{"id":65199,"date":"2016-05-06T12:12:47","date_gmt":"2016-05-06T16:12:47","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=65199"},"modified":"2016-05-15T00:39:11","modified_gmt":"2016-05-15T04:39:11","slug":"why-is-that","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/05\/06\/why-is-that\/","title":{"rendered":"why is that?&#8230;"},"content":{"rendered":"<div align=\"justify\" class=\"small\">The Randomized Clinical Trial of a psychoactive drug follows a monotonous and simple course:<\/div>\n<ul><sup><font color=\"#200020\">                      <\/p>\n<li>\n<div align=\"justify\">a <strong><font color=\"#660033\">Protocol<\/font><\/strong> defines how the study is to be conducted and analyzed<\/div>\n<\/li>\n<li>\n<div align=\"justify\">the protocol is submitted to the Institutional Review Board [<strong><font color=\"#660033\">IRB<\/font><\/strong>]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">on approval of the protocol, the trial is <strong><font color=\"#660033\">Registered<\/font><\/strong> on clinicaltrials.gov<\/div>\n<\/li>\n<li>\n<div align=\"justify\">the <strong><font color=\"#660033\">Trial<\/font><\/strong> is conducted, double blinded<\/div>\n<\/li>\n<li>\n<div align=\"justify\">the <strong><font color=\"#660033\">Results<\/font><\/strong> are <strong><font color=\"#660033\">Analyzed<\/font><\/strong> per the protocol, then submitted\/published<\/div>\n<\/li>\n<p>                      <\/font><\/sup><\/ul>\n<div align=\"justify\" class=\"small\"><strong><font color=\"#660033\">Protocol &raquo; IRB &raquo; Registration &raquo; <\/font><\/strong><strong><font color=\"#660033\"><strong><font color=\"#660033\">Trial &raquo; <\/font><\/strong>Results &raquo; Analysis.<\/font><\/strong> In the majority of cases, one could program the whole process into a PC at the beginning and simply get a printed report at the end. As I&#8217;ve often said, this is a <em><font color=\"#200020\">product testing<\/font><\/em> scenario, not <font color=\"#200020\">scientific research. <\/font>Yet every trial is written up differently. Why is that? The paper published yesterday deconstructing a 2004 Citalopram Clinical Trial Report opens a window into the answer [see <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2016\/05\/05\/the-jewel-in-the-crown\/\">the jewel in the crown&hellip;<\/a>].                  <\/div>\n<blockquote>\n<div align=\"center\" class=\"middle\"><a href=\"http:\/\/content.iospress.com\/articles\/international-journal-of-risk-and-safety-in-medicine\/jrs671\" target=\"_blank\">The citalopram CIT-MD-18 pediatric depression  trial: Deconstruction of medical ghostwriting, data mischaracterisation  and academic malfeasance <\/a>                <\/div>\n<div align=\"center\" class=\"middle\">by<span class=\"generated\"> <\/span>Jon Jureidini, Jay <sup>Amsterdam, and Leemon McHenry<\/sup><\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#000099\">International Journal of Risk &amp; Safety in Medicine<\/font><\/strong>. 2016 28[1]:33-43.<\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">is an analysis of&#8230;<\/div>\n<blockquote>\n<div align=\"center\" class=\"middle\"><a href=\"http:\/\/ajp.psychiatryonline.org\/doi\/pdf\/10.1176\/appi.ajp.161.6.1079\" target=\"_blank\">A Randomized, Placebo-Controlled Trial of Citalopram  for the Treatment of Major Depression  in Children and Adolescents<\/a><\/div>\n<div align=\"center\" class=\"middle\">by <strong><font color=\"#990000\">Karen Dineen Wagner<\/font><\/strong>, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. Heydorn<\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#004400\">American Journal of Psychiatry<\/font><\/strong>. 2004 161:1079-1083.<\/div>\n<div align=\"center\" class=\"middle\">[<a href=\"http:\/\/ajp.psychiatryonline.org\/doi\/pdf\/10.1176\/appi.ajp.161.6.1079\" target=\"_blank\">full text online<\/a>]<\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">The Jureidini et al paper is not available as a full text on-line yet, though it may become open access soon. However, if your interested, you can contact the corresponding author for a copy. In the meantime, I&#8217;ll briefly summarize some of their findings:<\/div>\n<ul>\n<li>\n<div align=\"justify\" class=\"small\"><em><strong><font color=\"#200020\">Who designed, analyzed, and wrote the article?<\/font><\/strong><\/em><\/div>\n<div align=\"justify\"><sup>Reviewing subpoenaed internal emails, it was clear that the protocol was written by under the direction of the sponsor&#8217;s Associate Medical Director, analyzed by the Forest Laboratory&#8217;s staff, and the first draft was written by a contracted ghost-writer, so it was first seen by the listed academic authors in its second draft. The later denial that the academic authors didn&#8217;t know it was ghost written was directly contradicted by the subpoenaed emails. Simply put, the academic authors were merely figure&middot;heads for this industry produced article. This finding is well referenced in Jureidini et al.<\/sup><\/div>\n<\/li>\n<li>\n<div align=\"justify\" class=\"small\"><em><strong><font color=\"#200020\">How was the data analyzed and reported?<\/font><\/strong><\/em><\/div>\n<div align=\"justify\" class=\"small\"><font color=\"#200020\">Primary Outcome Parameter:<\/font><\/div>\n<div align=\"justify\"><font color=\"#200020\"><sup>Change from baseline to week 8 on the Children&rsquo;s Depression Rating Scale-Revised [CDRS-R] total score<\/sup><\/font><\/div>\n<ol>\n<div align=\"justify\"><sup>The Protocol specified that &ldquo;<em>Any patient for whom the blind has been broken will immediately be discontinued from the study and no further efficacy evaluations will be performed<\/em>&quot; There were nine such cases. Jureidini et al didn&#8217;t have the raw data, but they did have the Clinical Study Report. In fact, several versions. On 09\/12\/2001 &#8211; these cases were removed, acknowledged in a footnote. the p-value was 0.052. In a later version, these subjects were added back in, the footnote disappeared, and the p value was 0.038. It&#8217;s the second version that made it into the paper. Again, this finding is fully referenced in Jureidini et al.  There were other irregularities, among them, a reported effect size of 2.9 [an outrageous number]. When confronted, it was revised to 0.32 without explanation of the error.<\/sup><\/div>\n<\/ol>\n<div align=\"justify\" class=\"small\"><font color=\"#200020\">Secondary Outcome Parameters:<\/font><\/div>\n<div align=\"justify\"><font color=\"#200020\"><sup>Clinical Global Impression [severity and improvement subscales], Kiddie Schedule for Affective Disorders and Schizophrenia [depression module], and Children&rsquo;s Global Assessment Scale.<br \/>           <\/sup><\/font><\/div>\n<ol><sup> <\/p>\n<div align=\"justify\">While they reported the CGI-S and CGI-I scales [not significant], they failed to report the other two. Instead, they reported&nbsp; the CDRS responders [as significant] &#8211; an outcome parameter that wasn&#8217;t even mentioned in the <em>a priori<\/em> Protocol.          <\/div>\n<p> <\/sup><\/ol>\n<div align=\"justify\" class=\"small\"><font color=\"#200020\">Adverse Events:<\/font><\/div>\n<ol>\n<div align=\"justify\"><sup>By reporting the quantitative numbers, they were able to avoid mentioning agitation and a case of hypomania.<br \/>         <\/sup><\/div>\n<\/ol>\n<\/li>\n<\/ul>\n<div align=\"justify\" class=\"small\">So we can return to my original question:      <\/div>\n<ul>\n<div align=\"justify\"><strong><sup><em><font color=\"#200020\">&quot;&#8230; every trial is written up differently.  Why is that?&quot;<\/font><\/em><\/sup><\/strong><\/div>\n<\/ul>\n<div align=\"justify\" class=\"small\">We all already know the answer. It&#8217;s the same reason the pharmaceutical companies have put up such a fight to keep the actual raw data from Clinical Trials a secret. It doesn&#8217;t have anything to do with patient confidentiality or commercially confidential information. They want to be able to continue to do exactly what they did here &#8211; <em><font color=\"#200020\">fudge a little here<\/font><\/em>,<em><font color=\"#200020\"> tweak a little there<\/font><\/em>,<em><font color=\"#200020\"> leave out some of this and that, find a KOL on the take to sign on<\/font><\/em>&#8230; As long as they have the option to work their spin machine, they can turn even the slightest signal of a medicinal effects into a <em><font color=\"#200020\">significant<\/font><\/em> effect into a <em><font color=\"#200020\">blockbuster<\/font><\/em> worth billions.      <\/div>\n<p align=\"justify\" class=\"small\">This negative study was used to support an FDA Approval for <font color=\"#200020\">Citalopram <\/font>[<font color=\"#200020\">Celexa&reg;]<\/font> in adolescents, even though by that time, Dr. Karen Dineen Wagner, the first author, had been cited by the US Senate for unreported industry income. When the <strong><font color=\"#004400\">American Journal of Psychiatry<\/font><\/strong> discovered that this article was ghost written, they published a strong note [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2016\/05\/05\/the-jewel-in-the-crown\/\">the jewel in the crown&hellip;<\/a>], but did not retract the study. The case against Forest Laboratories that brought all of these documents to light ultimately settled [see <a href=\"http:\/\/www.fda.gov\/ICECI\/CriminalInvestigations\/ucm226396.htm\" target=\"_blank\">September  15, 2010: Drug Maker Forest Pleads Guilty: Will Pay More Than $313  Million to Resolve Criminal Charges and False Claims Act Allegations<\/a>]. And unscathed, Dr. Karen Dineen Wagner is the President Elect of the <em><font color=\"#990000\">American Academy of Child and Adolescent Psychiatry<\/font><\/em>, the recipient of <a href=\"https:\/\/bbrfoundation.org\/brain-matters-discoveries\/karen-dineen-wagner-wins-2012-colvin-prize-for-mood-disorders-research\" target=\"_blank\">lifetime achievement awards<\/a> for research in Mood Disorders in Children, and she was recently promoted to <font color=\"#200020\">Chairman of the Department of Psychiatry<\/font> at <a href=\"https:\/\/www.utmb.edu\/Provost\/pdfs\/Leadership_positions\/Wagner_Chair_October%202015.pdf\" target=\"_blank\">UTMB<\/a>.  <\/p>\n<div align=\"justify\" class=\"small\">Dr. Wagner was involved in four clinical trials in the years leading up to the Black Box Warning being appended to all antidepressants for use in children and adolescents &#8211; an FDA decision that has weathered an impressive assault from many quarters. Two studies have recently been definitively shown to be improperly reported. Of the remaining two, the <font color=\"#200020\">Sertaline <\/font>[<font color=\"#200020\">Zoloft&reg;<\/font>] trial has always been thought of as questionable [see <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/07\/22\/tuning-the-quartet\/\" target=\"_blank\">tuning the quartet&hellip;<\/a>]. It&#8217;s two negative studies that became positive when pooled together [?] [ergo <em><strong><font color=\"#200020\">false + false = true<\/font><\/strong><\/em>][?]:<\/div>\n<ul><span class=\"small\">     <\/p>\n<li>\n<div align=\"left\"><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11437014\" target=\"_blank\"><img loading=\"lazy\" decoding=\"async\" width=\"482\" height=\"95\" border=\"0\" align=\"texttop\" src=\"http:\/\/1boringoldman.com\/images\/jay-1.gif\" \/><\/a><\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#660033\">2002<\/font><\/strong>: <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12364842\" target=\"_blank\">Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial<\/a>.<em>  &quot;Fluoxetine  was superior to  placebo in the  acute phase treatment of  major  depressive disorder in  child and  adolescent outpatients with  severe,  persistent depression<\/em>.&quot; <\/div>\n<div>by Emslie GJ, Heiligenstein JH, <strong><font color=\"#990000\">Wagner KD<\/font><\/strong>, Hoog SL, Ernest DE, Brown E, Nilsson M, and Jacobson JG<\/div>\n<\/li>\n<li>\n<div align=\"left\"><a href=\"http:\/\/jama.ama-assn.org\/content\/290\/8\/1033.long\" target=\"_blank\"><img decoding=\"async\" width=\"482\" border=\"0\" align=\"texttop\" src=\"http:\/\/1boringoldman.com\/images\/jay-2.5.gif\" \/><\/a><\/div>\n<\/li>\n<li>\n<div align=\"left\"><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/15169696\" target=\"_blank\"><img loading=\"lazy\" decoding=\"async\" width=\"482\" height=\"66\" border=\"0\" align=\"texttop\" src=\"http:\/\/1boringoldman.com\/images\/jay-2.gif\" \/><\/a><\/div>\n<\/li>\n<p>    <\/span><\/ul>\n<div align=\"justify\" class=\"small\">This paper by Jueidini, Amsterdam, and McHenry is a landmark study that brings the use of subpoenaed documents to an academic journal to show a clinical trial being actively distorted to fraudulently claim efficacy where none exists &#8211; a trial used to obtain FDA Approval for use of the drug in children. While many of us are wracking our brains trying to figure out how to get its message through to clinicians, we&#8217;re not the ones that need to be thinking about it. It is rightly in the domain of the government\/<font color=\"#200020\">FDA<\/font> to press for data transparency to prevent any more repetitions of this kind of fraud. And it is rightly within the domain of the <font color=\"#200020\">Department of Justice<\/font> to pick up the ball at this point with this particular case. It&#8217;s what they&#8217;re for&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>The Randomized Clinical Trial of a psychoactive drug follows a monotonous and simple course: a Protocol defines how the study is to be conducted and analyzed the protocol is submitted to the Institutional Review Board [IRB] on approval of the protocol, the trial is Registered on clinicaltrials.gov the Trial is conducted, double blinded the Results [&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-65199","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/65199","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=65199"}],"version-history":[{"count":38,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/65199\/revisions"}],"predecessor-version":[{"id":65531,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/65199\/revisions\/65531"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=65199"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=65199"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=65199"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}