zoloft: the approval III…

Posted on Monday 18 February 2013

When I read the post that mentioned the Pfizer Lawsuit about Zoloft on Pharmalot [Pfizer, Zoloft And The Vexing Placebo Effect], I pursued it because I was intrigued that the suit was unique, "we want our money back because Zoloft doesn’t work and Pfizer knew it didn’t" – pretty bold. But when I read the complaint [Laura A. Plumlee et. al. v. Pfizer], the studies in the last two posts caught my attention, but it’s the part in this post and the next that fueled my interest in pursuing it further. I’ve operated on the naive assumption that the pharmaceutical industry used to play it straight, but gradually became corrupted in the post-Prozac era when the money for CNS drugs began to flow. This story is from those early days. This post is about "insider trading" in the approval process. I don’t have the incriminating document they used [Transcript of Psychopharmacological Drugs Advisory Committee Meeting (Nov. 19, 1990)] and I don’t know if I can get it, so I’m quoting from the complaint itself [Laura A. Plumlee et. al. v. Pfizer]. The next post will be about the "perversion" of the psychiatric literature for the purposes of advertising. It’s obvious that all of this jury-rigging was already going on in the late 1980s

So we know from the last two posts that Pfizer was going for approval of Zoloft with a mighty weak hand. A questionable fixed dose study and a titration study that was significant but couldn’t be replicated in a second study.

And this story requires that you know who Dr. Paul Leber is. Here’s a brief CV:
  • Medical Officer and Group Leader for Psychopharmacology Unit 2, DNDP [1978 – 1980]
    Reviewed INDs and NDAs. In 1979 became the Group Leader of Psychopharmacology Unit 2 that was responsible for antipsychotics, anxiolytics and drugs intended to modify the behavior of the cognitively and emotionally impaired elderly.
  • Director, Div of Neuro-Pharmacological Drug Products, FDA [1981 – 1999]
    Ran the Division that was responsible for the monitoring of clinical research and the evaluation of NDAs submitted for new drug products in the therapeutic fields of Neurology and Psychiatry, including, for a time, the evaluation of drugs of abuse.
  • Director, Neuro-Pharm Group, LLC [1999 – Present]
    Consultant on strategic and technical matters pertaining to the design, execution and interpretation of findings of clinical investigations intended to persuade regulatory authorities that a new drug product is both safe for use and effective in use as claimed.
He was the "boss" at the F.D.A. and was on the Zoloft advisory committee. From the complaint:
On November 19, 1990, the Psychopharmacological Drugs Advisory Committee for the FDA convened to discuss Pfizer’s Zoloft NDA. The focus of the meeting was to discuss Zoloft’s efficacy and safety. However, prior to the meeting, according to an internal Pfizer document dated September 5, 1990, Dr. Paul Leber, Director of the FDA’s Division of Neuropharmacological Drug Products, informed Pfizer that the he would be
    "solicit[ing] the support of the Advisory Committee that the two key pivotal depression studies are adequate and well controlled."
He pointed out problems with the studies Pfizer had submitted to prove Zoloft’ s efficacy and safety, but assured Pfizer that he thought he could convince the Committee that the studies were sufficient to recommend approval.
In case you missed that, read it again. The Director of the FDA’s Division of Neuro-Pharmacological Drug Products is reassuring Pfizer that he knows their application for a new drug approval is weak but that he thinks he can "convince the Committee that the studies were sufficient to recommend approval." In what alternative universe is that okay?
During the meeting, the committee members discussed the relatively small treatment effect of Zoloft on depression in the only two studies showing efficacy. One committee member explained:
    "[W]e have been provided with mean change scores from baselines and the outcome of statistical analyses for the difference in mean change scores between drug and placebo. However, it is difficult to determine the clinical significance of the statistically significant differences in mean change scores, particularly when you are looking at differences in change of only 2 or 3 points on the HAM-D total score … which is not a tremendous difference."
In addition, the committee members were very concerned with whether two studies, in the context of several others to the contrary, was sufficient to establish that Zoloft was effective for the treatment of depression. As one committee member stated:
    "Can I toss a few statistical issues as the statistician here? In a sense, what we have is not just an effect size problem but, in a sense, what we are trying to wrestle with is sort of an intuitive multiple comparison problem. If all we had was the two out-patient studies and they fairly clearly showed some Sertraline effect, we would have what I interpret as the criteria necessary for us to say go ahead and approve the drug. That is, we have more than one well-documented study that demonstrates an effect. So the question is how do we interpret these two positive results in the context of several more studies that fail to demonstrate that effect? I am not sure I have an answer to that but I am not sure that the law requires me to have an answer to that – fortunately or unfortunately. That would mean, in a sense, that [Pfizer] could just do studies until the cows some home until he gets two of them that are actually statistically significant by chance alone, walks them out and says that he has met the criteria."
Uh Oh! The advisory committee isn’t sounding too impressed with Zoloft. Enter, stage left, the "boss" with a speech for posterity:
… Dr. Leber, the FDA Director who had previously pledged to help get Zoloft approved, told the Committee that:
    "I think it should be understood that all comparisons are probably odious. We do not have a comparative efficacy/safety drug law, although, clearly, clinicians using drugs are interested in determining relative efficacy, relative safety and relative utility – whatever that means. I think you have to understand that when we face an application from a regulatory perspective, we are asked to face what the law requires us to do. We are obligated to approve an NDA unless our review finds that the drug is unsafe for use; that inadequate testing has been done to show that the drugs is safe. We are required to approve the drug unless we find that the tests submitted failed to contain substantial evidence of efficacy. That means more than one investigation which adequate and well controlled which would allow experts – experts by experience, training and background – to reach a conclusion that the drug is effective. And we are obliged to approve the drug unless we find that the labeling is false or misleading in some particular. So if we can come back to the regulatory flavor of the questions, I think it would be useful."
Dr. Leber further stated that
    "[w]e are always in a position of trying to make a fair judgment, knowing that we have to weigh the requirements of the law, the expectations of a public that wants freer access to new and effective drugs, even if they are not necessarily as potent on a milligram basis or even in terms of the size of the treatment effect as others." He then explained that "[w]e take the data base as we have it … At the end of that, we have to go back to the regulatory charge that I raised. It is not that they are entitled to every claim, every superlative ever made, but is the application, as submitted, such that we have a right to conclude it does not have evidence of safety for use; it does not have evidence of efficacy or it is inadequately labeled… If we cannot reach those conclusions, you have to approve the application."
According to Dr. Leber, he had
    "no idea what constitutes proof of efficacy, except on the basis of what we, as a Committee, agree on an as ad hoc case as there needs to be. You can be guided by the past but the inference is an abstraction – what is an antidepressant?"
I can’t quote the F.D.A. mandate, but the last step in the process is obviously the opinion of experts assembled for the task. As things went, Dr. Leber carried the day by a vote of 6 to 3 to approve. But his interpretation of the rules of the road essentially creates a committee I wouldn’t be willing to serve on myself. I doubt anyone reading this would. I have to approve the drug unless I can come up with an airtight reason not to? It’s such a cynical view to me, everything is stated in the obverse, the negative. Who needs an expert for that? But if I were on that committee and found out that the head of the F.D.A. Division had been assuring the drug company that he would personally shepherd the drug through the committee, I’d be on the phone with the New York Times, Washington Post, maybe Baum Hedlund.

Notice that the suit is not levied against the F.D.A. for approving the drug. It’s against Pfizer. It claims that Pfizer knew that it was not efficacious, and focuses on the labeling Pfizer used throughout the patent life of the drug. Here’s a label from 1997. The studies mentioned are old friends. Notice the comment about in-patients [I guess they forgot about those two negative trials that never got published]:

They had trouble getting approved in Europe, and that was withheld from the F.D.A. There was a problem of insider information in Europe as well:
It was because of Zoloft’ s lack of efficacy that Pfizer had substantial difficulty in gaining approval from European regulators. In an April 18, 1991 memorandum, a Pfizer employee expressed "serious concerns regarding the approval of sertraline in key European countries." According to another memorandum dated April 11, 1991, Pfizer "received an unfavorable review in a number of countries. The common key issue is that regulators are not convinced ofsertraline’s efficacy versus placebo." Pfizer recognized that an "analyses of [placebo controlled U.S. studies] strongly indicate that they are not highly convincing of sertraline eflicacy versus placebo and will not provide the strong database required to overcome regulatory obstacles." Pfizer, therefore, decided to create a "strongly positive, placebo controlled study … to ensure regulatory success." This was to be accomplished by designing a study "to enhance the probability of success drawing on the knowledge gained from past trials."

In the United Kingdom ("UK"), Pfizer improperly sought help in obtaining approval of sertraline (known as "Lustral") in the UK from a consultant to the regulators reviewing Zoloft, Dr. Stuart Montgomery. According to an April 24, 1989 memorandum, Dr. Montgomery told Pfizer he would remain a "disinterested party" at the U.K. Regulatory Agency until Pfizer appealed any negative decision and, thereafter, "he would be happy to act as an advisor to Pfizer and declare an interest." In addition, according to a memorandum dated April 26, 1989, Dr. Montgomery provided Pfizer with inside information that the UK regulators’ decision on Zoloft was "borderline" at that time and that the company "should be wary of providing them with efficacy data against placebo."

Yes, it’s the same Dr. Montgomery that wrote the favorable review mentioned in the last post. While I didn’t think much of those studies; I don’t like Dr. Leber’s view of the F.DA.’s job; and I think that labeling is a decepticon, that’s for Baum Hedlund and Pfizer to fight out. The main point I wanted to focus on is the extent of "Insider" influence exerted in both the US and UK approval processes.

We’ve moved from the question of shaky Clinical Trials to shaky practices in the drug approval process. Next, we move from "shaky" to "shady" – how Zoloft went from questionable approval to the top of the charts!…

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