Pharmalot: Why is there such a fuss over a seeding trial? Why does it matter: Hill: The idea isn't new. Physicians have been recruited to participate in marketing studies in order to allow them to become familiar with a drug. And that's what happened here. This trial allowed physicians to have experience with Vioxx. But as far as I know, our paper is the first to show how a pharmaceutical company planned and executed a seeding trial. There are documents showing how Merck could have gained an advantage. But what's troubling is that physicians and patients weren't told of the objective of the trial. And that's problematic, because patients risk their health when they are signed up for such a trial, instead of advancing the cause of science.
Pharmalot: Well, Merck says the trial was designed properly. Hill: Most clinical trials have a legitimate scientific question. Now, if the Advantage trial was the only trial Merck had undertaken to look at the issue of GI (gastrointestinal problems), Advantage could have stood alone. But they had looked at this quesion in many other trials. And in that way, Advantage wasn't necessary. They knew the answer to the questions. They looked at it in the Vigor trial (which was being run simultaneously). You know, the merits of Advantage as a clinical trial have been debated. I actually thought it was designed in a fairly good way, but the issue is they didn't tell people the objectives.
Pharmalot: So, if the trial had an acceptable design, why does it matter if it's for marketing: Hill: Again, patients risk their health in clinical trials. They need to trust the science, and seeding undermines that trust. These people were taking a potentially harmful drug that was being studied, essentially, for marketing purposes. It's a question of informed consent. If you look at Figure 1 in our report, it clearly attributes numerous marketing objectives to the study. The memo makes it appear that Merck is most interested in the prescribing habits of the investigators. The case could be made there was a scientific purposes, but GI tolerability had been looked at already. How many times do you have to look at that to know the answer? And patients weren't given a chance to make an informed decision about their participation.
Pharmalot: You mention a memo by Ed Scolnick (formerly Merck's chief scientist). Why was that significant? Hill: Scolnick called the trial 'scientifically redundant' and lamented the fact that the marketing branch had a very large trail and ran many trials with a marketing purposes, and called attention to Merck products in a way that could be problematic. I think he was afraid that if his department didn't have any say in what was going on, bad things would happen.
Pharmalot: What do you think this paper will really accomplish? These events happened years ago. Hill: Well, hopefully this will create a dialogue and create transparency between academia, physicians and pharma. The paper focuses on the evidence and we're hoping readers will read the paper and draw their own conclusions. We didn't steer readers one way or the other.
Pharmalot: There's a conflict of interest issue raised - you and your co-authors consult for lawyers who are suing Merck. How do you answer accusations of bias? Hill: The question of bias should always be asked and I welcome the question. We've been very transparent about the fact that we receive compensation with respect to the litigation. We were paid to analyze the data and we were hired for our collective expertise in reviewing clinical trials. But we went into this without pre-formed hypotheses. We weren't looking to cherry pick evidence. And you can't spin an article in a journal such as the Annals of Internal Medicine that way. Hopefully, readers can draw their own conclusions.
4 Comments
Interesting interview.
I believe I am right that a difference between ADVANTAGE and VIGOR is that pts using low-dose aspirin were not excluded in former, but were in latter. This is underlined in the protocol (p. 8) that is linked on the other thread on this issue. I assume Merck intended to highlight this point for FDA reviewers.
As I recall, and here I could certainly be wrong, some of the internal memos suggest that there was some debate within Merck on this point - whether allowing ASA would erase whatever GI benefit and/or whether it might be used as evidence (in the context of other company materials) that Merck anticipated potential CV problems. Again, I could be wrong, but I think the discussion of whether the study was "redundant" was partially shorthand for: Why do an additional study that could show problematic results on both GI and CV sides - and risk "killing the drug"?
In that context, I must say that ADVANTAGE being done had a certain "advantage" - but this is independent of the ethical issue of informed consent.
From the protocol, I also note that pts with the most debilitating OA (class IV) were excluded from participating. I acknowledge that class III is no picnic! It would be interested to know the breakdown of subjects by OA class. As noted on another thread, Merck has justified the study on the basis of helping people with "deblilitating arthritis."
The nine Merck documents cited in the Hill paper, and others, can be viewed at the University of California, San Francisco's Drug Industry Document Archive (http://dida.library.ucsf.edu) by entering "cs:humeston" without the quotations in the query box.
Kim Klausner Digital Libary Manager
study 058 was a pre-nda oa trial that permitted aspirin up to 350 mg. this was completed by April 1998. This was a 30 week tial while advantage was 12 weeks.
Merck had a trial, (036), to test Vioxx and low dose aspirin combined use. Aspirin defeated Vioxx gi protection thus making Vioxx a more dangerous more expensive motrin. This study never made it into the label although results were avaialble in November 2001.
Vigor had more patient years & patients on aspirin than Advantage even though the protocol prohibited such use. Another disparity between the things Merck said it was doing & what it actually did.
Fascinating. thanks, David.