déjà vu…

Posted on Friday 12 October 2012

I was scanning through older posts looking for something. I stopped on the one about Solanezumab for Alzheimer’s [SHOW ME THE DATA!…] and my eyes lingered on the titles of the two articles I’d listed:
I forgot what I was looking for because my mind was full of another thought – "I’m having déjà vu!" Here’s the essence of what those articles said for a reminder – the first article:
As Lilly conceded earlier, both of its late-stage studies for solanezumab failed to produce a statistically significant response for mild-to-moderate patients on two key endpoints. Simply put, the study failed. But after a secondary analysis of the first study showed that there was a 42% reduction in the rate of cognitive decline among a subpopulation of patients in the solanezumab arm with only a mild form of the disease, investigators decided to hunt for confirmation of that endpoint in a second Phase III. They didn’t find it, seeing the numbers fall short of statistical significance after switching from one measure [ADAS- Cog11] to another [ADAS-Cog14]. But by "pooling" the data they came up with a 34% reduction in cognitive decline in that particular group. None of the data indicated a significant reduction in the rate of functional decline.
and the second:
The main measures were two tests — one reflecting language, memory and thinking and the other, ability to perform daily activities such as eating and grooming. The combined results on the mild disease patients showed a nearly 2-point difference in the roughly 90-point score on thinking abilities. Previous studies suggest that a change of 3 to 4 on the score is needed to show a clinical benefit, like an improvement in how well patients can take care of themselves.
Those things are completely crazy! Talk about massaging the numbers! They massaged and massaged, and found nothing. Finally, by pooling the two studies together, they came up with a massage technique that vaguely went in the direction they wanted. They had preordained that they needed something like a 4% improvement for success, and even with all the massage, they ended up with only 2%. No way to call that anything but a failed study. As a matter of fact, this is what they said a month ago:

After enduring months of criticism about its late-stage effort to determine the efficacy of the last big Phase III hope for Alzheimer’s, Eli Lilly this morning announced that solanezumab flunked both primary endpoints. The failure, widely forecast by a long lineup of analysts, will raise more doubts about the theory that cutting levels of toxic amyloid beta in patients with mild to moderate Alzheimer’s can help patients with the disease.

Lilly, though, isn’t giving up on the drug, its second major try at treating Alzheimer’s. CEO John Lechleiter, who has bet his job that the company’s R&D division can develop a new generation of therapies, noted that a secondary analysis of pooled data "showed statistically significant slowing of cognitive decline in the overall study population of patients with mild-to-moderate Alzheimer’s disease. In addition, pre-specified secondary subgroup analyses of pooled data across both studies showed a statistically significant slowing of cognitive decline in patients with mild Alzheimer’s disease, but not in patients with moderate Alzheimer’s disease."

"We recognize that the solanezumab studies did not meet their primary endpoints, but we are encouraged by the pooled data that appear to show a slowing of cognitive decline," said Lechleiter in a statement. "We intend to discuss these data with regulatory authorities to gain their insights on potential next steps." Expectations for this trial were so low that Lechleiter’s hopeful note apparently captured the attention of investors, who initially pushed up shares of the company by 5% in early trading…

This is what has been wrong with the whole psychopharmacology scene for the last thirty years! Having put so much effort into some drug, they just can’t let it go when it doesn’t work. So if they can find anything positive, even if they have to roll it around with their statistical package for a month, they start turning cartwheels. Not because the drug is going to do anything much for people with Alzheimer’s disease, but because they know that if they can get it approved by the FDA for Alzheimer’s, they can sell it to the people who are watching their aging parents deteriorate in front of their eyes. All they have to say to sell it is "Solanezumab may slow the progression of Alzheimer’s disease" or "FDA Approved for Alzheimer’s disease" or "Ask your doctor if Solanezumab is right for her." I can see it now. Some attractive elderly woman who was sitting in a rocking chair staring in the first frame is out pushing her blond granddaughter in a swing with a big smile in the second. There were no cases remotely like that in the whole study!

Here’s the déjà vu part, it’s the same thing that happened with Paxil Study 329. They got a dismal report on the trial, but after a thorough massage by a professional masseuse named Sally, they found a way to jury-rig the numbers. In that case, it was already on the market so they didn’t have to go through the FDA – they just sold it by word of mouth. If they can get it  to market, they can sell it to the desperate people who will try anything and pay almost any price. The market is that hungry – still. People hate to see their kids depressed just like they hate watching their parents deteriorate with Alzheimer’s. And here’s another similarity with Paxil Study 329. In that study, neither subject nor parent ratings showed any difference with the treatment. In these studies of Solanezumab, "None of the data indicated a significant reduction in the rate of functional decline." They got nothing. So that’s why I wrote:
"It’s telling that ‘The $60 billion question here is whether Eli Lilly and its science team has the kind of data indicating that they are on a solid path to an approval’ rather than ‘Does it work in Alzheimer’s Disease?’ "
and Dr. Carroll commented:
"An FDA approval is the lowest bar possible, especially when nominal statistical significance is valued over good clinimetric evidence. That is what I have called the Cheshire cat effect – the only evidence that the drug was there is a disembodied p value, grinning in statistical space, with no connection to clinical reality."
We’re older and wiser now than we were in 2001, but I worry that with the famous empty pipeline crisis that something like this might slide through on some innovation gap fast track. Solanezumab is innovative. It just doesn’t happen to work! This one bears keeping up with…
  1.  
    Annonymous
    October 12, 2012 | 5:41 PM
     

    “Another theme of the meeting was the relationship between the academy and the pharmaceutical industry, Ryan said. During a plenary address, Catherine D. DeAngelis, M.D., editor of the Journal of the American Medical Association and recipient of the academy’s annual “Catcher in the Rye Humanitarian of the Year Award,” delivered a speech entitled “Conflict of Interest in Medical Research: Facts or Fiction.” “She addressed the importance of ensuring that studies are well-reported with correct statistical analysis and talked about some of the things that have gone astray in some publications,” Ryan said.”

    http://www.ecommunity.com/news/physicianstory.aspx?id=620928

    You say “Deja Vu?”

    I continue to be surprised at your surprise.

    No staff, officer, any of the 8500 child psychiatrist members of the AACAP have called him on that mother of all ironies in the 4 years since it was said.

    Your fellow physicians could not care less. This is doubly so for psychiatrists and even more so for child psychiatrists. Read that link above from 2008 and tell me one reason that Dr. Ryan, Dr. Hendren, and whoever else there is currently at AACAP should think that that same approach won’t work again in 2012?

    Dr. Carroll referred to all eyes now being on AACAP. If only that we’re true. People have learned the lesson of Study 329. That Dr. Ryan’s approach worked and with absolutely no fallout of an consequence to him.

    Seriously, NO ONE in your field has called him on that quote above. And that was in relation to kids. NO ONE in the field has publicly questioned Dr. Wagner’s choices.

    You think the KOLs who are going to push this Alzheimer’s Drug haven’t learned the lesson of Study 329.

    They’ve learned it well.

    So 1BOM and Dr. Carroll will be annoyed. Their fields will stand by and do nothing. Yes, they will acknowledge that 1BOM and Dr. Carroll talked about some of the things that have gone astray in some publications.

    Meanwhile they will go on to positions of esteem within their societies. Just like Wagner. Just like DelBello. Just like Bostic.

    Remember 329! They do, all too well.

    What a shame.

    What a shame neither you not Dr. Carroll are child psychiatrists.

    If you were, you’d probably be silent, so maybe all for the better.

  2.  
    Annonymous
    October 12, 2012 | 5:42 PM
     

    Please allow comment to post.

  3.  
    October 12, 2012 | 5:54 PM
     

    Annonymous,

    Please make up a name that my spam filter won’t pick up and automatically jettison without notification. I have no control over its ways…

    Mickey

  4.  
    October 12, 2012 | 9:54 PM
     

    Remember when Alzheimer’s was all the headline grabbing rage in the eighties? A few years later, if you were lucky to catch it in the whatev’s part of a newspaper you could see an embarrassed couple of paragraphs admitting that a lot of what they thought was Alzheimer’s was actually the advanced stages of alcoholism.

    In the elderly all kinds of other conditions that cause Alzheimer-like symptoms should be investigated, including the drugs the person has been taking, deficiencies, liver function, etc.

  5.  
    October 12, 2012 | 11:01 PM
     

    Wiley,
    That’s the danger with something like Solanezumab. People will hand it out like candy without doing the proper work-up [particularly bad because it doesn’t work even in Alzheimers]. Those Lilly studies aren’t published so there’s no way to know how they verified the diagnosis…

  6.  
    October 13, 2012 | 4:01 PM
     

    Alzheimer’s is another one of those vaguely defined diseases that are gold mines for pharma. Anyone can get it and people are terrified of it — enough to get millions to take it for many years prophylactically.

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