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Re: So, marilyn, please don't drop dead » SLS

Posted by JLM on August 14, 2004, at 8:45:13

In reply to Re: So, marilyn, please don't drop dead, posted by SLS on August 14, 2004, at 8:27:00

> > That doesn't wash. Lilly could have went ahead and
> > carried out the Beasly Protocol, as they had promised the FDA, and chose not to. Is that perhaps because they feared what the result would be?
>
>
> I am not at all familiar with this. Were they asked to do this in the early 1990s in association with the law suits? I'm sure they did fear what the result would be. Someone must have had some suspicians. What is the Beasly Protocol?
>
> Thanks.
>
> You might want to take a look at the Cymbalta labelling. It does cite treatment-emergent suicides as an infrequent occurrence.
>
>
> - Scott

Scott:

"The short attachments to this paper contain deposition transcript excerpts and a couple of exhibits from a public domain deposition of Eli Lilly's Dr. Charles Beasley. Dr. Beasley was, for several years, Lilly's "point man" on the issue of SSRI induced suicidality. It was he who flew immediately from Indianapolis to Boston, in January of 1990, to meet with Dr. Martin Teicher in an attempt to neutralize the now famous Teicher & Cole articleii. It was he who authored the "meta-analysis" of Lilly's studies, an analysis which, among other serious flaws, excluded 76 out of 97 actual suicides! And it was this same Dr. Beasley who was the principal author of a study protocol, written with the input of "somewhere between 10 and 100" in-house and outside scientists. But more of that below.

On one particular day in late 1990 or early 1991, Dr. Beasley was a scrivener. His attached handwritten notes chronicle the concerns and recommendations of several very prominent outside consultants. These private concerns, voiced only in the veiled secrecy of the hallowed halls of Lilly corporate headquarters. Dr. Gary Tollefson, who would later come in-house and rise to a high executive level position at Lilly, said that it is "possible [that a] small # get paradox." (See my Puzzling Paradox of Prozac Induced Suicidality graphic at www.JusticeSeekers.com.) When he was still on the outside looking in, Dr. Tollefson suggested that the "risk" was related to "akathisia" and he recommended prospective studies of "agitated dp [depression], using sophisticated suicide scales." He even intimated that the study results should be "published."

Dr. Jan Fawcett realized that the company had "group data," but told Lilly that it "should look at cases." This Committee will hear many compelling cases. Big Pharma will urge you to brand them as mere "anecdotes" and relegate them to the field of "hypothesis generators." But, as Dr. Fawcett obviously realized, considerable scientific truth inheres in each of these cases. Each merits careful, individual evaluation.

But it was Dr. Jerold Rosenbaum, one of the chief public apologists for Lilly in 1991iii , that put it most bluntly:

data problems . . . if exist won't find " don't look " means find then rechallenge

Why was it that Dr. Rosenbaum was so concerned about finding the phenomenon by reviewing the existing data? He doesn't say. But there are many reasons why he should have been. One was that nobody was looking for the phenomenon when the data was gathered. The investigators were not sensitive to it and the rating scales were inadequate to detect it. Another was that seriously suicidal people were excluded from most of the clinical trials. Another was the drop outs or "lost to follow up." Yet another was the assumed rarity of the phenomenon. If it was as rare as Teicher and Cole themselves postulated, then it would take a very large study indeed to have adequate statistical "power" to detect and measure it. These and other reasons militated against finding the "needle in the haystack."

But another reason, one about which I queried Dr. Beasley in the deposition, was what I shall call the "robbing Peter to pay Paul" phenomenon. It was expressed to Lilly by Dr. Gordon Parker of New South Wales in a letter dated August 24, 1990. If, as everyone was willing to assume, Prozac was an effective antidepressant, then it would certainly reduce suicidality for some patients. Dr. Parker assumed a 15% reduction of suicidality in the fluoxetine (FT) group. ABut what if a small percentage (say 1%) of the FT patients had a paradoxical increase in suicidal ideation. The overall analysis would show FT to be superior to PT as both a general antidepressant and in reducing suicidal ideation " and the paradoxical side-effect phenomenon would be buried." Buried! Like a needle in the haystack!

So, back to Dr. Rosenbaum's recommendation. "Find then rechallenge." What result would that yield? As noted above, somewhere between 10 and 100 Lilly scientists rejected RCT's and rejected large scale epi studies in favor of this prospective study design. Find the group which Dr. J. John Mann had labeled as a "small vulnerable subpopulation" of patients, and rechallenge them, in protected circumstances, with Prozac. In the spring of 1991 Lilly met with officials at the FDA and pledged to conduct the Beasley Rechallenge Protocol. But Lilly reneged on that pledge, and to its shame and discredit, the FDA did not force them to honor it. Consequently, there has been no systematic study via rechallenge.

However, many of the "cases" before this Panel have elements of challenge-dechallenge and rechallenge. So, too, do many of the "case reports" published in peer reviewed journals. The most dramatic example, of course, is the 1991 article by Rothschild & Lockeiv. In 1991, years before he became a paid litigation expert for Eli Lilly, Anthony Rothschild and his colleague wrote that "the Patients need to be reassured that the overwhelming symptoms [of akathisia and its concomitant suicidality] being experienced are the side effects of medication and are treatable."

IF this Committee really wants to get a handle on the issue, then it should couple its laudable comprehensive review of the existing data with an insistence of appropriately designed and conducted, independent, prospective studies, preferably via rechallenge.

This will take time. In the meantime, in view of the paucity of evidence of real antidepressant efficacy in the children/adolescent population, the Committee should recommend that the FDA couple a contraindication of all SSRI's for children/adolescents with a warning about the very real dangers of SSRI induced suicidality and aggression. There are those who will argue that such a "ban" will deprive those patients who benefit from these drugs of their drug of choice. Not true. Informed physicians and informed patients can still choose to encounter the risks. After all, the Supreme Court itself has held that "off label" prescribing is still legal in this country. "

If you want to test whether a side effect is indeed REAL, then a simple way to do it is:

1. give it to a healthy volunteer
2. see if it happens
3. if it does, take them off the drug, and see
if it resolves.
4. give them the drug AGAIN, and see if they become suicidial again.

Challenge/Dechallenge/Rechallenge

That is what Dr. Beasely proposed, what Lilly promised the FDA, and what was never carried out.

And obviously you want to give the drug to a healthy volunteer, so you don't have the easy out of 'well of course they killed themselves, they were depressed'


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poster:JLM thread:208072
URL: http://www.dr-bob.org/babble/20040811/msgs/377500.html