Comments on: Pharma, Conflicts Of Interest And Fingerpointers

By: Justice in MI

Justice in MI — Thu, 17 Dec 2009 05:34:29 +0000

re: ‘vets’ point on post hoc anlyses, Peter Honig–who was then at Merck but previously at FDA–was quoted in 2004 as follows:

“When I was at the F.D.A.,” Dr. Honig said, “I would read peer-reviewed articles in journals and realize that the endpoints weren’t the original ones from the study because I had reviewed the original protocols myself.”

At that time, at least, it was clear that FDA would say nothing about post hoc spin in journals, and journals themselves were soft targets.

That may have changed some, but most rx’ers will go by what the journals say anyway, regardless of what is or isn’t on the label.

By: Chris

Chris — Thu, 17 Dec 2009 02:37:26 +0000

If certain pharma companies would just publish the comparative effectiveness trials they have already conducted, then we would be at least part way there.

By: pharmavet

pharmavet — Thu, 17 Dec 2009 02:07:19 +0000

Thanks Chris and Atlex for explaining how hypotheses generated from preliminary data in Phase II trials are used to design and power Phase III trials. When the hypotheses are not confirmed in Phase III it is usually a result of overestimation of presumed effect size, larger than expected variance, or both. As for post hoc analyses or data dredging, those tactics might get something published, but will not pass muster with FDA reviewers. A good journal should require the author to state which were the prespecified endpoints so that the reader will know which analyses were done post hoc. A good reviewer should be able to spot design bias, such as when dose of a comparator is deliberately low to widen the treatment difference. The government says it wants to do comparative effectiveness trials. If so, they will soon learn that such studies (i.e. non-inferiority trials) are very expensive, even for Pharma. If the taxpayers want to bear the costs then that’s a decision society will have to make.

By: Justice in MI

Justice in MI — Thu, 17 Dec 2009 01:43:28 +0000

Thanks Chris and Atlex–

I can understand why industry would have the means, and the incentive, to fund high-powered trials.

But, from the same motives, there would be incentives to fund trials that have bias built into their design.

So I suppose it ultimately comes down to the issue of trust and a review of specific cases. My guess would be one would find, in whatever proportion, confirmation for both views. Personally, I have no idea what that proportion would be, but this has been a useful exchange.

By: Chris

Chris — Wed, 16 Dec 2009 21:58:35 +0000

Justice -
One can have a “properly designed, properly powered and properly funded trial” versus placebo which would tend to favor a positive outcome. If you compared the drug to standard of care, the results might be substantially different.

Not sure the converse is true. It would seem to depend on your definition of ‘well designed’. If well-designed means that you are fairly sure of the outcome, then perhaps a less well designed trial leaves more uncertainty as to the results and thus might increase the risk of a negative outcome.

By: Atlex

Atlex — Wed, 16 Dec 2009 21:51:44 +0000

JiM,

If a study sponsor has done a good job of determining treatment hypotheses through previous research, a large, well-designed trial should work a majority of the time. Small trials are used to weed out poor prospects and large trials are then conducted on the products that have the greatest likelihood of success. Of course, from a statistics perspective, it is more likely to reach a definitive outcome with a larger trial. An underpowered trial, common outside of pharma because of budgetary constraints, may directionally show successful treatment, but may not reach statistical significance. Thus, it did not prove successful treatment and is often termed a treatment failure.

In a related issue, many (I’m not saying all) times, pharma companies early smaller trials in order to develop or test hypotheses. These more commonly fail and can make up a significant portion of the trials that go unpublished.

Atlex

By: Justice in MI

Justice in MI — Wed, 16 Dec 2009 20:39:09 +0000

It’s an interesting perspective, pharmavet. As you know, less complimentary explanations include changing endpoints post hoc, choosing inappropriate comparators, etc..

But I think there is a logical flaw in your explanation, even if one were to accept your premise.

Why would a “properly designed, properly powered and properly funded” trial favor _either_ a positive or negative outcome? Wouldn’t either outcome be equally likely, if more reliable, in such a trial?

Conversely, why would a less well designed trial favor a negative outcome?

By: pharmavet

pharmavet — Wed, 16 Dec 2009 18:23:59 +0000

There is an easily understood reason why Pharma-sponsored trials have a higher reported frequency of positive outcomes, and has to do with the expense of conducting trials, as anyone on this board will tell you. In Phase III trials, a trial with a power (probability of success in layman’s terms)of 80 or 90% often requires many thousands of patients and is extremely expensive. Few entities other than Pharma can afford to properly design a trial with adequate power. Many if not most non-Pharma sponsored trials are underpowered because they are underfunded, and thus have a higher likelihood of failure. This has nothing to do with “publication bias” and everything to do with properly designed, properly powered and properly funded clinical trials, which Pharma is simply better at because it can afford to be better.

By: Condor

Condor — Wed, 16 Dec 2009 15:07:48 +0000

H I L A R I O U S!

Merck just named the “Fosamax® Guy” as its Chief Medical Officer, and new executive vice president.

Well, at least we can tell this particular tiger — by its stripes — eh?

I congratulate Merck for being so bluntly honest — it will save the shareholders money, by making this guy an “on-staff” (fixed cost) expert witness in its defense of what will likely grow to be more than 1,000 Fosamax bone death lawsuits.

“Crafty,” eh?

[With my tongue firmly in cheek.]

Namaste

By: Anon

Anon — Wed, 16 Dec 2009 14:18:45 +0000

“Leading medical journals are fostering an anti-business bias that will stifle “creativity and productivity,” ultimately forcing R&D to go abroad.”

What a joke. Merck was severely rationing access by its scientists to essential drug discovery information tools such as SciFinder, Crossfire, etc. while Hirsch was there.

All to save a few million $ a year. Talk about “stifling creativity and productivity.”