More on Vytorin - Confusion will be my epitaph

There is a worthwhile report in the Wall Street Journal today on the apparent manipulation of the Enhance trial of the drug Vytorin (zetia ezetimibe/simvastatin-combination). The explanation requiring the fewest assumptions is most likely to be correct. It is going to take more than a "duck and cover" approach to restore trust.

Despite their recidivism, one would hope that Schering Plough and Merck realize that they have not chosen an appropriate path yet again. Albert Einstein defined insanity as:

Insanity: doing the same thing over and over again and expecting different results.

If everything is against you, bully your critics. If critics aren't fooled, argue "data quality". I'll discuss the discreditable "data quality" defence and the statistics of data quality in clinical trials later. I have extracted the various data quality excuses forwarded by Schering Plough. These are unlikely to stand up to any form of serious scrutiny.

The full WSJ article (link below) is worth a read. In the meantime, the executives involved may want to listen to the 1970's song 'Epitaph' by King Crimson.

Epitaph (UTube here or here, full lyrics here)

Knowledge is a deadly friend
When no one sets the rules.
The fate of all mankind I see
Is in the hands of fools.

Confusion will be my epitaph.
As I crawl a cracked and broken path
If we make it we can all sit back
And laugh.
But I fear tomorrow Ill be crying,
Yes I fear tomorrow Ill be crying.

TRIAL AND ERROR: Delays in Drug's Test Fuel Wider Data Debate
By RON WINSLOW and SARAH RUBENSTEIN
Extracts from Wall Street Journal March 24, 2008; Page A1 Link to full article

"The firms said they had merely been trying to correct irregular data."

The companies brought in a second lab to compete to produce more accurate results than the original research team.

"The companies say they didn't peek at the results or know Vytorin had failed in the study until very recently".

"What we were trying to do was to improve...the precision and the accuracy of the data so that at the end, the results would be credible," says Enrico Veltri, Schering-Plough group vice president of global clinical development

They also emphasize that early data checks turned up another problem they found even more troubling: missing or "implausible" data that the companies have previously cited as the reason for the long delay in reporting the findings. In some cases they were concerned about wide fluctuations in readings that were supposed to be precise. Other researchers say variation in readings is inevitable in most imaging studies, and that enrolling enough randomly assigned patients spreads any problems among both groups to avoid affecting the overall results.

Early in 2006, the companies' committee proposed a different approach to reading the still-blinded data, and pitted Dr. Kastelein's lab against an outside research team to see whether one would be more accurate. There was no meaningful difference. In January 2007, an independent consultant told the companies that the quality of the Enhance data was similar to what was found in other comparable trials.

But company officials still weren't satisfied. They say they kept exploring different ways to eliminate wayward readings and hone the study's precision. "It's very atypical for a trial to go through this sort of scrutiny," says Allen Taylor, chief of cardiology service at Walter Reed Army Medical Center, Washington, D.C., and an expert in imaging of neck arteries.

The companies defend the effort. "It wasn't that the study looked like it was totally inadequate," says Merck's Dr. Musliner. "The more you can reduce your variability, the greater your chances of showing the significance of smaller differences."

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Contemptible response of the week - from Health Canada

The prize for the most ludicrous letter of the week goes to Health Canada (the Canadian equivalent of the American FDA or the UK MHRA).

This letter could serve as a model template for all regulators. It is as timely as it is informative. I am sure that the writer is not personally responsible but perhaps she needs to consider the part she plays in the farce. The letter no doubt reflects with some honesty the spirit of the actual procedures used to deal with a serious complaint. Below the letter are details of the complaint (of 2005) that precipitated the response received last week. It is truly amazing how hilarious these "regulatory" bodies are - and how little they care that actual human beings die as a result of their actions.

This letter was the sole response to a formal complaint made by four Canadian health policy researchers about illegal and misleading direct to consumer advertising of the drug Diane-35 (cyproterone and estradiol) during 2005. The complaint mentioned that the advertisements were in contravention of the Food & Drugs Act. Diane-35 increases the risk of venous thromboembolism compared to other similar hormone combinations, and there were at that stage at least six reported deaths in Canada. Diane-35 was the subject of two safety advisories in Canada which warned doctors not to use Diane-35 for two unapproved (off-label) uses: for birth control or mild acne. Diane-35 was only approved for a restricted indication in Canada: treatment of a subgroup of patients with endocrine disorders and very severe acne who have failed to respond to all treatments. Nevertheless the DTC advertisements promoted Diane-35 for unapproved uses, and targeted a vulnerable population: adolescent girls. The ads conveyed scientifically false information. Risks were also not mentioned.

Mild acne was promoted as an indication through the use of images of young girls with flawless skin preening in the mirror and the message to 'Ask your doctor or your dermatologist' at the end of the ad. The addition of dermatologist was a clear hint of the indication. Anyone who had severe acne that had failed to respond to previous treatment would not have the flawless skin of these models, either before or following treatment. There is also no indication for the use of Diane as a contraceptive. Three to 10 extra cases of venous thromboembolism occur per 10,000 women taking Diane-35 per year, as compared to the rate of venous thromboembolism in users of other oral contraceptives. Several other illegal aspects of the advertisements were noted.

Of course it is possible that the "satisfactory" actions taken by Health Canada might have included prison sentences for those implicated (the usual sanction in a sane society when individuals recklessly break laws and endanger real people). Readers might wish to contact Saveen Kamarn at (604)666-8516 or Saveen_Kamarn@hc-sc.gc.ca to find out what happened. As usual my profession remains silent.

Onwards and upwards for honest science.

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Procter and Gamble and the rigmarole of integrity

It is obvious to several people that I have been extremely lazy the past week. I have been struggling to catch up with the memory hole feature after attending (and presenting at) a few great meetings.

The excellent picture of Sisyphus sleeping is with kind permission of artist Michael Bergt. Sisyphus is condemned to roll a large rock up a hill. Upon reaching the top the rock rolls back, and the task has to be repeated - endlessly. The story appears to be one of eternal and pointless labor.

I haven't said much about recent progress with the first of the three shonky Procter and Gamble publications. I felt it best to allow time for the excuses to be finalized, and to allow others to comment first. A few examples of those comments are referenced.[1][2][3][4][5][6] I don't necessarily agree with all commentary, but generally people are not morons.[7]

I am finding the "Memory Hole feature" quite useful myself as a way of understanding how we got where we are. To catch up I am going to skip the dates 13-20 November. I'll get back to filling in the blanks over the next few weeks.

References:

1. Colquhoun, Professor David (2007-11-06). Universities Inc. in the UK, Corporate Corruption of Higher Education: part 2.
2. Baty, Phil. "Expert admits he did not have full access to data", Times Higher Education Supplement, 2007-10-12.
3. Silverman, Ed. Boning Up: Journal Tightens Disclosure Policy. Pharmalot.
4. Woodhead, Michael (2007-10-28). A double dose of dodgy data.
5. Saunders, Professor Peter (2007-11-01). Actonel, Dog that Did Not Bark in the Night. Institute of Science in Society.
6. Poses, Roy (2007-10-12). Journal Changes Policy After Blumsohn Case.
7. Moron - n. a person whose actions are explained by motives one is not smart enough to understand. See also * Dullard, Idiot, Ignoramus (Author: S.R. Brubaker, Devil's Dictionary Defiled)

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