><\/td>\n<td align=\"center\"><strong><font color=\"#200020\">Control<\/font><\/strong><\/td>\n<td width=\"10\" align=\"center\" rowspan=\"3\"><strong><font color=\"#200020\">&nbsp;<\/font><\/strong><\/td>\n<td align=\"center\"><strong><font color=\"#200020\">NNT<\/font><\/strong><\/td>\n<td width=\"10\" align=\"center\" rowspan=\"3\"><strong><font color=\"#200020\">&nbsp;<\/font><\/strong><\/td>\n<td align=\"center\"><strong><font color=\"#200020\">OR<\/font><\/strong><\/td>\n<td width=\"10\" align=\"center\" rowspan=\"3\"><strong><font color=\"#200020\">&nbsp;<\/font><\/strong><\/td>\n<td align=\"center\"><strong><font color=\"#200020\">95% CI<\/font><\/strong><\/td>\n<\/tr>\n<tr>\n<td><strong><font color=\"#200020\">Lenze et al. &sect;<\/font><\/strong><\/td>\n<td align=\"center\">40\/91<\/td>\n<td align=\"center\">26\/90<\/td>\n<td align=\"center\">6.6<\/td>\n<td align=\"center\">2.0<\/td>\n<td align=\"center\">1.1-3.7<\/td>\n<\/tr>\n<tr>\n<td><strong><font color=\"#200020\">Kamijima et al<\/font><\/strong><\/td>\n<td align=\"center\">159\/392<\/td>\n<td align=\"center\">55\/195<\/td>\n<td align=\"center\">8.1<\/td>\n<td align=\"center\">1.4<\/td>\n<td align=\"center\">&#8211;<\/td>\n<\/tr>\n<tr>\n<td><a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22286203\"><strong><font color=\"#200020\">Fava et al<\/font><\/strong><\/a>  <\/td>\n<td align=\"center\" colspan=\"9\">essentially a negative study [crossover]<\/td>\n<\/tr>\n<\/table>\n<div align=\"center\"><sup><font color=\"#200020\">&sect; an independently funded study<br \/><\/font><\/sup><\/div>\n<p align=\"justify\" class=\"small\">So back to the main thread here. I was disappointed that the NIMH had funded the Scahill et al study of Guanfacine in Autism Spectrum Disorder with the in-patent Extended Release form of the drug rather than the generic. It struck me as an ad for Shire&#8217;s product. I&#8217;m currently of the mind that it&#8217;s time for us to stop allowing PHARMA to use our journal articles for any commercial purposes. The article, however, was useful so I would&#8217;ve settled for just a comment about the funding somewhere. But with the Geodon article, I can see no reason for the NIMH to fund that study period. Its only purpose is to say, &quot;<font color=\"#200020\">Me too. My drug augments TRD too!<\/font>&quot; And with as much literature as we already have on this point, who actually needs to hear that? So I didn&#8217;t like the NIMH funding it nor the <strong><font color=\"#004400\">American Journal of Psychiatry <\/font><\/strong>publishing it. Send it to the Journal of Clinical Psychiatry [and let Pfizer pay for it]. We&#8217;ve had enough of that use of the scientific literature in psychiatry for this whole century already.     <\/p>\n<div align=\"justify\" class=\"small\">Parenthetically, these Effect Size numbers [Odds Ratios, NNT] are not that impressive, particularly for as much effort as has gone into generating this literature. I haven&#8217;t personally had a case yet where I was willing to add an Atypical Antipsychotic to an SSRI. I can conceive of such a case, but it just hasn&#8217;t shown up in my office. But I expect I&#8217;m on the conservative end of some spectrum&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>I know creative funding I&hellip; and creative funding II&hellip; were probably as tedious to read as they were to write, but since they were not available on-line, I felt like I had to say what they were in order to talk about them. I&#8217;ve sort of slacked off of vetting Clinical Trials for a while. [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-62027","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/62027","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=62027"}],"version-history":[{"count":62,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/62027\/revisions"}],"predecessor-version":[{"id":62090,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/62027\/revisions\/62090"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=62027"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=62027"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=62027"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}