| 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 results as defined at the time of registration [Primary and Secondary Outcome Parameters]. |
| THEN |
| … by simply looking at the ClinicalTrials.gov site, one could decide for yourself quickly if it were a positive or negative study. |
| AND IF |
| … 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. |
| AND IF |
| … 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. |
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.
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 for anything. They’re the getting started standard for regulators. And even at that, the gold standard for these getting started RCTs is replication, 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 rather than the replication of a positive study [those aren’t the same thing]. And the over-valuing of single RCTs is pretty ubiquitous. A recent example:
PSYCHIATRICNEWSby Aaron LevinJune 16, 2016In 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…
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?”
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.
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…
by Jon Jureidini, Jay Amsterdam, and Leemon McHenryInternational Journal of Risk & Safety in Medicine. 2016 28[1]:33-43.
by Karen Dineen Wagner, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. HeydornAmerican Journal of Psychiatry. 2004 161:1079-1083.
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 GroupJournal of the American Medical Association. 2003, 290[8]:1033-41.
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® 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?
back to the future:
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® because the information just isn’t available, I do know that none of the papers mentioned in this post [Celexa®, Zoloft®, Paxil®] 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® study, so you’d surmise she should’ve known that.
The new “concreteness” has an Orwellian flavor to it. When I was in training, it was well understood that if one talked about mental illness with such a bio uber alles reductionism, such persons would risk the label of a fool for denying the complexity of the human condition in variable environments. DSM and bio claims were taken with a grain of salt, and often openly mocked, not parroted as gospel. This may be the corrosiveness of careerism and conformity, I guess, combined with too much Powerpoint. I doesn’t help that school systems are reimbursed and parents are deemed guiltless once their 11-year-olds are placed on meds.
Let me suggest a new treatment protocol for 11 year old children who do not respond to Prozac.
1. Take a comprehensive history. Map out all the psychological injuries that the child experienced to date, such as experiencing sexual abuse, bullying, divorce of parents.
2. Refer to psychotherapist. Make sure the therapist measures if the child is improving, and the child’s therapeutic alliance with the therapist. Since the therapeutic alliance is the single best predictor of progress in therapy, measuring it increases the effectiveness of therapy.
3. If child does not connect or improve with first therapist, refer to second therapist.
3. Augment therapy with placebo that produces vivid, but harmless, side effects. Beet root juice is an example, it turns the urine an exciting color, and concentrated vegetable juice has a very favorable risk benefit profile.
4. If child still has mood disorder, switch therapists and active placebos.
This protocol focuses on interventions which have no negative side-effects, proven efficacy, and is congruent with patient wishes. Parents and children strongly prefer therapy over pills in many studies. It also harnesses the power of the placebo response. The placebo response is 85-90% of the response to SSRI’s in adults.