"This drug is undergoing review by the U.S. FDA. If it becomes available in the United States and elsewhere, its position within the algorithm is likely to evolve as experience in the clinical setting accumulates. The panel noted that the extensive preclinical and clinical data obtained as part of a formal drug development program exceeds the data available for other drugs used for intrathecal infusion and will probably lead to placement of ziconotide on an upper line of the algorithm, unless accumulating experience suggests a narrow therapeutic index in practice."
In the 2007 article, one rationale for ziconotide being "recommended as a Line 1 drug in this algorithm...comes from substantial data from preclinical and clinical studies." So the data has grown from "extensive" to "substantial." Or what is downgraded from "extensive" to "substantial?" I'm not quite sure which is better.
Clearly, the excitement for ziconotide was brewing before it was FDA approved. The question is, was all this enthusiasm based on the quality of the available research? I'm not so convinced. A search on clinicaltrials.gov (4), only yields three trials. I don't think that qualifies as either "extensive" or "substantial."
In December 2005, The Medical Letter (5) reviewed the current literature on ziconotide. Only one study reviewed by the Medical Letter is also reviewed in the 2007 Polyanalgesic Conference articles. All other studies in the 2007 article were published in 2006. One is a case study on a 13-year-old girl (6). Another is a lit-review (7). Yet another is a series of case reports (2 patients; 8). That's hardly gold standard quality research (but is it substantial?). Only three of the studies cited are randomized controlled studies (9, 10, 11). So how does a group of people not receiving money from Elan feel about ziconotide?
"Ziconotide (Prialt), a new intrathecal nonopioid analgesic, lowered pain scores in some patients when added to standard therapy for refractory severe chronic pain. Development of tolerance to the analgesic effects of ziconotide was not reported during clinical trials, but its long-term effectiveness and tolerability are unknown. Serious psychiatric and CNS adverse effects have occurred and may be slow to resolve after discontinuation of the drug." [my emphasis]
That's hardly a resounding endorsement. However, the Medical Letter issue was about one-year before those three randomized trials were published. Is there any reason to doubt their findings? Two were funded by Elan. The third was funded by both Neurex (which was bought by Elan) and Medtronic. As I mentioned before, industry sponsored studies are more likely to generate positive results than independently funded studies (12). Remember that Elan provided "generous financial support" for the 2007 conference where ziconotide was anointed as a 1st-line agent. What about the 2003 conference? Who was the sponsor of that? Medtronic! The same Medtronic that co-sponsored this study (9), which has a very interesting history by the way.
The lead author is Peter Staats (don't forget that name). It was published in JAMA in 2004. However, the study was conducted between 1996 and 1998. For a reason I still can't figure out, the data went unpublished for over 5 years. Strangely, during that five year period, multiple articles on ziconotide were published, including this study (13) published in 2000. In this study by Vandana S. Mathur, two unpublished (at the time) studies are reviewed. One was a study on "malignant" (i.e., cancer & AIDS) pain and the other on "nonmalignant" pain. Interestingly, the study published by Staats et al in 2004 (9) is on people with cancer and AIDS, and this study (Wallace et al, 11) is on patients with nonmalignant pain . In Mathur (2000), the malignant study has 112 patients as opposed to the 111 in the Staats et al study. The Wallace et al study lists 255 subjects while the Mathur study list 256 studies. VASPI scores from baseline to the end of the initial titration period is the primary measure in each study. In the Staats study, the mean improvement in VASPI was 53.1% for ziconotide and 18.1 % for placebo. In the Mathur study, the results are 53.1% for ziconotide and 18.1% for placebo. In the Wallace et al study, mean improvement for ziconotide was 31.2% and 6% for placebo. In the Mathur study, mean improvement for ziconotide was 31% and 6% for placebo. Isn't it interesting how similar these results are? It's as if these data were published more than once. As I learned last week, that's a big no no (14).
As it turns out, these data for published more than once (15). Dr. Staats' reply is here (16). In his reply he stated, "I was involved from the outset of the ziconotide trial, including the design, collection, and analysis of data and the drafting of the initial manuscript." He continued, "The initial draft of our manuscript was sent to Neurex/Elan (the sponsors of our trial) by my coauthors and me around 1998, well before Dr Mathur, a former employee of Elan, published her review in June 2000." He Added, "Her submission was sent without my permission or notification and without citing my coauthors or me."
As it turns out though, "Neurex Pharmaceuticals apparently condoned the publication of Mathur’s article since it provided access to the data file and signed off on the article by Mathur" (15). Moreover, "the article by Staats et al does include a citation to the article by Mathur." A citation? How could that be? Well according to Staats, "our in-house manuscript used a reference to an abstract by Brose et al, and in our successive revision process the reference was augmented by the citation of the article by Mathur. When this occurred I assumed that the Mathur reference had been added simply to update the Brose reference we continued to use, adding nothing new. My assumption was not correct; I should have read the manuscript." [my emphasis] In a previous post (17) I highlighted the importance of reading the studies you cite. If only this blog existed back then (sigh...).
Staats continued with "The system for preventing these infractions broke down...in the present case the previous publication was in a nonindexed medium and none of the authors knew that the review included data from our work." I'm not sure what a "nonindexed medium" is. Regardless, I'm not sure how valid of an excuse that is, since Staats is one of the many co-authors of the 2003 and 2007 Polyanalgesic Conference articles. Shouldn't Dr. Staats have come across that study when he was supposedly reviewing the literature for ziconotide in preparation for the 2003 conference?
At the bottom of Staats' article, this is printed regarding the sponsor "The sponsor was responsible for the overall conduct of the study and the collection, analysis, and interpretation of the data obtained...the preparation and review of the manuscript were a joint effort among the authors, the sponsor, and a contract medical writer." I wonder how involved the "authors" actually were in writing and reviewing this article?
As it turns out, Mark Wallace was one of the many co-authors of Staats' study and the 2007 polyanalgesic article. He's also was the lead author of the 2006 nonmalignant study. If only Wallace was on the 2003 polyanalgesic committee, perhaps he would have seen that Mathur study before he re-published those data. (To date, I have not found any "duplicate publication" notices for this study, 11). The funny part is, Wallace cites two studies in which Mathur is an author, yet somehow her 2000 article with his data was not included.
So perhaps ziconotide is not the wonder drug that some have made it out to be. Also, according to The Medical Letter, a 30 days supply of ziconotide costs approximately $4200. If you don't have an intrathecal device installed, that procedure costs approximately $20,000. That's quite a price tag. Good thing all these decisions about ziconotide were made by un-biased people who check and re-check their work and base their decisions on hard science..., right?
Update: From Bad Science (12)