Tuesday, April 10, 2012

Yet Another Evergreening Ploy--More on Peddling Useless Drugs

I will introduce this topic with a fictional story, about a drug company, Scam Pharmaceuticals. This company managed to get FDA approval for its wonder drug, Placebo Plus, whose contents, in generic terms, consists of 100 milligrams (mg) of lactose (milk sugar). During the period of patent protection, Scam can market this drug at whatever they wish to charge without any generic competition, so they sell their drug at $5 per pill.

But all good things must come to an end, including patent protection, and a generic company now files with the FDA to market an equivalent 100-mg-lactose product. Scam immediately does what it's entitled to do under current law and regs--file a lawsuit against the generic firm claiming patent infringement. This suit may not have any chance of succeeding, but merely by filing it, Scam earns a 30-month reprieve from any generic entering the market.

Now, as the 30-month grace period winds down, Scam announces that it's discovered a superior version of its drug, now named Placebo Plus One. This new wonder drug also contains lactose, but this time it contains 99 mg, not 100 mg. Scam can easily get FDA aproval because it does not need to do any clinical trials of Placebo Plus One. All it has to do is show that in the human body, 99 mg of lactose acts just about the same as 100 mg does (bioequivalence). Placebo Plus One now has patent exclusivity for another period of time and cannot have any generic competition. Because it's new, it must be better, so Scam prices this new brand-name drug at $6 per pill.

Pharmacists are in a bind. By now, there are generic equivalents of the old Placebo Plus formulation, 100 mg lactose. And the FDA has just gotten finished saying that that formulation is virtually the same as 99 mg. But no pharmacist can substitute the generic lactose for Placebo Plus One because of the 1-mg dose difference. Officially, doing that means changing the dose of a medicine, which no pharmacist can do without a doctor's prescription.

Well, once again the clock ticks down, and Placebo Plus One is about to lose its patent protection. And indeed an eager-beaver generic firm files to provide a 99-mg pill. So again Scam files a countersuit and wins its automatic 30-month extension. At the end of this 30 months, Scam proudly announces that it has made yet another breakthrough discovery, which it calls Placebo Plus Two. And this new drug product also consists of lactose, but this time the dose is 101 mg, and it costs $7/pill. You get the drift.

Now, this must be pure fantasy, right? No drug company could be so blatant as to engage in such sleazy behavior that so obviously does nothing whatever to improve patients' health, right? And if they did, no docs would be so lemming-like as to actually prescribe all the "new" products, right?

At this point I thank faithful reader and fellow blogger Marilyn Mann who sent me a copy of a paper just out on line (subscription required) by Nicholas Downing , co-authored by our old friends Drs. Joseph Ross and Harlan Krumholz. And the story of Abbott Laboratories and its versions of the drug fenofibrate, a drug intended to lower cholesterol and triglycerides, just about exactly parallels my fictional story of Placebo Plus (though I did not check the actual prices). Abbott managed to market sequentially three versions of fenofibrate, Tricor-1, Tricor-2, and Tricor-3. The lowest-dose capsules of the three drugs respectively contained 67 mg, 54 mg, and 48 mg of the active compound. For the fourth interation, the people at Abbott were apparently bored out of their minds and wanted at least to go into the lab and clink a few test tubes together. So the latest brand-name version is called Trilipix and contains not fenofibrate, but fenofibric acid--which just happens to be the natural metabolite that the human body makes when its swallow fenofibrate.

As you would guess, the improvement in patient's health from any of the new formulations compared to the original version is nil. The cost, of course, is far otherwise. The authors state that the current annual bill for all versions of fenofibrate and its cousins is $1.4B and if instead, docs prescribed the equivalent generic forms, the savings would amount to $700M.

As you might also guess, the people footing the bill for Abbott's shenighans have not failed to notice what's going on, and several antitrust lawsuits have been filed. The cost to Abbott for settling all these suits to date has been around $300M, which, as the authors note, comes in at about 4% of total sales so far for all the fibrates.

Now, critics of my little story about Scam would say that I unfairly stacked the deck by calling my pill "Placebo Plus," since placebos supposedly do nothing for your health, while fibrates lower cholesterol and triglycerides. But the critics would be premature, which gets us back to the work of another co-author of the paper, Dr. Cynthia Jackevicius, whose work we previously encountered:http://brodyhooked.blogspot.com/2011/11/some-capsules-of-recent-pharma-related.htmlIn her previous work, Dr. Jackevicius reminded us that if we're now spending $1.4B annually for fibrate-type drugs, we're probably throwing all that money down the drain--since no research study has ever shown that actual patient outcomes like death, heart attack, stroke, etc. are improved by taking fibrates. As was said in that earlier article, the fibrates should have been added to medicine's trash heap years ago. Yet prescriptions are actualy on the rise, showing the effectiveness of Abbott's marketing campaigns.

At the end of the present article, the authors list the various policy changes and could prevent this sort of scam in the future. (Obviously the 30-month extension comes in for some attention.) But the one that mostly jumps out at me is--how about us docs following the example of the Scarecrow in the Wizard of Oz, and going out to get ourselves a brain, instead of being led around by drug reps?

Downing NS, Ross JS, Jackevicius CA, Krumholz HM. Avoidance of generic competition by Abbott Laboratories' fenofibrate franchise. Archives of Internal Medicine (e-pub April 9, 2012).

ADDENDUM 4/10: Drs. Bruce Psaty and Rita Redberg commented in Archives in an editorial on the Downing et al. paper reviewed above. Their remark on the evergreening technique employed by Abbott Laboratories is telling: "Without endorsement, we note the methodological artfulness." They cite with approval the various policy changes Downing et al. propose to prevent such skullduggery in the future, but also add that the blame for lemming-like behavior should be extended from physicians to medical guideline committees, since several practice guidelines recommended fibrate treatment for high triglycerides despite lack of evidence of change to any outcomes that matter to patients. The whole episode is yet more evidence of both physicians' and patients' fixation on surrogate endpoints like blood test numbers instead of on actual improvements in health, playing right into the hands of "artful" pharmaceutical marketing.

Psaty BM, Redberg RF. Evidence of pharmaceutical innovation and therapeutic enthusiasm [editorial]. Archives of Internal Medicine, e-pub April 9, 2012.


Judy B said...

Another bravo, Dr. Brody! (and congrats for your mention in the NY Times)

Carolyn Thomas said...

"...how about us docs following the example of the Scarecrow in the Wizard of Oz, and going out to get ourselves a brain, instead of being led around by drug reps?"

When I questioned a physician who had just spoken to 200 of us heart attack survivors at an annual cardiac rehab reunion event recently (he had just recommended to us a mega 'miracle dose' of drugs in case any of us experienced another MI), he said he could not actually remember the rationale for his recommendation - so instead, he just gave us the phone # and email info for HIS DRUG REP. Unbelievable. :-(

El Toro said...

This is very useful. I am currently doing a lot of research around the Trans-Pacific Partnership which has patent-linkage which as I'm sure you know is connected is one way that Evergreening is possible. I did have a question 1) how difficult is it for the doctor to just prescribe the generic version (i.e. after the dosage has been changed from 100 mg to 99 mg in the 2nd patent)? Also when a patent is extended through a secondary usage, wouldn't the patent just apply to the secondary usage and not to the primary one? Thank you.

El Toro said...

This is very helpful. I've been looking everywhere to understand better how a change in dosage or even discovery of secondary usage leads to an extension of the previous patent. I had a question 1) how difficult is it for the doctor to just prescribe the generic drug 2) when a pharmaceutical company extends a patent through the discovery of a second usage, wouldn't the drug just apply to the secondary usage and not to the primary usage, so that the generic could still be prescribed for that? I guess the question is around enforceability, so does that mean that the drug's primary usage is also banned? 3) if a pharmaceutical company extends a different patent by changing the appearance of the drug (i.e. changing the color of it) wouldn't that apply to just that color of the drug? (I heard that this was possible)