{"id":67509,"date":"2016-08-17T23:30:16","date_gmt":"2016-08-18T03:30:16","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=67509"},"modified":"2016-08-18T04:47:08","modified_gmt":"2016-08-18T08:47:08","slug":"and-then-there-was-one","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/08\/17\/and-then-there-was-one\/","title":{"rendered":"and then there was one&#8230;"},"content":{"rendered":"\n<div align=\"justify\" class=\"small\">I&#8217;ve gotten email along the way asking me [or chiding me] about my being preoccupied with clinical trials that are more than a decade old, I guess implying that it&#8217;s even too boring for the likes of me. I&#8217;d like to respond, because I think there&#8217;s something very important in the answer. These trials are designed to detect short term efficacy and log adverse effects to determine regulatory approval. They were <u>never<\/u> intended to direct clinical use of the drugs in practice. And yet they&#8217;ve frequently been treated as if they&#8217;re the final word, the gold standard in clinical psychiatry. And further, in the published reports, the subjects&#8217; self-rating scales are often insignificant, if they&#8217;re even reported, even though the thing that really matters with many of the conditions is the patient&#8217;s subjective experience of symptom relief. Then after a drug is approved, further testing is directed towards greener pastures, lucrative approvals for other diagnoses. And as to the continued relevance of these ancient trials, Karen Wagner&#8217;s update at the 2016 APA meeting relied on her same old studies [see <a target=\"_blank\" href=\"http:\/\/psychnews.psychiatryonline.org\/doi\/full\/10.1176\/appi.pn.2016.6b3\"><font color=\"#7f6f57\">Child Psychiatrists Look at Specialty From Both Macro, Micro Perspectives<\/font><\/a>]:        <\/div>\n<ul><sup>                         <\/p>\n<li>\n<div align=\"justify\"><strong><font color=\" #7f6f57\">2001<\/font><\/strong>: <strike><a href=\"https:\/\/www.justice.gov\/sites\/default\/files\/opa\/legacy\/2012\/07\/02\/complaint-ex2.pdf\" target=\"_blank\"><font color=\" #7f6f57\">Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial<\/font><\/a>. <em><font color=\"#7f6f57\">&quot;Paroxetine is generally well tolerated and effective for major depression in adolescents.&quot;<\/font><\/em><\/strike><\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#200020\">2002<\/font><\/strong>: <a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12364842\">Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial<\/a>.<em>  <font color=\"#990000\">&quot;Fluoxetine    was superior to  placebo in the  acute phase treatment of  major    depressive disorder in  child and  adolescent outpatients with  severe,    persistent depression.&quot;<\/font><\/em><\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#200020\">2003<\/font><\/strong>: <a href=\"http:\/\/jama.ama-assn.org\/content\/290\/8\/1033.long\" target=\"_blank\">Efficacy       of sertraline in the treatment of children and adolescents with    major    depressive disorder: two randomized controlled trials<\/a>. <em><font color=\"#990000\">&quot;&hellip;sertraline is an  effective and well-tolerated  short-term treatment for children and  adolescents with MDD.&quot;<\/font><\/em><\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#7f6f57\">2004<\/font><\/strong>: <strike><a href=\"http:\/\/ajp.psychiatryonline.org\/doi\/full\/10.1176\/appi.ajp.161.6.1079\" target=\"_blank\"><font color=\"#7f6f57\">A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents.<\/font><\/a> <em><font color=\"#7f6f57\">&quot;&hellip;treatment    with citalopram reduced depressive symptoms to a significantly  greater   extent than placebo treatment and was well tolerated.&quot;<\/font><\/em><\/strike><\/div>\n<\/li>\n<p>                         <\/sup><\/ul>\n<div class=\"small\">Notice my formatting. I think that the 2001 Paxil Study 329 and the 2004 CIT-MD-18 papers have been convincingly debunked by the recent exhaustive second looks: <a href=\"http:\/\/www.bmj.com\/content\/351\/bmj.h4320\" target=\"_blank\"><font color=\"#7f6f57\">Restoring Study 329&#8230;<\/font><\/a> and <a href=\"http:\/\/content.iospress.com\/articles\/international-journal-of-risk-and-safety-in-medicine\/jrs717\" target=\"_blank\"><font color=\"#7f6f57\">The citalopram CIT-MD-18 pediatric depression trial&#8230;<\/font><\/a>. And as long as we&#8217;re in the neighborhood, what about Wagner&#8217;s 2003 <font color=\"#200020\">Pfizer<\/font>-funded <font color=\"#200020\">Sertraline<\/font> trial?              <\/div>\n<blockquote>\n<div align=\"center\" class=\"big\"><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12941675\" target=\"_blank\">Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials<\/a><\/div>\n<div align=\"center\" class=\"middle\">by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group<\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#990000\">Journal of the American Medical Association<\/font><\/strong>. 2003, 290[8]:1033-41.<\/div>\n<div align=\"center\">[<a href=\"http:\/\/jama.jamanetwork.com\/article.aspx?articleid=197174\" target=\"_blank\">full text online<\/a>]<\/div>\n<p>               <\/p>\n<div align=\"justify\"><em><strong><font color=\"#200020\">CONTEXT<\/font><\/strong><\/em>: The efficacy, safety, and tolerability of selective serotonin reuptake inhibitors [SSRIs] in the treatment of adults with major depressive disorder [MDD] are well established. Comparatively few data are available on the effects of SSRIs in depressed children and adolescents.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">OBJECTIVE<\/font><\/strong><\/em>: To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">DESIGN AND SETTING<\/font><\/strong><\/em>: Two multicenter randomized, double-blind, placebo-controlled trials were conducted at 53 hospital, general practice, and academic centers in the United States, India, Canada, Costa Rica, and Mexico between December 1999 and May 2001 and were pooled a priori.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">PARTICIPANTS<\/font><\/strong><\/em>: Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined MDD of at least moderate severity.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">INTERVENTION<\/font><\/strong><\/em>: Patients were randomly assigned to receive a flexible dosage [50-200 mg\/d] of sertraline [n = 189] or matching placebo tablets [n = 187] for 10 weeks.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">MAIN OUTCOME MEASURES<\/font><\/strong><\/em>: Change from baseline in the Children&#8217;s Depression Rating Scale-Revised [CDRS-R] Best Description of Child total score and reported adverse events.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">RESULTS<\/font><\/strong><\/em>: Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score [mean change at week 10, -30.24 vs -25.83, respectively; P=.001; overall mean change, -22.84 vs -20.19, respectively; P=.007]. Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders [P=.05]. Sertraline treatment was generally well tolerated. Seventeen sertraline-treated patients [9%] and 5 placebo patients [3%] prematurely discontinued the study because of adverse events. Adverse events that occurred in at least 5% of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea, vomiting, anorexia, and agitation.<\/div>\n<div align=\"justify\"><em><strong><font color=\"#200020\">CONCLUSION<\/font><\/strong><\/em>: The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD.<\/div>\n<\/blockquote>\n<div align=\"justify\"><sup><img decoding=\"async\" width=\"90\" hspace=\"4\" border=\"0\" align=\"right\" src=\"http:\/\/1boringoldman.com\/images\/zoloft-wagner.gif\" \/><em><strong><font color=\"#200020\">Figure 2. Weekly and Overall Adjusted Mean CDRS-R Scores<\/font><\/strong><\/em><br \/>          <em><font color=\"#200020\">CDRS-R indicates Children&#8217;s Depression Rating Scale&mdash;Revised Best Description of Child total score. Data are least square means at each visit week, with mean scores averaged to give the overall mean, from a repeated-measures mixed-model analysis with age category, site, treatment, week, and week-by-treatment interaction used as fixed effects, subject as a random effect, and baseline effect as a covariate. Error bars indicate SE of the adjusted means, derived from the repeated-measures mixed-model procedure. P values are as follows: week 1. P=.09; week 2, P=.08; week 3, P =.01; week 4, P=.008; week 6, P=.37; week 8, P=.18; week 10, P=.001; and mean response, P=.007.<\/font><\/em><\/sup><\/div>\n<p align=\"justify\" class=\"small\">Right out of the gate, we have good reason to question these conclusions just by looking at the primary outcome variable graph which only achieved significance at 3, 4, and 10 weeks. But there&#8217;s a lot more to give us pause. In all of the depositions, Wagner makes it clear that she neither saw all the data nor checked the analysis in this study either, and that it was written at <font color=\"#200020\">Pfizer<\/font> with her coming in as the drafts were revised. <font color=\"#200020\">Pfizer<\/font> has gotten off light in the critiques of these clinical trials in that they had a writing firm, <em><font color=\"#200020\">Current Medical Directions<\/font><\/em>, that ghost wrote their Zoloft articles faster than they could find KOLs to sign up as guest authors [see <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2013\/02\/19\/zoloft-beyond-the-approval-i\/\">zoloft: beyond the approval I&hellip;<\/a> for this part of the story].<\/p>\n<div align=\"justify\" class=\"small\">But there&#8217;s something else that has always bothered me about this paper, and it&#8217;s right there in the title &#8211; <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12941675\" target=\"_blank\">&#8230; two randomized controlled trials<\/a>. What&#8217;s that about? Everywhere this trial is reported, they say some version of, &quot;<span class=\"Paragraph 25094409\"><em><font color=\"#200020\">Data from both studies were pooled in a <\/font><\/em><\/span><em><strong><font color=\"#200020\">prospectively defined<\/font><\/strong><\/em><span class=\"Paragraph 25094409\"><em><font color=\"#200020\"> combined analysis<\/font><\/em>.<\/span>&quot; So we are to believe that they had two identical studies that they planned to pool together for analysis, and the obvious question is <em><font color=\"#200020\">what makes them two studies?<\/font><\/em> Sounds like one big study to me [and plenty of others reading this paper]. If you were planning two identical studies, it would be likely that you were trying the speed things up to get the two studies needed for FDA Approval. And then we read this from one of the study group investigators in the study:<\/div>\n<blockquote>\n<div align=\"justify\"><a href=\"http:\/\/jama.jamanetwork.com\/article.aspx?articleid=198466\" target=\"_blank\">Sertraline and Depression in Children<\/a><\/div>\n<p align=\"justify\">To the Editor: Dr Wagner and colleagues reported that sertraline was more effective than placebo for treating children with major depressive disorder and that it had few adverse effects. As one of the study group investigators in this trial, I am concerned about the way the authors pooled the data from 2 trials, a concern that was raised by previous letters critiquing this study. The pooled data from these 2 trials found a statistically marginal effect of medication that seems unlikely to be clinically meaningful in terms of risk and benefit balance.<\/p>\n<div align=\"justify\"><strong><font color=\"#990000\">New information about these trials has since become available. The recent review of pediatric antidepressant trials by a British regulatory agency includes the separate analysis of these 2 trials. This analysis found that the 2 individual trials, each of a good size [almost 190 patients], did not demonstrate the effectiveness of sertraline in treating major depressive disorder in children and adolescents.<\/font><\/strong><\/div>\n<ol>\n<div align=\"justify\">E. Jane Garland, MD, FRCPC<br \/>        Department of Psychiatry<br \/>        University of British Columbia<br \/>        Vancouver<\/div>\n<\/ol>\n<div align=\"justify\">Committee on Safety of Medicines. Medicines and Health Care Products Regulatory Agency. Selective Serotonin Reuptake Inhibitors [SSRIs] &mdash; overview of regulatory status and CSM advice relating to major depressive disorder [MDD] in children and adolescents: summary of clinical trials. Available at: http:\/\/medicines.mhra.gov.uk\/ourwork\/monitorsafequalmed\/safetymessages\/ssrioverviewclintnaldata_101203.htm. Accessibility verified March 12, 2004.<\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">Well, if that&#8217;s not enough of a nail in this coffin, there&#8217;s even more in Wagner&#8217;s response to Dr. Garland&#8217;s letter:<\/div>\n<blockquote>\n<div align=\"justify\">Reply: In response to Dr Garland, <strong><font color=\"#990000\">our combined analysis was defined <\/font><em><font color=\"#990000\">a priori<\/font><\/em><font color=\"#990000\">, well before the last participant was entered into the study and before the study was unblinded.<\/font><\/strong> The decision to present the combined analysis as a primary analysis and study report was made based on &#8230;<\/div>\n<\/blockquote>\n<div align=\"justify\" class=\"small\">I won&#8217;t even finish her explanation because it doesn&#8217;t matter, since <em><font color=\"#200020\">a priori<\/font><\/em> means <em><font color=\"#200020\">before the study starts<\/font><\/em>, <u>not<\/u> &quot;<em><font color=\"#200020\">well before the last participant was entered into the study and before the study was unblinded<\/font><\/em>&quot; [this ploy of redefining the meaning of <em><font color=\"#200020\">a priori<\/font><\/em> is familiar to us from a similar bit of sleight of hand in Paxil Study 329]. So looked at from any angle, this is yet another negative clinical trial reported as positive after much jury-rigging &#8211; just as worthy of retraction as the other two.<\/div>\n<ul><sup>                         <\/p>\n<li>\n<div align=\"justify\"><strong><font color=\"#7f6f57\">2001<\/font><\/strong>: <strike><a href=\"https:\/\/www.justice.gov\/sites\/default\/files\/opa\/legacy\/2012\/07\/02\/complaint-ex2.pdf\" target=\"_blank\"><font color=\" #7f6f57\">Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial<\/font><\/a>. <em><font color=\"#7f6f57\">&quot;Paroxetine is generally well tolerated and effective for major depression in adolescents.&quot;<\/font><\/em><\/strike><\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#200020\">2002<\/font><\/strong>: <a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12364842\">Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial<\/a>.<em>  <font color=\"#990000\">&quot;Fluoxetine    was superior to  placebo in the  acute phase treatment of  major    depressive disorder in  child and  adolescent outpatients with  severe,    persistent depression.&quot;<\/font><\/em><\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#7f6f57\">2003<\/font><\/strong>: <strike><a href=\"http:\/\/jama.ama-assn.org\/content\/290\/8\/1033.long\" target=\"_blank\"><font color=\"#7f6f57\">Efficacy       of sertraline in the treatment of children and adolescents with    major    depressive disorder: two randomized controlled trials<\/font><\/a>. <em><font color=\"#7f6f57\">&quot;&hellip;sertraline is an  effective and well-tolerated  short-term treatment for children and  adolescents with MDD.&quot;<\/font><\/em><\/strike><\/div>\n<\/li>\n<li>\n<div align=\"justify\"><strong><font color=\"#7f6f57\">2004<\/font><\/strong>: <strike><a href=\"http:\/\/ajp.psychiatryonline.org\/doi\/full\/10.1176\/appi.ajp.161.6.1079\" target=\"_blank\"><font color=\"#7f6f57\">A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents.<\/font><\/a> <em><font color=\"#7f6f57\">&quot;&hellip;treatment    with citalopram reduced depressive symptoms to a significantly  greater   extent than placebo treatment and was well tolerated.&quot;<\/font><\/em><\/strike><\/div>\n<\/li>\n<p>                         <\/sup><\/ul>\n<div align=\"justify\" class=\"small\">Wagner is scheduled for her usual presentation [<a href=\"https:\/\/aacap.confex.com\/aacap\/2016\/meetingapp.cgi\/Session\/16451\" target=\"_blank\">Treatment of Depressive Disorders in Children and Adolescents<\/a>] at the October <font color=\"#200020\">American Academy of Child and Adolescent Psychiatry<\/font> annual meeting. I wonder what she&#8217;ll find to talk about this year?<\/div>\n","protected":false},"excerpt":{"rendered":"<p>I&#8217;ve gotten email along the way asking me [or chiding me] about my being preoccupied with clinical trials that are more than a decade old, I guess implying that it&#8217;s even too boring for the likes of me. I&#8217;d like to respond, because I think there&#8217;s something very important in the answer. These trials are [&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-67509","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/67509","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=67509"}],"version-history":[{"count":38,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/67509\/revisions"}],"predecessor-version":[{"id":67547,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/67509\/revisions\/67547"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=67509"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=67509"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=67509"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}