Experimental Antidepressant Moves Closer to US Approval
by Deborah Brauser
May 20, 2013
The experimental antidepressant Vortioxetine is safe and effective for treating major depressive disorder [MDD], findings from several new phase 3 randomized controlled trials [RCTs] suggest. Three studies of a total of 1545 US patients with MDD showed that those who received 20 mg of Vortioxetine had significantly decreased symptom scores on the Montgomery–Asberg Depression Rating Scale [MADRS] after 8 weeks of treatment compared with those who received matching placebo. However, there was no difference in symptom scores between the 10-mg and the 15-mg dose compared with placebo.
Interestingly, a fourth study conducted in Europe and South Africa with 608 patients showed that both the 15-mg and 20-mg doses of Vortioxetine were associated with significantly lower MADRS scores than placebo. "We wanted to address the correct dose, and across the studies, the 20-mg had the most consistent findings over placebo," principal investigator Madhukar Trivedi, MD, professor of psychiatry at University of Texas Southwestern Medical Center in Dallas, told Medscape Medical News. Dr. Trivedi noted that "it’s very hard to figure out why" the 15-mg dose did well in the European study but not in the US studies, "but this often happens in antidepressant trials."
"Overall, the way I think about this as both a clinician and a researcher is that there are currently a lot of antidepressants with varying degrees of efficacy. And yet we know a very large number of the patient population doesn’t achieve remission with the currently available treatments. If Vortioxetine gets approved, I think it will be a welcome addition," he said.Data from 7 trials, including these 4 that were presented here at the American Psychiatric Association’s [APA’s] 2013 Annual Meeting, have been jointly submitted to the US Food and Drug Administration [FDA] by Takeda Pharmaceutical Company and H. Lundbeck A/S as part of a New Drug Application. "Vortioxetine is an investigational multimodal antidepressant thought to work through a combination of 2 pharmacological modes of action: serotonin [5-HT] receptor activity modulation and 5-HT reuptake inhibition," write the investigators…
A few days ago, I had a post based on an article/press·release about a new antidepressant called Vortioxetine that has been submitted to the FDA for approval and was being presented in posters at the American Psychiatric Association Convention this week in San Francisco [beyond unacceptable…]. Then I ran across this Medscape article about it from the APA Convention itself. In my earlier post, I questioned Dr. Trivedi’s endoresment because I could find no evidence in PubMed or ClinicalTrials that he had been part of any study. But in this second article, he’s listed as the Principle Investigator. I rechecked my work, but he wasn’t there [more below]. So I spent more time than I’d like to admit making this table of the history of the Vortioxetine studies:
|Notes: The studies are ordered by Completion Date. The un-numbered studies are 1 year extensions of other studies in the list. In the Dose[s] or Active Comparator columns, significant values are BOLD and those where the significance is unknown are in RED. The studies labeled GLOBAL are from multiple sites all over the planet.
Narrative: All of these studies were industry funded. It looks like they got off to a good start in 2007 with a successful study at the 5mg and 10mg doses, but then hit a wall for the next several years, unable to reproduce their initial success in the US along with a failed study. When they finally achieved significance again [5 & 6], they had a poster at the 2011 APA meeting with Dr. Michael Thase presenting [Investigative Depression Drug Does Better in Europe than United States]. That Medscape report reads very much like the one above two years later [same reporter]. To their credit, the negative and failed studies were published. Dr. Thase was an author on two [2 & 5] though they were published 5 and 3 years after completion, after the APA meeting. Buoyed by their success, they launched a new round of studies at a higher dose [20mg] which were reported by Dr. Madhukar Trivedi last week [above]. They mention submitting 7 studies to the FDA, the 4 in the poster presentation and 3 others [?].
clinicaltrials.gov: All of these studies were industry funded. Studies 1-11 have been completed for over a year, and yet none of these studies have results posted on clinicaltrials.gov as prescribed. Worse, no study has the Principle Investigator listed on clinicaltrials.gov. Instead, they say something like "Study Director: Email contact via H. Lundbeck A/S LundbeckClinicalTrials@lundbeck.com" or "Study Director: Senior Medical Director, Takeda Global Research & Development Center, Inc". The same for the PI at the individual clinical sites. I’ve been vetting these studies for several years now and there used to be an actual person listed. Then, about a year ago, they started putting in these depersonified placeholders [I’ve tried emailing several and never gotten a response and I wrote clinicaltrials.gov and never heard back].
I can think of no legitimate reason for not listing a Principal Investigator. I can only assume that there wasn’t one – that these clinical trials are farmed out and handled by staff. What I suspect is that neither Dr. Thase nor Dr. Trivedi were involved in any of these studies directly, but were brought on board to legitimize the presentations later by looking over the results. I can’t prove that because the information that’s supposed to be available on clinicaltrials.gov isn’t there [and I imagine that’s the reason why it’s not there]. Likely, these are studies run by industry staff and only later apportioned to willing academics [KOLs]. That just shouldn’t be. It’s not even close to the point of having clinicaltrials.gov, or for that matter, having an actual scientist as Principle Investigator.
Today I was informed that UT Southwestern will be investigating the complaint I submitted to the Ethics and Compliance Hotline on 05/20/13. As well, I heard from the UT Board of Regents. The Chancellor’s office will be reviewing the Viibryd article and the Vortioxetine article. The Board representative said they take these things seriously. I like that.