{"id":68645,"date":"2016-10-14T17:28:12","date_gmt":"2016-10-14T21:28:12","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=68645"},"modified":"2016-10-14T17:35:39","modified_gmt":"2016-10-14T21:35:39","slug":"congressional-action-time-redux","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/10\/14\/congressional-action-time-redux\/","title":{"rendered":"congressional action time, redux\u2026"},"content":{"rendered":"
\n\n\n\n\n\n\n\n\n\n\n\n
IF<\/font><\/strong><\/td>\n<\/tr>\n
… at the time of Registration [before the study started], the ClinicalTrials.gov database defined the a priori<\/font><\/em> Primary and Secondary Outcome Parameters and the methods by which they were to be analyzed.<\/td>\n<\/tr>\n
AND IF<\/font><\/strong><\/td>\n<\/tr>\n
… at the end of rhe study [after the blind was broken], the ClinicalTrials.gov results database were populated with the results as defined at the time of registration [Primary and Secondary Outcome Parameters]. <\/td>\n<\/tr>\n
THEN<\/strong><\/font><\/td>\n<\/tr>\n
… by simply looking at the ClinicalTrials.gov site, one could decide for yourself quickly if it were a positive or negative study. <\/td>\n<\/tr>\n
AND IF<\/font><\/strong><\/td>\n<\/tr>\n
… you knew how to do a few simple calculations, you could generate the Effect Sizes [NNT, OR, Cohen’s d, etc] to estimate the robustness of the drug’s effect.<\/td>\n<\/tr>\n
AND IF<\/font><\/strong><\/td>\n<\/tr>\n
… at the end of rhe study [after the blind was broken], the ClinicalTrials.gov results database were populated with tabulations of adverse effects and severe adverse effects, you could reach something of a conclusion about the drug’s short-term safety profile.<\/td>\n<\/tr>\n<\/table>\n

Isn’t that an overly simplistic view? What are you trying to do, put the journals out of business? Of course it’s simplistic. But RCTs are themselves simplistic. They’re not intended to be the standard for clinical medicine. They’re only designed to say something about the short-term safety of a drug and it’s medicinal properties. The actual worth of the drug as a therapeutic agent is to be determined in clinical use – not the heavily structured environments of a multicentered RTC. <\/p>\n

But of course there’s a lot a journal can tell us. It can show us the longitudinal response – over time. It can display the self-rated scales from the subjects themselves.  But RCTs themselves are not the gold standard<\/font><\/em> for anything. They’re the getting started<\/font><\/em> standard for regulators. And even at that, the gold standard<\/font><\/em> for these getting started<\/font><\/em> RCTs is replication<\/font><\/em>, not a single or even a collage of studies. As an aside, we have something of a quirk in our approval process in that we base our approval on two positive studies<\/font><\/em> rather than the replication of a positive study<\/font><\/em> [those aren’t the same thing]. And the over-valuing of single RCTs is pretty ubiquitous. A recent example: <\/p>\n

\n
Child Psychiatrists Look at Specialty From Both Macro, Micro Perspectives<\/a><\/div>\n
PSYCHIATRIC<\/font>NEWS<\/font><\/strong><\/div>\n
by Aaron Levin<\/div>\n
June 16, 2016 <\/div>\n

In the clinic, managing mental illness in young people requires subtle but significant shifts in thinking, said Karen Dineen Wagner, M.D., Ph.D., a professor and chair of psychiatry and behavioral sciences at the University of Texas Medical Branch, Galveston…<\/p>\n

As for treatment, only two drugs are approved for use in youth by the Food and Drug Administration [FDA]: fluoxetine for ages 8 to 17 and escitalopram for ages 12 to 17, said Wagner. “The youngest age in the clinical trials determines the lower end of the approved age range. So what do you do if an 11-year-old doesn’t respond to fluoxetine?” <\/p>\n

One looks at other trials, she said, even if the FDA has not approved the drugs for pediatric use. For instance, one clinical trial found positive results for citalopram in ages 7 to 17, while two pooled trials of sertraline did so for ages 6 to 17. Another issue with pediatric clinical trials is that 61 percent of youth respond to the drugs, but 50 percent respond to placebo, compared with 30 percent among adults, making it hard to separate effects. <\/p>\n

When parents express anxiety about using SSRIs and ask for psychotherapy, Wagner explains that cognitive-behavioral therapy [CBT] takes time to work and that a faster response can be obtained by combining an antidepressant with CBT. CBT can teach social skills and problem-solving techniques as well. Wagner counsels patience once an SSRI is prescribed…<\/div>\n<\/blockquote>\n
Note<\/font><\/strong><\/em>: This is the 7th time I’ve quoted this particular blurb from PSYCHIATRIC<\/font>NEWS<\/font><\/strong> [1<\/a>, 2<\/a>, 3<\/a>, 4<\/a>, 5<\/a>, 6<\/a>]. I guess I see it as a paradigm of sorts – a paradigm for something very, very wrong. Each time, I want to insert "Take a history!<\/font><\/em><\/strong>" after the second paragraph – or even better, "Refer the kid to someone who knows something about children besides how to write prescriptions!<\/font><\/em><\/strong>" <expletive deleted><\/font><\/strong><\/em>
<\/sup><\/div>\n

<\/p>\n

It’s the concreteness of Dr. Wagner’s remarks that I want to call attention to. Prozac®<\/font> was approved for children and teens early in the game, based on a couple of studies [see tuning the quartet…<\/a> and eyes wide shut<\/strike> open III…<\/a>]. While it’s data has never been independently confirmed, the studies are accepted as showing a significant signal though some of us would question that. A recent meta-analysis lists it as the only such drug though doesn’t recommend using it [see antidepressants in kids? a new meta-analysis…<\/a>]. So Doctor Wagner poses the example of an 11 year old who doesn’t respond to Prozac®<\/font>. She suggests going off-label and mentions two clinical trials [she was an author on both]! The first, Celexa®<\/font>, is a trial finally taken down definitively on any number of grounds, including outcome switching<\/font><\/em> [see the jewel in the crown…<\/a>]:<\/div>\n
\n
The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance <\/a> <\/div>\n
by Jon Jureidini, Jay Amsterdam, and Leemon McHenry<\/div>\n
International Journal of Risk & Safety in Medicine<\/font><\/strong>. 2016 28[1]:33-43.<\/div>\n<\/blockquote>\n
is an analysis of…<\/div>\n
\n
A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents<\/a><\/div>\n
by Karen Dineen Wagner<\/font><\/strong>, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. Heydorn<\/div>\n
American Journal of Psychiatry<\/font><\/strong>. 2004 161:1079-1083.<\/div>\n
[full text online<\/a>]<\/div>\n<\/blockquote>\n
The second suggestion, Zoloft<\/font>®<\/font>, also comes from one of her papers:<\/div>\n
\n
Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials<\/a><\/div>\n
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
Journal of the American Medical Association<\/font><\/strong>. 2003, 290[8]:1033-41.<\/div>\n
[full text online<\/a>]<\/div>\n<\/blockquote>\n
… which I consider one of the worst of the worst. They glued two negative trials together somewhere in mid-study[s] and declared the combo positive [?!?], and there was more [see and then there was one…<\/a>]. At least this time around, she left out Paxil® Study 329<\/font> [also one of hers]. So we’re making progress. <\/div>\n

There’s so much wrong here it’s hard for me to stay on point. Dr. Wagner takes the pronouncement of over a decade before based on a couple of RCTs about Prozac®<\/font> as if it is gospel. And brings up two thoroughly debunked trials from twelve and thirteen years ago as off-label alternatives – without mentioning that other similar studies were negative or that the ones she mentions are destined to the hall of the infamous. But beyond all of that, have we learned nothing more in the last decade plus? Once a clinical trial is published, does it enter some realm of infallability in perpetuity? <\/p>\n

back to the future:<\/font><\/strong><\/em><\/p>\n

At last I make it back to my point! While I don’t know about the two papers used for the initial approval of Prozac®<\/font> because the information just isn’t available, I do know that none of the papers mentioned in this post [Celexa®<\/font>, Zoloft<\/font>®<\/font>, Paxil®<\/font>] would make it through the simple scheme proposed at the beginning. Every one of them is a gross example of switching the outcome parameters during the study, probably from peeking through the blinds or thereafter. We can never prove that, but there’s really little doubt in the mind of anyone who has looked closely. Dr. Wagner is an author on all of them except the first Prozac® <\/font>study, so you’d surmise she should’ve known that. <\/p>\n

By the way, that scheme suggested above is the essence of our proposal in The Petition<\/a> [in case you’ve neglected signing it yet]…<\/div>\n","protected":false},"excerpt":{"rendered":"

IF … at the time of Registration [before the study started], the ClinicalTrials.gov database defined the a priori Primary and Secondary Outcome Parameters and the methods by which they were to be analyzed. AND IF … at the end of rhe study [after the blind was broken], the ClinicalTrials.gov results database were populated with the […]<\/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-68645","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/68645","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=68645"}],"version-history":[{"count":31,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/68645\/revisions"}],"predecessor-version":[{"id":68676,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/68645\/revisions\/68676"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=68645"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=68645"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=68645"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}