Princess Zetia and the pea

Is it a nugget for Zetia?

Or a pebble?

Or a pea?

Here is a bit of junk sounding research.

Or at least junk inferences drawn.

85 patients perhaps taking Zetia who improved compared to a "control" group
with different blood pressure control,
on (perhaps) a surrogate endpoint
in an underpowered study.

The study enrolled 499 Native American diabetics, half of whom were assigned to achieve LDL or bad cholesterol levels of 70 or lower while the others aimed for 100 or below.
The aggressive treatment group also aimed for systolic blood pressure readings of 115 compared to 130 for those assigned to standard of care.
About a third (perhaps) of the aggressively treated patients took Zetia (maybe 85 or so), but no one knows which.

Some got thick carotid artery walls and flabby ventricles. No clinical endpoints studied.

The dissection is continuing.

See Wall Street Journal Blog 9 April 2008: From ENHANCE to SANDS: A Nugget for Zetia?

See also

Pharmalot: Vytorin Prescriptions Will Plummet. Surprised?
Pharma Giles: Mr. Ten Percent... Redundancies at Scherigh Plough
Dr. Peter Rost: How does it feel to fire 5,000 employees, Mr. Hassan?

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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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Zetia - something brewing on Cafe Pharma

Cafe Pharma, the anonymous bulletin board for Pharmaceutical Sales Representatives, is always amusing and insightful. The mud flows freely. From these anonymous comments today on the Schering Plough board [Link, Link], one wonders what innovations are brewing with Zetia and a "49 day plan". Some great science I suspect.

Yesterday, 06:33 PM Zetia 49 Strategy
Wondered what everyone thinks about this Zetia 49 plan??

I hate having extra $$ that I have to spend on Drs that I can barely see. I have a hard time spending all my lunch/dinner $$ now. Can't get docs out to dinner anyway - especially the ones they've targeted for me...... This instruction that we are to have a lunch or dinner EVERY DAY - come on!! Like all the Drs offices aren't booked already for the year - or have stopped doing lunches/dinners altogether! ....

Throwing money at a problem is not the way to fix things - it will only make matters worse. Have the company come clean about the study, give us some good (or even not so good) evidenced based medicine - and let us earn back the business the right way.

Yesterday, 07:55 PM Zetia 49 Strategy
Hey how about replacing the Vytorin combination of Zetia and Simva with Zetia and Cheerios.... You could call it something creative like Cheatios. Come on, I know you SP shitheads can make something out of all of this. Run a trial call Son of Enhance and use a Priest as the "Head Investigator and enroll only 8 year old little boys. Then hold the results for 10 years until they reach legal age and then reveal the truth. Send this one up to your marketing team.....

Yesterday, 10:25 PM 49 day plan ... hahahahahahahahaha RIGHT !!!??
this is a joke....??? right.

Yesterday, 10:32 PM Re: 49 day plan ... hahahahahahahahaha RIGHT !!!??
My 49 day plan consists of seeing how many of the next 49 days I cannot work. Hell I'll probably extend the plan if it works out for me.

Today, 01:50 AM Re: 49 day plan ... hahahahahahahahaha RIGHT !!!??
at least you'll be kept busy until 1Q 08 numbers go public .....

Today, 06:08 AM Zetia 49 Strategy
Does any one think that having all this extra money thrown at us looks and feels like we are "buying" back the business - not "earning" back the business?
Once again, SP is seeing just how far it can go without crossing the line...
Hey Fred, Carrie - the line HAS been crossed! Integrity counts!...

Today, 06:08 AM Zetia 49 Strategy
Here is why it will not work: ...We have lost the trust of doctors. It is not the message, but until there is DATA showing that Zetia reduces CV events and mortality, doctors will say that we are just spewing the same old shit, and get even more pissed....

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ENHANCE trial - mystery solved: CEO sees outcome in piece of toast

PRESS RELEASE
Schering Plough CEO Sees Image of ENHANCE Trial Outcome in Piece of Toast
For Immediate Release: 20 February 2008
Amazing Toast provides explanation

(PMPA-London) There has been much excitement over the mysterious prediction of the Vytorin clinical trial (Enhance) and how and what Schering Plough knew and when. Schering Plough has been dogged by accusations and questions about predictive sales of stock, reporting delays and misconduct. There have been questions about mathematical expertise and honesty. Now it appears that the mystery is solved.

An unnamed insider initially reported that a Schering Plough executive was about to eat his breakfast, when an unusual toast pattern caught his eye. "I was about to butter my toast when I realized that there was an unusual pattern of darker crumbs which meant that the Enhance trial was a bust". "It was the beginning of the end, and I immediately went out and sold £25,000,000 worth of my company stock" the executive added.

The actual piece of toast has been retained by Congressional and State investigators and the original toast is copyright to Schering-Plough CEO Fred Hassan. We can therefore only show this image of an unmanipulated slice of toast.

Ever since news of the parallel scientific universe of the ENHANCE study made headlines, Schering Plough and Merck have been inundated with requests to explain several mysterious events. "Now we are satisfied that everything is fully explained" said Hassan. "There has been no fraud. We need to look at the totality of the evidence, including the toast."

"This is astounding news" said Dr Nissen, "seeing is not believing".

"God in heaven forbid that a company profit from helping sick people" said a spokesperson from the Center for Medicine in the Public Interest (Drug Wonks). "Why don't we just not offer any treatment and then we will never have to worry about being accused of conducting shoddy science". "We'll just have thousands of people dying of heart attacks all over the place. Of course there will be arguments about the meaning of the toast. It remains a pity, though, that so much premature confusion has been created in the minds of the public simply by individuals who want science to work in the way it has traditionally worked".

If you'd like more information about this topic, or to schedule an interview with Fred Hassan, please call Carrie Cox at 666/25-MILLION or E-mail Carrie at carriecox@transparency.com

50% of readers found this article helpful.

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What is the half-life of a pharmaceutical scientific scandal?

Using Google Trends it is possible to plot the frequency of google searches against time, as well as the incidence of news reports for particular key words (with flags showing the timing of key incidents). I thought it would be interesting to look at a few scientific scandals

• Vioxx
• Vytorin, Zetia
• Avandia

The half-life is about 3 weeks, and is fairly reproducible. Patient deaths and other accumulative effects are not shown.

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Vytorin - the mechanism for no-clinical-benefit ?

This pre-print manuscript (in press, Atherosclerosis) doesn't seem to have been mentioned on a single blog - so I thought I would stick it up here. Could it explain all sorts of anti-pleotropic effects, and possible paradoxical worsening of atherosclerosis (or lack of effect) of Vytorin in the ENHANCE study?

Any lipidologists out there please interpret.

Ioanna Gouni-Berthold et. al. Atherosclerosis (2008) in Press: Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: A randomized trial in healthy men.



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Micro Statistics Tutorial 06: Histograms - The Vytorin data so far

Drawing histograms is a useful skill. Choosing the correct number of bars (size of interval) is important. Too few yield an uninformative plot. Too many will be difficult to read. This shows the number of studies designed to prove any clinical benefit of the drug Vytorin (zetia ezetimibe/simvastatin-combination) and the outcome.

Figure 1: The data so far

On a serious note: It is always important to visualize data before doing complicated statistical tests.
PLOT THE BLOODY DATA. That is the most important rule of statistics (and of honest reporting of findings).

To draw a histogram for continuous data, you need to group measurement into discrete intervals. There is some "best" number of intervals that maximizes visual information. Several scientific papers have been written on the optimum number of intervals (K) given the number of data points (N). The Sturgis formula (1) states:

K = 1 + 3.322 log10(N)

1. Sturgis, H.A., “The Choice of a Class Interval”, Journal of the American Statistical Association, Vol. 21, pp.65-66, March, 1926.

See here for Collated Micro-Statistics Tutorials

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Micro Statistics Tutorial 05: Functional Unblinding and Vytorin (Method 1)

As discussed in the last post, concerns have been raised about possible "functional unblinding" in the ENHANCE trial of the drug Vytorin (zetia ezetimibe/simvastatin-combination). In other words "could Schering Plough have cheated by trying to work out the outcome of ENHANCE before the "opening" the unblinding codes".

This tutorial does not address whether they "did it" but evaluates one proposed mechanism for "functional unblinding".

One mechanism is to examine the primary outcome variable for bimodality (two camel-like humps indicating separation of treatment arms). Is this possible? Some bloggers and imaging experts suggest that this might have happened in ENHANCE (See Brandweek, Pharmagossip).

Jack Friday explains the potential mechanism thus:


is this possible?

The short answer is no, at least for the primary response variable in a usual clinical trial. It all depends on study power. Usually, trials are sized so as to provide reasonable power (say 70% to 90%). The greater the power, the greater the chance of getting obvious bimodality in unblinded data. However, even at 95% power, bimodality in combined unblinded responses would never be a reliable indicator of a treatment response (or lack of response). It is possible to show this using complicated equations, but a simple graphical example with simulated data (based on the ENHANCE study) is easier.

Enhance had a prior declaration of power as follows:



As discussed in Tutorial 04, this power calculation was slightly wrong. However leave that aside for now.

Assume that the study showed the desired effect of Vytorin. This would mean a "left" shift of 0.05mm (or one quarter of a standard deviation) in the Vytorin arm (with both arms having SD=0.2mm). The plot below shows the distribution of a mix of those two distributions, each at N=325. For convenience, the "placebo" distribution is centered at zero. The vertical dashed line shows the mean of the Vytorin distribution (for an outcome Schering Plough would have deemed as "positive"). This small change that would have been regarded as "positive" is interesting in its own right. Clearly, there is no evidence of bimodality on visual inspection. There are tests for bimodality, but these would not help much more than simple "eyeballing".



Even if the desired (or expected) treatment effect was eight times bigger at 0.4mm (2 x SD), it would be hard to be sure about bimodality (there would be broadening of the distribution, but this would provide dubious evidence). Such a study would have practically 100% Power (highly unlikely in any study powered on the primary outcome).



Bimodality would however become evident if the SD was halved to 0.1mm in each arm together with the eight fold increase in the treatment effect.



Bottom line: Bimodaility of response (for the primary outcome variable) is not going to be a reliable mechanism to "functionally unblind" a trial.

There are far better methods.

See here for Collated Micro-Statistics Tutorials

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Micro Statistics Tutorial 04: Power - Can Schering Plough count?

As discussed earlier, there have been concerns raised about the possibility of "functional unblinding" in the ENHANCE trial of the drug Vytorin (ezetimibe/simvastatin-combination).

As the first part of this exercise, let us take a look at the POWER of the ENHANCE trial. There is something slightly odd here (I think). The question is: Can Schering-Plough count?

Power, for neophytes out there, is the probability of rejecting a false statistical null hypothesis. The goal is to allow you to decide (in advance of an experiment)

• How many people (or things) you need to study to answer your question
• How likely it is that your statistical test will be able to detect an effect of a given size

Good experiments must ensure that power is high enough to answer the question. To calculate power we need to know:

• The precise question
• The kind of statistical test that will be used
• The size of the sample (bigger = more power)
• The size of the experimental effects you want to detect (bigger effects need a smaller sample)
• The amount of noise in the measurements (measurement error or biological variability)

Power calculations for the ENHANCE trial were published with the study protocol [Ref 1]. It states:


Although it is possible to perform power calculations taking account of covariates or confounders (such as baseline IMT, center and so on) this is difficult, and no estimated covariate parameters are provided. One therefore has to assume that the power calculations were carried out using conventional methods (a t-test). In the end Schering Plough recruited slightly more patients than their prior power calculation suggested they should recruit as a minimum. However this is not the issue here. They could also claim that this is just a bit of rounding error (see further discussion in comments). This is again irrelevant - the fact remains that it is not possible to add two and two from the numbers they give, or to resuscitate their rather simple calculations. This bypassed the entire system of safeguards that is supposed to check these little details.

So on to the power. Well, as far as my humble brain can establish, Power for N=650 is in fact 88.9%, not 90%.
The required N for 90% Power, 2-tailed alpha 0.05, between group difference of 0.05mm and SD=0.20mm is not N=650.
It is N=674.

A small difference perhaps, but it does tell us something interesting about the process:

1. Perhaps I can't count
2. Perhaps Schering-Plough or Merck can't count
3. Perhaps the authors of the protocol paper didn't read their paper
4. Perhaps peer reviewers didn't back-check anything
5. Perhaps there is something Merck or Schering-Plough aren't telling
6. Perhaps Carrie Smith Cox can only count in units of $28 million

Reference
J. Kastelein, P. Sager, E. de Groot, E. Veltri (2005). Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia. Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. Am Heart J. 2005 Feb;149(2):234-9.

See here for Collated Micro-Statistics Tutorials

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Micro Statistics Tutorial 02: Double Blind (Trust)

Blinding in clinical trials refers to a type of study design. The graphic explains the concept. It does not refer to the hiding of science from authors of papers, "regulators", doctors, or the public.



In a blind study, the researcher or the participant or both (double blind) are blind to (unaware of) the type of treatment being administered. Double-blind trials are more likely to produce objective findings. This is because the expectations of researcher and participant cannot alter the outcome. It also makes cheating more difficult. Practitioners of "complementary" medicine such as bone throwing are not too keen on blinded trials (bone throwing is not yet available on the NHS - but watch this space).

For a good example of blinding in practice see: Vioxx and a quacking duck

A few of us have been agonizing over the potential problem of "functional unblinding" in Vytorin/Zetia trials. This is where effective unblinding happens without officially opening the book of randomization codes. There are a few possible mechanisms for this including a) inspection of treatment surrogates or confounders, b) looking at data distributions, c) inspection of treatment side effects, or d) taking a sneak peek at the codes when no-one is looking. Each of these will form the subject of a later tutorial.

See here for Collated Micro-Statistics Tutorials

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Micro Statistics Tutorial 01: Lessons from Dave, the forecasting pig

Most (not all) statistics is about prediction. Forecasting is about prediction of future events (usually, but not always, in advance of those events). For example, Carrie Smith Cox, President of Schering-Plough, dumped $28 million worth of stock before anyone knew about negative studies, altered endpoints or anything at all about the drug Vytorin (ezetimibe/simvastatin-combination). That is an example of forecasting. We might however want to predict events in one group of people, knowing what happened in another group.

Here is where we introduce Dave, the Forecasting Pig (Reuters 31 Jan 2008). Dave lives in Ohio. He opines (or oswines) on US economic status, and is a key statistical tool used by the Ohio treasurer's office. Dave decides between a trough of sugar or one of sawdust to gauge the economy's future. Sadly, better methodologies are available (ask Carrie Smith Cox).

Tutorial take home message:
The ingredients of good statistics:

1. A decent, honest, well described set of data
2. Proper definition of terms, specified in advance
3. A clear, well framed and unambiguous question (or problem), specified in advance
4. A plan for examining those data, specified in advance
5. Honest intent

Example of a well framed unambiguous question:
Have you had the measles?
If so, how many?
(Armstrong Ward)

See here for Collated Micro-Statistics Tutorials

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Ezetimibe Zetia Vytorin - Headless Chicken Award

The Ezetimibe data are out (all those thousands of un-analyzed images that formed the excuse for non release of the results were obviously analyzed at the speed of light). From the WSJ "The long-delayed and much-speculated-about data from Merck and Schering-Plough’s Enhance study comparing whether a combination of Zetia and Zocor works better than Zocor alone were finally released today."

It's a bummer. Time for the first Headless Chicken award of 2008.



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Ezetimibe - where are our medical journals?

The huge ethical and scientific problems with the drug Ezetimibe have been discussed widely in the lay press (especially in the New York Times and some excellent reporting in Forbes). The problems have been discussed by patients, on the internet and in the blogsphere. However as of today, a search of our key medical journals reveals no hint of any ethical discussion. No discussion of the principles of good science. Not even a worthy news report. Nothing at all.

• The British medical Journal : No discussion
• The Lancet: On 24 November 2007 in the midst of the saga, the Lancet published a review entitled "The safety of statins in clinical practice" Jane Armitage, Vol. 370, Issue 9601 Pages 1781-1790. There was no relevant discussion or associated editorial in that issue or in any subsequent issue.
• NEJM: No discussion
• JAMA: No discussion

And the multitude was silent, not a voice, not a sound was heard upon the hillsides, across the valleys where they stood.'
Richard Bach, Illusions

One wonders how long our key medical journals will retain any credibility as honest impartial portals for discussion of science and the principles of good medicine. For the record, here is some of the discussion on the top 100 medical blogs collated in date order. Some have called for a boycott of Ezetimibe.

• 21 Nov 2007 from Your Pharmacist May Hate You: Print Out The Article and Shove It Down The Throat Of your Merck/Schering Rep
• 22 Nov 2007 from PharmaGossip: Is Vytorin about to be renamed Whytorin?
• 24 Nov 2007 from Hooked: Ethics, Medicine, and Pharma: Here We Go Again: Everything That's Wrong with Industry Sponsored Trials
• 24 Nov 2007 from Scientific Misconduct Blog: Ezetimibe (Zetia, Vytorin): the smell of bad science
• 26 November 2007 from Junkfood Science: Even gold can be tarnished
• 26 Nov 2007 from Pharma Marketing Blog: Vytorin Study Stallin' - Notes from the Field Hands
• 26 Nov 2007 from Health Care Renewal: Is it (Clinical) Research, or is it (Pharmaceutical) Marketing? - the ENHANCE Trial of Ezetimibe
• 29 Nov 2007 from MDLinx: ezetimibe: The role of ezetimibe in cholesterol management (evidence-selective article for nurses)
• 22 Dec 2007 from Medical Evidence Blog: Patients and Physicians should BOYCOTT Zetia and Vytorin
• 22 Dec 2007 from Scientific Misconduct Blog: More problems with Ezetimibe (Zetia, Vytorin): Let there be light
• 23 Dec 2007 from Clinical Psychology and Psychiatry: A Closer Look: Changes?
• 24 Dec 2007 from The Healthy Living : Data About Ezetimibe Adverse Effects Suppressed?
• 24 Dec 2007 from Health Care Renewal: Data About Ezetimibe Adverse Effects Suppressed?
• 25 Dec 2007 from Your Pharmacist May Hate You: Merck/Schering don't want You To Know about studies on the liver
• 26 Dec 2007 from Scientific Misconduct Blog: On swearing versus thuggery: a statistical analysis
• 27 Dec 2007 from Your Pharmacist May Hate You: Once Again, The Drugmonkey Gets Results
• 12 Dec 2007 from Pharmalot: Merck & Schering-Plough Backpedal On Vytorin
• 12 Dec 2007 from PharmaGossip: Whytorin Saga contd. - clinical trials, ain't they a bitch!?
• 13 Dec 2007 from Medical Evidence Blog: ENHANCE trial faces congressional scrutiny
• 17 Dec 2007 from Health Care Renewal: Manipulation of ENHANCE Reversed
• 17 Dec 2007 from Pharmalot: Vytorin Researcher Regrets Not Fighting Back
• 18 Dec 2007 from PharmaGossip: ENHANCE your reputation
• 18 Dec 2007 from Dr. Peter Rost: It's never, ever right to change the primary endpoint of a study
• 18 Dec 2007 from PharmaGossip: More on ENHANCE - the case of the shifting endpoint
• 17 Dec 2007 From Pharma Giles: A Doctor's Christmas Carol...some drug reps gave to me, Twelve Zetia Calculators, Eleven Nexium totebags....
• 19 Dec 2007 from Schwitzer Health News Blog: Something smelly about statin trial: Congress investigates
• 21 Dec 2007 from Scientific Misconduct Blog: A ray of light - well done Dr John P. Kastelein
• 21 Dec 2007 from PharmaGossip: Merck/Schering Plough - Zetia: the liver is evil, it must be punished
• 21 Dec 2007 from Clinical Psychology and Psychiatry: A Closer Look: Zetia: But Why Would We Show You the Scary Data?
• 21 Dec 2007 from Pharmalot: How To Find Documents On The FDA Site
• 21 Dec 2007 from Hooked: Ethics, Medicine, and Pharma: New Cholesterol Controversies: Regaining Perspective
• 21 Dec 2007 from Pharmalot: The Vytorin Clock Tells You When To Hide Data
• 21 Dec 2007 from Drug Injury Watch: Cholesterol Drug Zetia May Cause Serious Liver Injury Including Hepatitis And Liver Failure
• 04 Jan 2008 from PharmaGossip: Schering Plough - Zetia/Vytorin: ENHANCE - Listen with Fred
• 05 Jan 2008 from Bad Science: The data belongs to the patients who gave it to you
• 10 Jan 2008 from Scientific Misconduct Blog: The Ezetimibe fiasco - the excuses continue

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The Ezetimibe fiasco - the excuses continue

Several bloggers have been following the saga of Ezetimibe (Zetia, Vytorin), the hidden data, and the threats to science which have resulted from the way in which Merck and Schering-Plough have thrown the usual safeguards of science into the gutter.

Earlier this week Schering-Plough CEO Fred Hassan spoke for 45 minutes at Morgan Stanley’s "Pharmaceutical CEOs Unplugged" conference. He tried to assert that the ENHANCE trial was unimportant anyway as it wasn't being counted on for anything. Also, it was a study conducted in a very rare population of patients and has no implications for the general population of patients with hypercholesterolemia.

Obviously, ENHANCE was THE study designed to demonstrate that ezetimibe has an impact on atherosclerosis. Any impact at all would be nice, since no clinically relevant benefit of Ezetimibe was demonstrated prior to licensing of the agent.

Scientific malfunction is fine when studies can be deemed (in retrospect) by important CEOs to "not matter anyway".

When individual scientists conduct themselves in such a way as to cause our understanding of science to be disturbed, then (unless they are very important people) they get thrown out of science, imprisoned, and their future "findings" are not believed. The rules of participation and believability are different for corporate "science".

Schering-Plough is of course the company that writes £10,000 checks to doctors in exchange for prescribing their drugs.

Schering-Plough clearly has a record, as does Merck. The examples are many. In 1999 it was reported that deaths in clinical trials involving gene therapy were being hidden on demand from companies who were worried that it would "have an impact on their business". The Washington post reported in that "Scientists and drug companies have failed to notify the National Institutes of Health about six deaths that occurred in gene therapy experiments in the past 19 months". Researcher Ronald Crystal "cited concerns about the impact on his business if the death were made public". "Schering-Plough also had demanded confidentiality for three recently filed reports of serious patient illness during gene therapy trials. The lead scientists in two of those studies determined that the complications "probably" were caused by the gene therapy; Schering-Plough officials had downgraded those assessments." It was then reported that Schering-Plough Corporation and the University of California had done preliminary trials in dying cancer patients, but "lowered the dose when two early participants experienced serious drops in blood pressure" (Nelson, Deborah, and Weiss, Rick. Hasty Decisions in the Race to a Cure? Gene Therapy Study Proceeded Despite Safety, Ethics Concerns. Washington Post November 21, 1999: A1, A26-A27 [Link]). These were not reported, and later trial participants were not informed.

Actual people died.

Wilson (the researcher) said: "If a mistake was made, we've got to own up to it and learn from it. Ultimately, the tragedy of Jesse's death would be if we don't learn anything."

What have we learned over 8 years Dr Hassan?

As Ben Goldacre writes in Bad Science, "the data belongs to the patients who gave it to you". Our patients deserve better Dr Hassan. Science deserves better.

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More problems with Ezetimibe (Zetia, Vytorin): Let there be light

Yet more problems with Zetia (ezetimibe) clinical trials are now being reported in the New York Times (see background to the Enhance trial of ezetimibe Ezetimibe (Zetia, Vytorin): the smell of bad science). This has to do with hidden data in other studies of the drug.

Part of the problem here is the redefinition of what we mean by scientific fraud, and a redefinition of science itself. If I (as an individual scientist) were to study 20 rats, and then plot a graph showing only the results from those rats "I liked", or those rats I "considered important enough" then I would be guilty of scientific fraud.

Somehow when the stakes are higher we confuse power with honesty, and the deception is tolerated. It's an oddly familiar pattern of deception.

From 2000 to 2003, Merck and Schering-Plough conducted eight long-term safety studies of Zetia in combination with statins. Only three of those studies were published. Now some questions are being asked about what those studies showed, and why prescribers and patients were not given a full view of the evidence.

A Schering executive, Dr. Robert J. Spiegel, said "the companies had not considered the studies scientifically important enough to publish their findings. Some may eventually be published".

Well fuck you Dr. Spiegel, it's not your decision. When patients might die it's always "scientifically important". You might personally think that other scientists and even patients don't need to know what the evidence is, but it really isn't your call. If you want to sell your product under the banner of science you have to behave like a scientist. Science which cannot be scrutinized is not science at all. If you disable doctors and patients from making rational (and scientific) decisions about the use of your product, then you cannot claim to be a science based-enterprise. There are many other serious problems with suppressing clinical data. Patients in these trials exposed themselves to unknown risks in the interests of all of us. Suppression or distortion of that data is an affront to their dignity as human beings.

Science is, as Carl Sagan put it, a candle in the dark. It shines a light on the world around us and allows us to see beyond our superstitions and fears, beyond our ignorance and delusions, and beyond the magical thinking of our ancestors, who rightfully fought for their survival by fearing and trying to master occult and supernatural powers.

Let there be light.

From other blogs:

1. Brody, Howard (2007-12-21). New Cholesterol Controversies: Regaining Perspective. Hooked: Ethics, Medicine, and Pharma.
2. Aberegg, Scott (2007-12-22). Patients and Physicians should BOYCOTT Zetia and Vytorin: Forcing MRK and SGP to come clean with the data. Medical Evidence Blog.
3. Aberegg, Scott (2007-12-20). Are Merck and Schering-Plough "enhancing" the ENHANCE data?. Medical Evidence Blog.

From the NY Times, By ALEX BERENSON, Published: December 21, 2007:

The discovery of the unpublished research comes as Merck and Schering are already under criticism for not yet releasing data from an important Zetia study, called Enhance, that they completed early last year.

"The unpublished Zetia studies, devised as safety tests, would not prove the drug’s effectiveness. But they would give the public more information about Zetia’s potential risks. All the unpublished studies covered periods at least one year in length and were intended to show whether long-term use of Zetia might pose dangers that short-term use did not.

Most of the studies about Zetia in which Merck and Schering have published the results covered periods of only 12 weeks — not enough time for liver problems to develop in most patients.

The unpublished studies, conducted from 2000 to 2003 according to the F.D.A. documents, were not listed on the industry Web sites where companies are supposed to register the results of all drug trials that were ongoing after October 2002. The New York Times discovered references to the studies in briefing papers on the F.D.A. Web site.

“We keep telling people we want to practice evidence-based medicine, and what we keep finding out is that much of the evidence is obscured,” said Dr. Harlan Krumholz, a cardiologist at Yale, when told about the previously undisclosed studies. “There is important evidence, but it’s not in public view. It’s hidden from investigators.”"

“You don’t want to have data missing,” said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. “When there have been adverse effects, when the benefits don’t look impressive, those are the trials that historically don’t make it to press.”

A Schering executive, when asked by a reporter about the unpublished studies, confirmed their existence. But the executive, Dr. Robert J. Spiegel, said the companies had not considered the studies scientifically important enough to publish their findings. Some may eventually be published, he said.

“We’re pretty comfortable that people don’t have trouble tolerating Zetia,” said Dr. Spiegel.

Dr. Eric J. Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif., said that he had asked Merck and Schering more than four years ago to conduct a large, long-term trial to prove that Zetia could reduce heart attacks and strokes. But the companies had little interest, he said.

“They looked at me like I was an alien,” Dr. Topol said.

Dr. Mark Stolk, a gastroenterologist in the Netherlands, last year reported two cases of patients who had developed hepatitis, a liver disease, after taking Zetia alongside Lipitor. One of the patients has since died.

But Dr. Beatrice A. Golomb, an associate professor at the University of California, San Diego, said doctors have lost sight of the purpose of prescribing drugs like Zetia.

The goal of prescribing cholesterol-lowering drugs is not reducing cholesterol, Dr. Golomb said. It is reducing the number of deaths and heart attacks in patients, he said. And without data to prove that Zetia actually reduces heart attacks, doctors cannot be sure they are helping patients when they prescribe the drug, she said.

See post followup: On swearing versus thuggery: a statistical analysis
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A ray of light - well done Dr John P. Kastelein

A note of congratulations to Dr John Kastelein for saying the right thing out loud. I would imagine this is only the first step in the tortuous path that might lead to honest reporting of the ENHANCE trial of ezetimibe. For background see Ezetimibe (Zetia, Vytorin): the smell of bad science.



From the Wall Street Journal

The lead researcher of a long-delayed drug study says he regrets not standing up to Merck & Co. and Schering-Plough Corp. when they first told him last month that they planned to alter the statistical analysis of their jointly sponsored trial.

Under mounting criticism, the companies last week reversed the earlier decision to change the primary measure to evaluate the drug.

John P. Kastelein, a cardiologist at Academic Medical Center, Amsterdam, and principal investigator of the study, said he breathed a 'sigh of relief' when the companies told him last week they were reversing course.

'It's never, ever right to change the primary endpoint of a study,' especially after all the data are in, he says. 'It is statistically not good and it gives the wrong impression to the outside world.' He says he initially went along with the plan but now regrets not firmly resisting it from the outset.

He says the episode was the culmination of a long-running battle over the conduct of the trial and the companies' worries that some deficiencies in the data would jeopardize a good result.

From Health care Renewal: Manipulation of ENHANCE Reversed:

"So this case is unusual, in that an early public outcry resulted in at least some of the clinical research manipulation being reversed. There may be hope yet."

Indeed. The problem is that with so much deception in clinical trials, and with so much at stake it is hard to know when data can be believed. Nevertheless this is a first step. However it still appears that the companies involved had control over the study database in this trial - a crucial problem.

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Ezetimibe (Zetia, Vytorin): the smell of bad science

Concerns are brewing over strange events, quack science and possible scientific misconduct during reporting of the "Enhance" trial of the cholesterol-lowering drug Ezetimibe[1][2][3][4][8]. Ezetimibe is sold by Merck and Schering-Plough (trade names Zetia and Vytorin with annual sales of $4billion). No trials have shown that Ezetimibe reduces cardiovascular events (the main endpoint). No such trials were required prior to FDA approval. The drug does however lower the bad form of cholesterol (LDL).

I personally have no problems with drug approval in the absense of evidence of efficacy, so long as customers (doctors and patients) are not misled. Its a free world. I guess all patients have been told that a) the relationship between LDL lowering and actual clinical disease is not straightforward, b) that some drugs lower LDL but increase risk, c) that the relevant science prescribers have been permitted to see is a sack of potatoes.

The "Enhance" study of Ezetimibe was supposed to look at a surrogate endpoint that is one step closer to actual cardiovascular events - namely the development of atherosclerotic arterial plaques. So what happened?

• Oddly the reporting of "Enhance" was put off by a year, and it is now planned to remove the shroud of secrecy sometime in 2008 (possibly.....). Cardiologists expected to see results at a medical meeting in November 2006, then at another in March 2007, then at another this month. But none materialized [8].
• It turns out the companies have decided to change the study's primary endpoint in retrospect. To convince everyone that this is the right thing to do, they brought in an "outside" expert advisory "panel" who concluded that the wrong thing is the right thing (presumably for a fee). They then refused to state who these supposed experts were.
• It turns out that the company has had full control over all of the study data and that the lead "author" has not yet seen any of it.
• Lead investigator of the study, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands)stated that "The suggestion that the results are being suppressed because they are negative is simply wrong. People are assuming that anyone can take a peek at the data, but how can they do that if it hasn't even been unblinded and there are 40 000 images to analyze?"

With respect Dr Kastelein, the assertion that altering endpoints before unblinding cannot cause bias is obvious and utter nonsense.

1. Firstly, we have no confidence (P=0.3) that the study has not in fact been secretly unblinded. This lack of confidence is the logical assumption following numerous odd events and data alterations which have taken place in the past (random examples here[5][6]). Unblinding codes are presumably held by the same entity holding the raw data (I guess). That same entity has a huge financial stake in the outcome. That entity is not yourself Dr Kastelein. Nor is that entity a secure impartial honest third party (a complete guess).
2. Secondly, as an experienced scientist you will be fully aware it is perfectly easy to fiddle the results of a randomized trial given a "blinded" study database even without the un-blinding codes. Ezetimibe has many side "effects" that distinguish it from placebo apart from it's intended clinical benefit (LDL lowering is itself such a "side effect"). It would be easy for an individual "exploring" the data to examine the relationship between LDL lowering and various "primary endpoints" without unblinding to get a pretty good idea of the "primary" endpoints to reject, exclusion criteria to be applied, or even the variables that might require a little "recoding".

There is no certainty here, but strange events have taken place on a sufficiently regular basis for the confidence limits to be wide (P=0.3). The smell is not one of science Dr Kastelein. I'm glad you expressed unease with the process, and queried the mysterious need to alter the endpoints. Word is that you are one of the honest people. I believe you should go the whole way, and stand up for honest science and integrity. You might also make some comment about the need for company statisticians to be involved with the data at all.

Others [4] have pointed out some of the key problems with this research, and I have added a few more:

1. Seek to get your drug on the market before we know whether it actually makes us live any longer or prevents real disease.
2. Keep all the data under your strict control; don't even let the (so-called) lead investigator see it.
3. Change the primary study endpoint in the middle of the trial.
4. Pretend that this is science.
5. Keep all the processes as secret as possible at each step of the way.
6. Conduct studies that focus on patients who are not at all representative of the intended target customer for the drug.
7. Pretend that you are a company based on science, but at the same time pretend out loud that altering data or endpoints in a still-blinded study cannot possibly be a means to induce bias.

If you are a patient taking one of these drugs, go ask your prescriber for a summary of the scientific evidence. Alternatively pay a visit to your nearest homeopath (an Ouija board may also prove useful).

References:

1. Hughes, Sue (2007-11-23). Concerns Raised on Delay of Ezetimibe Data. Medscape/Heartwire.
2. Merck/Schering-Plough Update on ENHANCE Trial. Merck Website.
3. Berenson, A (2007-11-21). After a trial, silence Page C1. New York Times.
4. Brody, Howard (2007-11-24). Here We Go Again: Everything That's Wrong with Industry Sponsored Trials. Hooked: Ethics, Medicine, and Pharma.
5. Blumsohn, Aubrey (2007-10-21). Vioxx and a quacking duck. Scientific Misconduct Blog.
6. Blumsohn, Aubrey (2007-05-19). On the redefinition of research misconduct. Scientific Misconduct Blog.
7. Berenson, Alex (2007-11-24). Cardiologists Question Delay of Data on 2 Drugs. New York Times.
8. Herper, Matthew (2007-11-19). Drug Trials: The Vytorin Question. Forbes. Retrieved on 2007-11-27.

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