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Tilting at Windmills

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April 25, 2006
By: Kevin Drum

FOX, MEET HENHOUSE....Shannon Brownlee says that allowing drug companies to fund most of the clinical studies of drug safety and effectiveness is like allowing the cigarette industry to fund most of the research into cigarettes and cancer:

The recent case of drugs known as atypical antipsychotics is instructive....Earlier this year, the American Journal of Psychiatry published an analysis of 30 separate trials involving head-to-head comparisons of five drugs. Nine out of 10 times, the drug made by the company that funded the study came out on top. When Eli Lilly, the maker of Zyprexa, funded five studies of its drug, Zyprexa was found superior in all five. But when Janssen, the maker of Risperdal, ran its studies, Risperdal came out ahead.

....Meanwhile, industry-funded research is failing to provide the clinically useful answers physicians and patients need in order to pick the best treatment....If we want answers to such questions, the public is going to have to start paying for them. Earlier this year, a $44-million National Institutes of Health study found that drug makers' claims notwithstanding, not one of the five newer antipsychotic drugs offered any meaningful improvement over an older drug that cost up to 10 times less.

Shannon suggests an independent federal agency similar to the Fed or the SEC to oversee clinical research. If the medical community and the public wants genuinely neutral information about drug safety and efficacy instead of the heavily subsidized marketing literature that's what we effectively get now, I suspect she's right.

Kevin Drum 12:10 PM Permalink | Trackbacks | Comments (90)

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Comments

C'mon, where' your faith? We can trust these companies to police themselves.

Posted by: Ringo on April 25, 2006 at 12:16 PM | PERMALINK

And who is surprised by this? After all, this is the same crew that regularly appoints former industry insiders to agencies charged with regulating and overseeing those same industries...your title for this thread could be the slogan for this whole administration...

Posted by: An Interested Party on April 25, 2006 at 12:17 PM | PERMALINK

Actually one of the most important issues in this area is outsourcing of clinical trials, which seems to be the new frontier of globalization. In addition to economics, the ethics of using unsuspecting third world populations for testing new drugs has not been adequately thought out.

Posted by: lib on April 25, 2006 at 12:18 PM | PERMALINK

But if we don't let them control evaluation of their own drugs we won't have the best medical care in the world because they need all their profits for R&D...

Wait, that didn't sound right. Some wingnut help me out here- I'm trying to trot out the tired, old argument that if drug companies weren't allowed to monopolize their sphere of healthcare and make obscene profits we'd all die because they couldn't make their miracle drugs. Parody is dead- someone do it for me.

Posted by: The Tim on April 25, 2006 at 12:22 PM | PERMALINK

How much of pharmaceutical profits are actually re-invested into R&D anyway? I always get the feeling that they're not being completely honest with us--at least their apologists and lobbyists aren't.

Posted by: Ringo on April 25, 2006 at 12:26 PM | PERMALINK

The real strategy of the drug companies is to get everybody on some form of Prozac, so we won't give a shit how bad they screw us.

Posted by: trueblue on April 25, 2006 at 12:26 PM | PERMALINK

What makes you think that publicly funded research will come up with more "neutral" answers? Does anyone really believe that a government-commissioned study under a Democratic administration won't favor a French drug company like Roussel-Uclaf, or advise taking ketchup supplements made by Heinz?

You guys can't be that naive. No, it's better to let the free market decide this one.

Posted by: shortstop brosz on April 25, 2006 at 12:27 PM | PERMALINK

The Tim:

Drug companies spend an average of $800 million per drug to clear each one for sale already. They don't get the money back if the drug fails. Their profits are in the same range as banking and many other industries. If you want more detailed information, do some research instead of absorbing your ideas through osmosis.

Come on, why not just get it all out of your systems at once and nationalize the drug companies? You know you want to. Schumer is already lusting for the oil companies.

Posted by: tbrosz on April 25, 2006 at 12:29 PM | PERMALINK

More hatred of companies. As if they don't want the best for everyone! As tbroz so eloquently and persuasively points out, you are all commies!

Posted by: Freedom Phukher on April 25, 2006 at 12:31 PM | PERMALINK

Take the $ to fund the oversight from the companies involved. They would have supposedly spent it on the same types of evaluation anyway. Probably would be cheaper for all concerned and no doubt better for the public.

Posted by: Michael7843853 G-O in 08! on April 25, 2006 at 12:32 PM | PERMALINK

I thought it was Reagan who promoted ketchup as health food?
After all this time, we find out that he was actually part of the evil Heinz-Kerry cabal.

Posted by: Ringo on April 25, 2006 at 12:32 PM | PERMALINK

Ha! My post was even broszier than brosz. But only slightly!

Ringo, try to keep up, hon. Ketchup was groooovy until John married Teresa. Then it became a socialist menace.

Posted by: shortstop on April 25, 2006 at 12:33 PM | PERMALINK

P.S. I love Freedom Phukher's posts.

Posted by: shortstop on April 25, 2006 at 12:35 PM | PERMALINK

A freind of mine told me about a university job talk (potential professors give a seminar to the department as part of the interview process) about environmental safety research. The way it works is that the EPA requires a company to study some impact of what they are doing. The company goes out and hires somebody to do the study. Typically they actually hire several groups to do the same study. It is quite common for the results to disagree somewhat, and the company will rehire groups who get the results they want for future studies.

I suppose I can leave the results of this system to your imaginations.

Posted by: jefff on April 25, 2006 at 12:36 PM | PERMALINK

The US has reentered the era of trust capitalism.

Posted by: Hostile on April 25, 2006 at 12:37 PM | PERMALINK

Add jefff to the list of communists.

When will you people ever get it? The invisible hand takes care of everything. All praise to the invisible hand.

Posted by: tbrosz on April 25, 2006 at 12:39 PM | PERMALINK

this is the same thing that happens with other biotech industries, such as corporations like monsanto that produce genetically modified seeds and synthetic chemical pesticides. most of the funding available -- even in public universities like the university of california, berkeley -- comes from biotech companies, thus directing research interests towards favorable studies of their products. alternative farming practices (organic and others) are funded far less often.

Posted by: dan on April 25, 2006 at 12:41 PM | PERMALINK

Kevin, "If the medical community and the public wants genuinely neutral information about drug safety and efficacy instead of the heavily subsidized marketing literature that's what we effectively get now,

that's what we = that we


Posted by: gramma grammar on April 25, 2006 at 12:44 PM | PERMALINK

These are the good times, spring will soon be here.
Paint the bedroom orange, buy a chandelier
Dance the polka, pour ketchup in your beer.


Ketchup...for the good times.

Posted by: Matt on April 25, 2006 at 12:46 PM | PERMALINK

They are saving the government lots of money that would otherwise increase the national debt -- and the free market has shown it is the most efficient way to get drugs to market.

Really it is no different than the process by which chemical companies demonstrate that pesticides and herbicides are safe for farmworkers and wildlife. I know several industry chemists and they are honest folks who would not design tests to have ambiguous or misleading results. Sometimes it's just hard to design an experimental control that doesn't kill frogs at a rate faster than the expected action of the chemical being tested.

Posted by: Al on April 25, 2006 at 12:52 PM | PERMALINK

I've got a question: There are drug companies in other countries besides the U.S.

How is this kind of testing done in Europe and other places, and how well does it work?

Posted by: tbrosz on April 25, 2006 at 12:55 PM | PERMALINK

Fuck you you stupid fucking fuckers.

Posted by: Atriot Drone on April 25, 2006 at 12:56 PM | PERMALINK

The NIH study has been exaggerated. There is a Part II showing that some of the new drugs are in fact better, and it underplayed the advantages the newer drugs had in terms of fewer side effects as opposed to their similar primary effects.

Also, companies often find their own drugs better because they find situations where their drugs do in fact work better in order to publicize those situations. It does not mean a priori that the system is corrupt and meaningless.

Posted by: reino on April 25, 2006 at 1:02 PM | PERMALINK

I'm not defending this, but psychotropics are a particuarly difficult case in the overall story - we're talking about measuring improvements in schizophrenics, manic depressives, etc. Yes, some things are quantifiable, but some study elements are (at least from what I saw when I worked on Risperdal) quite subjective (feel better/feel relief/feel "normal").

Yes, the drug companies are looking for studies that make their drug look good, and yes, they set up research that proves a particular point. But there's more drug research going on than just their own, and the point is, even when they try to control for outcomes, they can be unpleasantly surprised ("oops, more people died on our drug than others"). Worse, they can come up with .0001 type results that prove that... they're about as good as the other guy's product.

Again, I'm not defending any of this. I've had to try and dress up studies to make things look better than they were, and it's not pretty; but it's also the case that much of the research around launching a drug is done rigorously (again, within the parameter of wanting to look good) and in areas where they're the only product (e.g., it's the "me too" quality of Vioxx that's the problem, not just the research).

Many times pharma companies pull a drug rather than release bad results, or simply kill the study. The point is the problem's bigger than the drug companies - it's our whole "let's find a pill to fix it" mentality that insists on new compounds as quickly as possible marketed as widely as possible. That's harder to face up to, I think, than making the pharmas the bad guys in this, too.

weboy (who spent several years in Medical Education - pharma education programs for docs and other health professionals)

Posted by: weboy on April 25, 2006 at 1:04 PM | PERMALINK

As a professional in the clinical trial industry, I can tell you that a lot of the problem with clinical trials in the U.S. can be laid at the FDA's door -- because the agency does not require that new drugs be tested head-to-head against existing drugs. They require that they be tested against placebo. What a waste of time and money, of course "something" is going to be better than "nothing". But don't expect Big Pharma to protest this requirement, it's probably significantly cheaper for them to manufacture placebo than pay for the rights to use another company's drug.

Posted by: Constance Reader on April 25, 2006 at 1:05 PM | PERMALINK

As a professional in the clinical trial industry, I can tell you that a lot of the problem with clinical trials in the U.S. can be laid at the FDA's door -- because the agency does not require that new drugs be tested head-to-head against existing drugs. They require that they be tested against placebo. What a waste of time and money, of course "something" is going to be better than "nothing". But don't expect Big Pharma to protest this requirement, it's probably significantly cheaper for them to manufacture placebo than pay for the rights to use another company's drug.

Posted by: Constance Reader on April 25, 2006 at 1:06 PM | PERMALINK

Well, I'm going to get some flak for this, but I'm afraid both the LA Times article and this post are very seriously off-base, both in their conclusions and in their recommendations. The Times writer evidently doesn't understand what clinical trials produce, or how pharmaceutical marketing is regulated, or how the economics of drug development add up, or what would be the consequences of some new FDA that would somehow be better than the FDA.

For one thing, clinical trials are not races. They do not make one drug "come out ahead" in any but the narrowest technical ways, and the limitations on those conclusions, because of their technical precision, are evident to everyone who reads the results, including MDs reading drug labels.

For another thing, the claims that drug companies may make in their advertising and sales are extremely closely regulated -- down to the precise language that can be used -- and those regulations in turn require that the claims be substantiated by scientifically validated clinical trials.

Now it's true that pictures of happy children running through green fields are not subject to scientific validation. And it's also true that big pharmacos spend an awful lot of money on advertising: more than on clinical trials, in fact, when it comes to "blockbuster" drugs. But it's also true that anybody who makes prescription medication decisions based on pictures of smiling children is asking for trouble. It would be better if the pharmacos weren't wedded to the "blockbuster" model -- which incidentally is causing them a lot of trouble as well -- but that's not going to change because of any new regulatory structure.

Also, to claim that the FDA is has been "flunking" is simply ignorant of the facts. The rigor with which they scrutinize and regulate drug development is little short of breathtaking. New drugs frequently take over a decade, and hundreds of millions of dollars, to get to market, because of the breadth and degree of regulation. This is not to say that it shouldn't be that way, but it IS to say that the FDA certainly is NOT asleep on the job.

The only example the author provides is Vioxx, and not only was it the FDA that forced Vioxx (and Bextra) off the market, but as recent lawsuits seem to be making clear, the data took years to emerge, and Merck then withheld them in violation of their legal and moral obligations. It's nice to fantasize about some all-seeing, incorruptible policeman discovering every last little fact about the biological effects of new molecules, even those that have been studied for years, but it's only a fantasy; it's neither scientifically nor economically practical

Also, to suggest that the cure is some new "genuinely neutral" super-FDA -- when the author in the same article condemns the FDA as ineffective, and when many opponents claim it's overly influenced by industry -- is politically similarly impractical. Any regulatory industry must guard against "capture," and the FDA has done extremely well in that regard, as evidenced by the depth and rigor of their examination and regulation. And to suggest that the cost of clinical trials, which runs in the tens to hundreds of billions of dollars per year, should be subsidized by taxpayers, is to suggest a gargantuan subsidy to the industry. Taxpayers pay for the trials, the vast majority of which fail (thanks in no small part to the FDA), and then pharmacos reap the rewards from the few that succeed. Imagine the outcry against THAT kind of corporate welfare!

Sorry for the extended rant. I think I agree with the general concerns and outlook of the Times writer. But severely misinformed criticisms and poorly-thought-out recommendations are no way to engage in a policy debate.

Posted by: bleh on April 25, 2006 at 1:07 PM | PERMALINK

'The Tim', I'd help you out here, but I'm too jaded from working in the medical device industry. The problem is that the vast majority of are products are "me too" products that are no better or worse than what's already out there. We need to do out own studies to show that our product is somehow better than the others, which it isn't. But because everyone has a slightly different product, everyone can find a small segment of society that responds to their product better than the others. So we do a study on that segment and publish the results without mentioning the fact that our products is worse than others in other segments of the population. My solution would be to have scheduled tests evry two years for entire classes of products. Instead of having many studies that compare products one on one, we would have one mega study comparing all products at once, with identical data sampling and statistical methods. The medical companies won't like this, but maybe we could toss them a few bones. For instance, we could agree to publish the brand names of only the products that met approval and allow the rest of the products to be included in the results anonymously. This lets companies avoid negative publicity, while allowing approved companies to recrunch the full data to highlight the advantages of teir products. We could also change the approval proccess so that there isn't a set and arbitrary standard to pass and simply approve whatever products are best. This might sound strange, but it would help. The problem is that some FDA regulations are set so high that nobody can actually pass them, so we get the product approved for for another indication and then encourage doctors to use the product as an "off label usage." A great many products are used almost exclusively for indications that are not approved. I won't give you details about that here because it would cause unwarrented anxiety.

Posted by: tom on April 25, 2006 at 1:07 PM | PERMALINK

A great many products are used almost exclusively for indications that are not approved. I won't give you details about that here because it would cause unwarrented anxiety.

I don't know about y'all, but my anxiety is greater not having the rest of the dish on this.

Posted by: shortstop on April 25, 2006 at 1:13 PM | PERMALINK

Wow...I come back and several posters have come up with something that's actually more informative than the whole rest of the thread combined, including my posts. Thanks!

Posted by: tbrosz on April 25, 2006 at 1:24 PM | PERMALINK

They'll just stack the agency with cronies and lobbyists, and they'll be just as ineffective as today's SEC, FCC, FTC, etc.

Posted by: Osama_Been_Forgotten on April 25, 2006 at 1:31 PM | PERMALINK

does this mean we'll have to give up our free lunches and cool pens?

Posted by: Ross on April 25, 2006 at 1:33 PM | PERMALINK

does this mean we'll have to give up our free lunches and cool pens?

The employees of the Clinical Trials Office in the local Medical School have already been deprived of the Tuesday lunches given by the Pharmas. It was a great deal.

Posted by: lib on April 25, 2006 at 1:40 PM | PERMALINK

"Shannon suggests an independent federal agency similar to the Fed or the SEC to oversee clinical research."

Countered by....

"Also, to claim that the FDA is has been "flunking" is simply ignorant of the facts. The rigor with which they scrutinize and regulate drug development is little short of breathtaking. New drugs frequently take over a decade, and hundreds of millions of dollars, to get to market, because of the breadth and degree of regulation. This is not to say that it shouldn't be that way, but it IS to say that the FDA certainly is NOT asleep on the job."

Kevin, there's a few of us who work in the industry. Take a few moments to chat with us to learn about the pharma industry and the FDA. Amazingly enough, call up the Amgen, their in SoCal, ask to chat it up with their Representative and have him explain the whole process to you. Who knows, you may even get invited for a tour, and long chats over hot food.

Posted by: sheerahkahn on April 25, 2006 at 1:47 PM | PERMALINK

For another thing, the claims that drug companies may make in their advertising and sales are extremely closely regulated -- down to the precise language that can be used -- and those regulations in turn require that the claims be substantiated by scientifically validated clinical trials.

Yours was a great post, thanks. But this bit sets me off (and is, I grant, off topic).

It may be true that the advertising wording is regulated, bla bla, but the real problem here is that there is advertising at all. Creating demand by goosing people's natural hypochondria is irresponsible at best, and probably much worse than that.

Phew, now I feel better.

Posted by: craigie on April 25, 2006 at 1:50 PM | PERMALINK

This is actually one of the critical junctures where free market and libertarian economics breaks down.

One of the assumptions underpinning the free market is that consumers have perfect knowledge and will always make the best decisions based on that knowledge. As this latest drug study proves, we never really have perfect knowledge.

Remember, between 1957 and 1961 the German company Grunenthal, the manufacturer of Thalidomide, told women their drug was safe to take to relieve the symptoms of morning sickness. They didn't test the drug adequately on pregnant animals. The results were tragic.

If we can help people avoid unnecessary suffering by using public funds for more objective, third-party testing we have a moral obligation to do so.

Posted by: pj_in_jesusland on April 25, 2006 at 1:52 PM | PERMALINK

Drug companies spend an average of $800 million per drug to clear each one for sale already. They don't get the money back if the drug fails. Their profits are in the same range as banking and many other industries. If you want more detailed information, do some research instead of absorbing your ideas through osmosis.

Why are they wasitng their money on biased "studies" ?

Those poor drug companies, just barely scrapping by...

Posted by: Stephen on April 25, 2006 at 1:56 PM | PERMALINK

Shannon suggests an independent federal agency similar to the Fed or the SEC to oversee clinical research.

In addition to universities and the FDA? that makes no sense.

Posted by: republicrat on April 25, 2006 at 1:56 PM | PERMALINK

One of the assumptions underpinning the free market is that consumers have perfect knowledge and will always make the best decisions based on that knowledge.

Unfortunately, too often the countering argument boils down to that the government, or whoever you assign to make these decisions for the customer, does have perfect knowledge. One way or the other, people and their doctors will still have to be able to make judgments.

Posted by: tbrosz on April 25, 2006 at 1:59 PM | PERMALINK

It may be true that the advertising wording is regulated, bla bla, but the real problem here is that there is advertising at all. Creating demand by goosing people's natural hypochondria is irresponsible at best, and probably much worse than that.

Something definitely changed over the past ten years or so, allowing drug companies to advertise so much on television. It definitely hasn't been for the better, for several reasons.

Posted by: Ringo on April 25, 2006 at 2:02 PM | PERMALINK

One way or the other, people and their doctors will still have to be able to make judgments.

Nice, but I think that misses the point. You make judgements based on information. And if there is only one source of info, and that source is biased, then you invade Iraq... I mean, then you take drugs you don't need or that are actually dangerous.

Posted by: craigie on April 25, 2006 at 2:02 PM | PERMALINK

Let Sully try 'em, he likes everything.

Posted by: Mandrew Mullivan on April 25, 2006 at 2:04 PM | PERMALINK

Unfortunately, too often the countering argument boils down to that

not from anyone here--but thanks for more of your hackery, Mr. Strawman.

Posted by: haha on April 25, 2006 at 2:04 PM | PERMALINK

pj_in_jesusland: Remember, between 1957 and 1961 the German company Grunenthal, the manufacturer of Thalidomide, told women their drug was safe to take to relieve the symptoms of morning sickness. They didn't test the drug adequately on pregnant animals. The results were tragic.

Thalidomide was tested extensively on numerous species of non-human animals. In some species it caused no problems. In other species it caused birth defects. Which results were applicable to humans?

Would you want your child to be the first human being to take a drug that had only been tested on animals?

Posted by: SecularAnimist on April 25, 2006 at 2:21 PM | PERMALINK

Hmm, still waiting for that story on network neutrality by Reed Hunt. Did you contact him, Kevin?

Posted by: Gray on April 25, 2006 at 2:24 PM | PERMALINK

haha:

Try reading the original article again, and what was proposed to solve this perceived problem. Unless your lips are already tired.

Posted by: tbrosz on April 25, 2006 at 2:25 PM | PERMALINK

The real strategy of the drug companies is to get everybody on some form of Prozac, so we won't give a shit how bad they screw us.
Posted by: trueblue on April 25, 2006 at 12:26 PM | PERMALINK

How true.

My wife's doctor tried to put her on zoloft, to quell her anxiety over her cronic back pain, because the insurance company wouldn't pay to diagnose her properly to get any kind of real resolution to the problem (simple herniated disk).

Fucking HMO pukes will fucking burn in hell.

Posted by: Osama_Been_Forgotten on April 25, 2006 at 2:26 PM | PERMALINK

Kevin,

Are you really suggesting corporate welfare for drug companies?

Posted by: Yancey Ward on April 25, 2006 at 2:29 PM | PERMALINK

haha-

Don't mess with me. I have impeccable knowledge of these and all other things.

Posted by: tbrosz on April 25, 2006 at 2:34 PM | PERMALINK

I don't really need impeccable knowledge. As the old joke goes, "I don't have to outrun the bear. I just have to outrun you."

Posted by: tbrosz on April 25, 2006 at 2:37 PM | PERMALINK

RE: I don't know about y'all, but my anxiety is greater not having the rest of the dish on this.


Scared ya, didn't I? When we use products off label, we are not using unsafe products from what I have seen. I'd like to say "Trust Us", but that won't help. The problem comes from backlash. It all starts with a lawsuit that may or may not be valid. But with our legal system, verdicts are determined not by the validity of the claims, but by the eloquence of the attorneys. But when a drug or device loses a lawsuit, the entire class of products gets scrutinized. The public claims the FDA is incompetent and demands better regulation. So the FDA overcompensates and passes new regulations that are meant to calm the public, not ensure safety. We in the medical industry are now faced with an unneeded regulation that we cannot afford to pass. But we still have a good product that would easily have passed the old regulations. So, we look at the finances. When we see that the FDA is requiring a 10 year study that costs us $25 million for a product that gives us $1 million in annual profits, we balk at the study. We know that it would be better for us to not sell the product at all than to get it approved. So, we look for a back door and can often find one. If you are worried about this, ask your doctor if the products you are using are approved for the specific indication, or is being used off-label. He will tell you, I'm sure. And he will tell you why he thinks it's safe to use off-label if that is the case. When we encourage off-label use, we do provide the data to back it up to doctors. They may have to go to a foriegn website to get that information, but it's there. But the FDA won't let us openly publish the data to support our claims unless we do the full study. An easy to understand anaolgy would be this. If the FDA ran the Olympics, they would not give out gold. silver and bronze medals. They would give out a generic medal to anyone who could run 100 meters in 9.85 seconds. Imagine if everyone complained that the runners weren't good enough with this standard. Then the FDA might change the time to 9.75 seconds to get the runners to run faster. But 9.75 seconds is faster than the world record, so now nobody would get a medal. Are these runers now bad runners? Of course not. And what would the runners do? They would train harder for the 400 meter race, because they can get a medal in that one. This is why I like the idea of turning the approval process into a contest with rankings. It encourages companies to produce the best product they can, without making us play games to avoid an arbitrary standard. It also gives the public a more realistic way to judge products. We can all understand that a silver medalist is a damn good athlete. We should be able to understand that a silver medal product is still pretty damn good. And, in fact there is good evidence that the public understands this. People still buy Mercedes when BMW is a better car. But the Mercedes is still a damn nice car. And I say that as a Mercedes owner.

Posted by: tom on April 25, 2006 at 2:39 PM | PERMALINK

OT: President George W. Bush unveiled on Tuesday a raft of proposals and government moves to counter near record-high crude oil and gasoline prices, including giving oil companies more time to repay emergency oil loans and easing clean-burning gasoline rules to boost supply.

Bush's take on the high price of gas?

Big Oil isn't making enough money; that's why gas prices are so high.

Shameful behavior for a president that claims to be "compassionate".

Clearly he doesn't know what "compassionate" means.

Or doesn't care.

Posted by: Advocate for God on April 25, 2006 at 2:42 PM | PERMALINK
Shameful behavior for a president that claims to be "compassionate".

He has great compassion for the struggling oil company executives.

Posted by: cmdicely on April 25, 2006 at 2:56 PM | PERMALINK

Typical liberal whiners. They think that they and the government know more than private industry.

I can tell you this: I've been smoking pole for years and haven't had a hint of any side-effects like emphysema or cancer.

Posted by: Al on April 25, 2006 at 2:59 PM | PERMALINK

an independent federal agency similar to the Fed or the SEC to oversee clinical research.

As someone who works daily with clinical development organizations, this myth that the FDA is in the pocket of pharma is simply without any credibility. The physicians, scientists, nurses and other professionals I work with live in constant fear of crossing any FDA regulation, because such a mistake could result in tens of millions of dollars in a wasted study and years delay to get a drug to market when the FDA requests the re-running of a study. The FDA regulations on clinical trials ensure participant safety and excellent data collection and management. So please, please dispense with this simple talking point that the FDA has no real control over pharma. It insults the intelligence of anyone who really knows anything about the industry.

Can you argue that pharma companies, within the boundaries of good science, ask questions that are more likely to produce results that show their product can work either by choosing the populations of subjects or by avoiding head to head competition? Of course they do. They want their lifes work to be successful just like anyone else.

But, it you want that to change, all it will take is a regulation from the FDA saying head-to-head studies are required in the future. Why have they not done this? The primary reason is that it would not benefit the public. Why?

Lets say I have a drug (drug Y) that treats a problem already treated by drug X. If I did head-to-head studies, I would find that drug Y helps patients but not as well as drug X. Should drug Y be unavailable to patients? Of course not. Just because the majority of patients benefit more from X, what about the minority that benefit more from Y? Just because something works better in a small sub-population does not make it worthless. For example, it is not uncommon for a severely depressed person to need to try 2 or 3 different potential products before they find the one that works for them. Without these additional me-too drugs, they would not have the option.

Since the drug research is funded by the companies, it is in societys best interest to have the companies pay their own money to research the alternatives and have as many options as possible available for treatment. You never know which one will work best for a particular patient.

Posted by: Gazan on April 25, 2006 at 3:04 PM | PERMALINK

Constant Reader

It is really inacurate to say the FDA does not do it's job in terms of clinical trials for market approval of a new agent relative to other agents..

There are several types of trials that the FDA demands. there are efficacy trials. Which need to have as the control group a placebo in order to demonstate the efficacy of the drug.

Then there are safety trials, which are needed to demonstrate safety relative to a placebo.

To say that these basic trials need to be compared to other agents would mean that you are not assessing the safety and efficacy of the drug prior to marketing it.

These types of trials are the primary regulator role of the FDA. Based on the outcome of these trials the FDA advisory panel recommends to approve or not the mktg of the agent. It is this panel which now causes significant biases that we see in the industry. This panel use to be funded 90% by the government, today it is 90$ industry funded which creates the fox in the henhouse effect in terms of market approval vs. post approval comparison studies which the article talks about.

The type of trial, safety/efficacy/comparative also impacts the size of the trial which is needed in terms of the statistical power to evaluate the parameters of safety and efficacy.

Most comparative trials are POST-MARKETING studies which are done to expand indications of a agent on the market and compare efficacy against existing agents on the market.

All of these type clinical trials are essential for consumer safety. All of the trials are conducted at the costs of the mfgrs.

What needs to happen if the public does not trust the data from mfgrs, is that there needs to be funding provided by each mfgr, prior to mktg approval for the government to conduct post-marketing comparative trials with existing agents. Such that comparative trial funding is part of the financial costs the mfgr bears to bring an new agent to market.

That way the government does the trial and is in control of comparative data with existing marketed pdcts in any therapeutic class. Some of the comparative data is done when new indications are sought for a product.

As another poster already mentioned, this particular therapeutic group of products, psychotherapeutic agents. is very subjective along with osteoarthritis agents, where there are no real objective measures of efficacy, but where subjective parameters of how the patient feels are relied on much moreso to determine efficacy. None of these agents have been demonstrated to be disease modifying agents, they simply treat the symptoms.

Which is why the risks can be significant when evaluating the product...basically all the SSRI's cause libido problems (which should compound depression) and they do not intervene in the anxiety/depressive states...it is simply a bandaid. Yet they are approved to treat depression and anxiety based on how the patient felt.

The same is true for OA drugs...primarily they alleviate pain, without altering the underlying course of the disease.

So when you rely on subjective symptomatic assessments as the primary evaluative tool, you get products which are NOT going to show significant advantages over one another..you need quantative, clinical tests with objective measures to demonstrate any type of significant efficacy or safety of one agent vs. another.

One thing to keep in perspective is that the pharmaceutical industry funds 90% of the medical in this country when it comes to drug therapy, just like the auto industry funds most of the research in the car industry.

The difference though is that GM (until this year) made more revenues and profits than the ENTIRE pharmaceutical industry combined. It still brings in more than 90% of their revenues with their bankruptcy claims.

Posted by: elrapierwit on April 25, 2006 at 3:09 PM | PERMALINK

See now we should look at Tbroz and Al They used to have good jobs in the Clinton years and now that there line of work has been outsourced they picked there selves up and got nice little low paying jobs at the Heritage Center trolling blogs.Fine youg men they are.

Posted by: Booo on April 25, 2006 at 3:11 PM | PERMALINK

I'm an academic physician who does both clinical and basic research. Shannon Brownless is clueless, and Kevin does a real disservice not digging into this further (I like the idea of having Amgen take Kev on a tour).

The FDA is one of the more effective regulatory agencies for what it was designed to do: ensure that drugs are safe and effective. We have not had the many problems seen overseas with unsafe drugs, and the drugs we have are generally effective. As noted by others above, the research world does NOT want to cross the FDA.

As to industry-supported trials, I see this in my specialty all the time. Drug A made by company A is always better than drug B made by company B when company A funds the trial, and vice versa. As a reader of medical journals, it's easy to figure this out: each journal requires disclosure of funding sources in each article. When I see a drug company funded trial published in a journal, my radar is switched on. There's no surprise here, and I'll bet most every physician and biomedical investigator understands this.

As to getting answers as to which drug is best, NIH is already doing trials like this, and they understand that they need to do more (disclosure: I'm involved with one of these).

Finally, there is absolutely nothing wrong with a 'me-too' or 'copycat' drug. The second, third or fourth drug in a class that comes to market frequently has properties that make it useful. An example is the class of "H2-blocker" antiacids. The first one was Tagamet -- revolutionary drug for the treatment of peptic ulcers when it came out in the late 1970s. But you had to take it four times a day, it had all sorts of interactions with other drugs, etc. By the time the fourth drug came to market, it was a once-a-day drug that had way fewer side effects and problems, and it helped hammer down the pricing. So 'copycat' drugs can be very useful.

Both Kevin and Shannon would benefit from a round-table discussion with people commenting here who work one way or another in the biomedical industry.

Posted by: Steve White on April 25, 2006 at 3:36 PM | PERMALINK

Dude-

The invisible hand just rolled a joint. Anybody want to toke it up?

Posted by: tbrosz marley on April 25, 2006 at 3:56 PM | PERMALINK

craigie,

I'm with you! I don't understand why the hell GM spends good money advertising its cars either driving a false demand for new cars.

Posted by: angrylittledude on April 25, 2006 at 4:08 PM | PERMALINK

Thank you Steve White.
In my experience (not in the pharm or research biz but a survivor of multiple cancers) the FDA does it's job well. The real issue is when a particular mfgr is lining the pockets of an entire med assoc. A good example would be the makers of the thyroid replacement Synthroid, spending bzillions to support the American Endocrinology Assoc and fund studies that amazingly show Synthroid to be more effective than other synthetic or natural extracts.

The FDA has been on Synthroid's ass for years, yet the AEA continues to reccommend it and it has 85% market share when it's efficacy and potency is demonstrably no better than it's synthetic rivals, and both are worse than the natural extracts.

Posted by: smott on April 25, 2006 at 4:20 PM | PERMALINK

I ran into the same crap with the Tamoxifen Mafia. And the Leukine Mafia.

Yes, I have had both breast and thyroid cancer.

Posted by: smott on April 25, 2006 at 4:21 PM | PERMALINK

Steve White has a good post here. I may have implied that "me too" products are all the same, and that really isn't the case. He does a good job explaing why we need "me too" products. He also notes that doctors are well informed about the studies, so please ask them if you have any concerns. The system certainly has its problems, but it is not helpful to bash either the FDA or the industry it regulates. Sure, we want to make money, but we really are concerned about health.

Posted by: tom on April 25, 2006 at 4:37 PM | PERMALINK

I have to say, I haven't seen a thread this informative or interesting in a long time. This is what these blog thingies are all about!

Posted by: craigie on April 25, 2006 at 4:46 PM | PERMALINK

great many products are used almost exclusively for indications that are not approved. I won't give you details about that here because it would cause unwarrented anxiety.

unwarranted anxiety?! Too late! Where's my Xanax?!

Posted by: kgb on April 25, 2006 at 4:51 PM | PERMALINK

Not the problem because the research is reviewed. Remember a few years back all the complaints about the FDA being too slow to approve new drugs? This is the result I predicted. We will see more problems with new drugs because they are being approved faster. Some problems take time to show up.

Recall that Thalidimide was a huge problem in Britain, but not a problem in the US. The reason was that the slowness of FDA approval meant that thalidimide was never approved and the birth defects had come to light. Fast track means that needed new drugs will be on the market faster. Fast track also means that there will be more errors.

Posted by: bakho on April 25, 2006 at 5:03 PM | PERMALINK

The market driven research and sales model means we pay less up front (for reasearch) and more on the back end (at the pharmacy). The downsides to this are twofold: first, the cost for medicinal research is no longer progressively structured; second, the avenues and types of research pursued are those of most value to the drug companies, not the citizenry.

Posted by: Mavis Beacon on April 25, 2006 at 6:09 PM | PERMALINK

Mavis:

The market driven research and sales model means we pay less up front (for research) and more on the back end (at the pharmacy). The downsides to this are twofold: first, the cost for medicinal research is no longer progressively structured; second, the avenues and types of research pursued are those of most value to the drug companies, not the citizenry.

Addressing your second point: The problem with changing this is that you have to come up with someone else who gets to decide what research is the most valuable to the citizen. How would that be done? And who would do it? Politics is no better driver for science than profit is.

***

Boooo:

See now we should look at Tbroz and Al They used to have good jobs in the Clinton years and now that there line of work has been outsourced they picked there selves up and got nice little low paying jobs at the Heritage Center trolling blogs.Fine youg men they are.

Just think, if you could write you might pick up a cushy job like that!

Posted by: tbrosz on April 25, 2006 at 6:29 PM | PERMALINK

Since there are some actually knowledgable people around this thread, anybody with a relevant background want to comment on how appropriate off-label usage standards evolve and if you see the lack of full testing necessary to get it approved for that application having a noticable impact on efficacy or safety? It would be interesting to see how much clinical efficacy varies for on-label vs off-label usages.

And if we have any clinicians hanging around - what kinds of studies beyond the basic safety and efficacy vs placebo would be most useful for getting patients the optimal medications? Would resource be better spent teasing out what factors makes individuals react better or worse to a given drug or doing head to head comparisons of the drugs to determine which produces the best results in the general population of patients?

Posted by: MattXIV on April 25, 2006 at 6:35 PM | PERMALINK

On off-label usage:

IMO, the FDA should largely stick to safety issues, and leave effectiveness issues for off-label usage to the users. If the drug company is up-front about the lack of complete information on effectiveness, why shouldn't the choice of whether or not to use it be left to the user?

Again, this pertains to effectiveness issues, not safety ones.

Posted by: tbrosz on April 25, 2006 at 6:38 PM | PERMALINK
IMO, the FDA should largely stick to safety issues, and leave effectiveness issues for off-label usage to the users.

Safety, effectiveness, and indications aren't exactly separate concerns.

A drug may be suitable "safe" (and effective, too) to use to treat a condition which is otherwise swiftly, painfully, and certainly fatal if it is 95% percent effective in eliminating the condition it treats but kills the user with its own effects 50% of the time, without being "safe" in the context of any other set of indications.

And its seems to me hard to imagine that there could be sufficient research to establish safety in a particular use without also establishing effectiveness, unless a drug was so demonstrably generically safe as to be unlikely to require a prescription in the first place.

Posted by: cmdicely on April 25, 2006 at 6:48 PM | PERMALINK

Re off-label usage, the FDA approves a drug as (1) safe and (2) efficacious for one or more particular indication(s). Thereafter, a physician is free to use the drug as s/he sees fit, as part of a course of treatment of a patient, whether or not a labeled indication is present, or is thought likely to be present, in that patient.

My understanding of at least some of the reasoning behind this is: (1) the physician is in a much better position to recommend what is appropriate for a particular patient than is a regulatory agency making general rules, and (2) even if the agency's judgment were somehow superior, there would be no way to enforce it other than to review every diagnosis and every prescription for every patient from every doctor, something that is obviously impractical.

In my opinion, this is by far the best arrangement of authority. It's the same reason we (mostly) have judges instead of statutory sentences: the closer the decision-maker is to the particular situation, the better s/he is able to tailor the decision correctly.

The down-side is, of course, that this discretion can be abused. Local bureaucrats and traffic cops can be corrupt, and doctors can prescribe impotence medication to men who are not impotent.

But tighter control is no answer. There IS tighter control on up-scheduled drugs, notably opioid painkillers, such that an entirely separate agency (the DEA) is notified of all prescriptions and can actually arrange for a doctor's prescribing license to be revoked. The resulting under-treatment of pain in this country, and the heavy politicization of the supervisory process, are widely known and as widely deplored.

Ultimately, judgment rests in the patient-doctor relationship. Doctors have a professional and ethical responsibility to prescribe appropriately, and patients have the responsibility to themselves (if no one else) to understand what they're taking and why. No regulatory process is likely to function any better than that, IMO.

Posted by: bleh on April 25, 2006 at 6:59 PM | PERMALINK

bleh:

I wasn't aware that physicians had that kind of latitude. That's an acceptable setup in my opinion.

Posted by: tbrosz on April 25, 2006 at 7:02 PM | PERMALINK

Well, thank dog that tbrosz is satisfied. We can all rest easy.

Posted by: craigie on April 25, 2006 at 7:08 PM | PERMALINK

Just going down the line of comments, is it possible that people are trying to "fix" something that actually works pretty well already?

Posted by: tbrosz on April 25, 2006 at 7:08 PM | PERMALINK
Just going down the line of comments, is it possible that people are trying to "fix" something that actually works pretty well already?

Its a near certainty that that is occurring somewhere in the world, on some topic.

If you have an argument to make that is occurring in a particular place on a particular topic, you could, of course, actually make the argument.

Posted by: cmdicely on April 25, 2006 at 7:19 PM | PERMALINK

cmdicely: Logically you're correct, but the practice is considerably more complex.

Safety is in fact assessed as "generically" as possible at first, before efficacy is tested, or efficacious doses are determined. This is true both in animal testing and in human testing. Drugs are first tested in animals to determine the safety-related effects at various doses, up to and including lethal doses. (Pretty much anything is lethal, at a high enough dose.) A drug that is considered unsafe at doses around what is (at that point, based on theory) thought to be an efficacious dose, is generally abandoned.

Experiments are also carried out at a smaller scale, on tissue samples and in chemistry labs, to assess other potential safety-related effects such as local toxicity and drug interactions.

Only once investigators are satisfied that the drug is "safe" (again, at doses believed on the basis of theory to be at least those required for efficacy) is it tested for efficacy. And only if it is found to be efficacious at safe levels in animals (multiple species, depending on the effects being investigated) is it considered for trials in humans.

And again in humans, it is first tested only for safety, at levels typically a tenth or less of those at which it is theoretically believed to be efficacious. Only after extensive safety testing (so-called "phase I," in healthy volunteers) is it tested for efficacy in patients with the target indication.

So, you're right that you can't really talk about a "safe" dose without reference to what is considered an efficacious dose, but the emphasis is always first on safety, regardless of efficacy.

As for over-the-counter (OTC) drugs, typically a drug isn't allowed to go OTC until it has been under prescription control for years, and then usually only at a dose a fraction of that in which it is available by prescription. For example, naproxen (Aleve) is available OTC at around 200 mg per tablet, while the prescription strength is 600 or 800 mg, and the same is true for ibuprofen.

Posted by: bleh on April 25, 2006 at 7:20 PM | PERMALINK

Just going down the line of comments, is it possible that people are trying to "fix" something that actually works pretty well already?

But that can't be right, Tom, because the current setup has government all over it. So by definition it's crap, right?

Posted by: craigie on April 25, 2006 at 7:32 PM | PERMALINK

craigie:

But that can't be right, Tom, because the current setup has government all over it. So by definition it's crap, right?

At least you got it. It looks like I'd have to explain it to cmdicely.

A number of people here have pointed out that the person who wrote the original article doesn't really know what she's talking about.

Posted by: tbrosz on April 25, 2006 at 7:37 PM | PERMALINK

MattXIV: Good questions! bleh gave a good response. I would add this. It is very difficult to get information on off-label efficacy. Nobody keeps track of the data, because there isn't any. The best you can really do is ask a bunch of doctors how they feel about a certain treatment. And you usually get a pretty nebulous answer. In my particular field, we even have a hard time with the efficacy of approved use. Our problem is that the device treats pain and numbness. There are no good ways to quantify these things, so we are reduced to asking "what is your pain on a scale of 1 to 10?" The question starts out as a subjective one, but it gets even worse. Patients who have taken a liking to their pain medications often exaggerate their pain to get another prescription. And we can't really tell if they are doing so. But, I digress. We often find out about about off-label efficacy after it becomes an approved use. For example, doctors prescribed aspirin for heart problems long before anyone did a study. They just thought it was a good idea because it tends to lower blood pressure. And, it's a pretty harmless drug. I suspect most of these doctors didn't really know if it helped or not. It just seemed right. Eventually, aspirin makers realized that this practice was common and did studies so they could advertise this usage. Now we have studies and it appears that arspirin does help, at least a little. So, the doctors were right to precribe it off label. And aspirin has been around for so long that we can be very confident of its safety. This isn't a very satisfying answer is it? Unfortunately, medicine is very complex and we often have to proceed with treating patients before we really have all the facts. You have to treat patients with the products you have, not the products you want.

Posted by: tom on April 25, 2006 at 8:06 PM | PERMALINK

Since there are some actually knowledgable people around this thread, anybody with a relevant background want to comment on how appropriate off-label usage standards evolve and if you see the lack of full testing necessary to get it approved for that application having a noticable impact on efficacy or safety? It would be interesting to see how much clinical efficacy varies for on-label vs off-label usages.

And if we have any clinicians hanging around - what kinds of studies beyond the basic safety and efficacy vs placebo would be most useful for getting patients the optimal medications? Would resource be better spent teasing out what factors makes individuals react better or worse to a given drug or doing head to head comparisons of the drugs to determine which produces the best results in the general population of patients?

Posted by: MattXIV on April 25, 2006 at 6:35 PM

Well Matt, your question is difficult to answer as posted...off label use does not affect safety and efficacy standards for a drug.

Physicians have the right to use any FDA approved agent for any medical purpose they deem. Drug mfgrs are required to provide physicians with all information on their product, independent of labelled uses. The only time a physcian is restricted in using a drug is if the product has not been FDA approved.

Generally, the way physicians evolve to off-label use is via clinical practice and experience. This entails sharing medical uses of the product, which is why companies provide the medical information on their product, this is generally called professional to professional information, as opposed to promotional information, which requires FDA approved indication (i.e. sales). Many companies, may have sales provide medical information on their product as long as the physician initiates the request for the information as opposed to a sales person provided the information unsolicited. As you might guess there is lots of wriggle room there.

Generally, speaking most HIV and oncology agents are prescribed for more off-label uses than they are for their indicated FDA approved use.

I am not sure why you think efficacy would vary for a product based on off-label vs. labelled use. Efficacy is seldom the issue, as generally the physician is prescribing the med based on its mechanism of action. The use is off-label, simply because the mfgr has not invested the money to do the research to get an FDA approved indication of use, not because the drug is ineffective. It costs lots of money to do clinical trials. If physcians are aware that the drug is effective for a use, they will prescribe it, without the indication, based on their clinical and medical expertise, which is the deciding factor when it comes to using all FDA approved drugs. As long as a physician prescribes the drug for the off-label use, it is not cost-effective for the mfgr to do the studies to get the indication.

I am not sure what you mean by getting patients the 'optimal drugs' There are basically 4 types of trials required by the FDA. They are called Phase I-IV trials. Phase I trials are dose- ranging studies generally done in healthy patients to assess, safety, tolerability, metabolism and excretion or pharmcokinetics of the drug. Phase II trials general involve 1-300 patients and they are used to assess efficacy, generally if it is an oncology or HIV agent they use oncology and HIV patients. Phase III trials are massive trials involving large randomized trials with general one to 3K patients, and these are tested against placebo to establish the safety and efficacy in large groups with the disease the agent is seeking indications of use for. These are all required PRIOR to FDA approval. Lastly there are Phase IV trials which are on-going massive trials POST-marketing, which are called surveillance trials for generally up to 5 years post-marketing to assess the drugs tolerability and safety in a much larger population which is not controlled. i.e. generally patients are screened in the other trials to minimize side effects in terms of them not having co-morbidities or health issues that might result in the agent not being approved for marketing.

What you need to know is that most drugs full safety profiles are not known until at minimum 5 years post-marketing, since the patient population size is not large enough until then to detect safety issues that may not have shown up in the smaller trials used to bring the drug to market. Typically, it is at the 5 year mark when you will see products withdrawn for safety issues, such as Vioxx.

So, as a consumer you should think, how long has this drug been on the market when your physician is prescribing you a therapeutic agent. Unless, your condition requires therapeutic intervention, i.e. diet and exercise will not ameliorate your disease...you should be cautious about using the new agent as its safety profile is still not well known. Which is why you see patients develop cardiac issues or kidney issues with products AFTER they are approved. Such as Viagra, once it was in the larger population tolerability issues were detected which were unknown (possible not reported) at the time of marketing. NSAIDs are known to cause renal issues for patients and we see athletes more and more having kidney issues who are on large and frequent doses of NSAIDs for inflammatory and pain symptoms.

Drugs are not panaceas, and in fact, as long as the company discloses the side effects and they are not toxic, the drug is approved. Each time you hear about a new medicine, you should wonder do the benefits outweigh the risk and if not, you should seek alternative ways to treat your symptoms if they are available.

Tagamet for ulcers was a big boon, because the benefit far outweighed having the risk of GI surgery. However, the cardiac and renal issues with Vioxx did not outweight the risk of what is basically a benign disease, i.e. osteoarthritis..particularly when there are other agents on the market with a better safety profile.Thus it was withdrawn from the market,but not before millions of patients were put at risk, given that there were older agents as effective already available to them.

We saw the same thing recently with estrogen supplements where the risk of cancer certainly does not outweigh the relief of hotflashes or sleepless nights, or night sweats.

Life is a trade off and drugs are no different. If it is not a life and death issue, think twice about taking a medication to treat your symptoms.

Posted by: elrapierwit on April 25, 2006 at 9:04 PM | PERMALINK

Thanks for the responses. Understanding how drugs are prescribed helps frame the question. It seems that moving to a more formalized regulation of efficacy may undermine the doctor's flexibility and either fail to analyze (or prohibit if off-label usage is banned or strongly discouraged) some of the important uses of a medicaiton. Issues like this are tricky, since policy-minded people tend to get hung up on whether their ideological disposition generallly views regulation as good or bad.

Posted by: MattXIV on April 25, 2006 at 9:11 PM | PERMALINK

I would add this. It is very difficult to get information on off-label efficacy. Nobody keeps track of the data, because there isn't any. ... . We often find out about about off-label efficacy after it becomes an approved use. For example, doctors prescribed aspirin for heart problems long before anyone did a study. They just thought it was a good idea because it tends to lower blood pressure. And, it's a pretty harmless drug. I suspect most of these doctors didn't really know if it helped or not. It just seemed right. Eventually, aspirin makers realized that this practice was common and did studies so they could advertise this usage. Now we have studies and it appears that arspirin does help, at least a little. So, the doctors were right to precribe it off label. And aspirin has been around for so long that we can be very confident of its safety. This isn't a very satisfying answer is it? Unfortunately, medicine is very complex and we often have to proceed with treating patients before we really have all the facts. You have to treat patients with the products you have, not the products you want.

Posted by: tom on April 25, 2006 at 8:06 PM

Tom, this is not really accurate when it comes to pharmaceuticals, perhaps it is for devices.

There is usually quite good data available for off-label uses of pharmaceuticals. Companies do conduct trials but the trials are generally not large enough nor powered for the regulatory requirements for FDA approved use indications. There is an avalanche of data available on oncology and HIV uses of agents which are off-label. The data is generally reliable and backed up with the clinical expertise and experience of the principal investigator. The investigators tend to often be thought leaders in the particular therapeutic area for the off-label use. Which means clinicians are comfortable relying on his judgement and expertise. Doctors generally talk with other clinicians or investigators who have experience using an agent off-label, prior to using it in their patients

As regards the comments on aspirins, they are also inaccurate. Aspirin has so many safety issues that is highly unlikely that a company would be able to get it approved for use by the FDA today. Consumers should not be confident about the safety of aspirin as it can cause serious GI bleeding as well as prolonged bleeding in general. The basic mechanism of action was well known when physicians began prescribing it for it's antiplatet effect, i.e. decrease clotting. prior to physicians precribing it as a cardio-protective agent. So, physicians were not guessing but made a scientific and medical judgement based on how aspirin works.

What consumers need to know is that low doses of aspirin prevent clotting in doses as low as 39mg daily you slow clotting for 7 days, which is the time it takes for your body to make new platelets.
Aspirin also relieves fever in low doses, not as low as 38mg but 80mg will do. Also at low does aspirin relieves pain, generally 325mg

Aspirin in high doses,1-2 grams, relieves inflammtion, but at those high doses it also causes GI irritation with prolonged use, and short use if you are geriatric, that GI irritation can result in a serious GI bleed and cause significant helath issues if not treated promptly.

At high does aspirin also can cause tinnitus, or ringing in the ears, which may not be reversible.

Aspirin is not one of those drugs that have a benign safety profile and should not be respected in the same way swimmers learn to have respect for the water

Posted by: elrapierwit on April 25, 2006 at 9:36 PM | PERMALINK

Aspirin is not one of those drugs that have a benign safety profile and should not be respected in the same way swimmers learn to have respect for the water


oops, delete the not, this should read:

and SHOULD BE respected in the same way....

Posted by: elrapierwit on April 25, 2006 at 9:41 PM | PERMALINK

Sometimes it's just hard to design an experimental control that doesn't kill frogs at a rate faster than the expected action of the chemical being tested.

word

Posted by: tbrosz on April 25, 2006 at 9:42 PM | PERMALINK

elrapierwit - I asked about on vs off label usage since my understanding (correct me if I'm wrong) is that the essential difference is that it has been mandated that the drug demonstrate efficacy for on-label usages. Thus, a comparison between problems arrising from the two categories of usage should illuminate whether differing to physician expertise or more stringent efficacy regulation would be better policy.

By the optimal drug, I mean the drug that has the combination of price, safety, and efficacy that best suits the patient. It seems that the core policy question is whether the physician sorting through multiple potentially contradictory studies from a variety of sources on efficacy before choosing a treatment is better or worse than basing the decision primarily on an overall assessment of which would be the best drug for the problem by a government agency.

Posted by: MattXIV on April 25, 2006 at 9:46 PM | PERMALINK

I asked about on vs off label usage since my understanding (correct me if I'm wrong) is that the essential difference is that it has been mandated that the drug demonstrate efficacy for on-label usages. Thus, a comparison between problems arrising from the two categories of usage should illuminate whether differing to physician expertise or more stringent efficacy regulation would be better policy.

By the optimal drug, I mean the drug that has the combination of price, safety, and efficacy that best suits the patient. It seems that the core policy question is whether the physician sorting through multiple potentially contradictory studies from a variety of sources on efficacy before choosing a treatment is better or worse than basing the decision primarily on an overall assessment of which would be the best drug for the problem by a government agency.

Posted by: MattXIV

Ok,Matt...not sure if I quite yet understand you but, if your question is should we DEFER to the clinicians medical expertise in terms of his or her medical judgement when prescribing a drug for an off-label use, I would say yes. Physicians, are treating a patient generally and they are going to be able to assess from qualitative and quantative clinical measures whether the drug is indeed effective for the patient, despite it not having an FDA approved use for that indication.

I am wondering if perhaps you are thinking that there is prescribing for some wildly unthought of use for the product, as opposed to it commonly being far more narrowly defined. Genreally, off label use relies on how the drug works, i.e. mechanism of action, which tells the physician where it is likely to be therapeutically beneficial, independent of a clinical study.

For instance, a drug may be approved for osteoarthritis,(OA) but not rheumatoid arthritis...physicians seldom hestitate to prescribe the drug for rheumatoid arthritis(RA) as well, despite the drug not being approved for use in RA, because the mfgr only funded studies to assess the efficacy in OA. Since physicians know that the inflammatory process is the underlying condition for both OA and RA, there is a strong likelihood, that the drug will work for RA as well, despite the mfgr not having done studies to gain an FDA approved indication for that use. The same goes for many cancer drugs.

Or take the use of aspirin(ASA) for cardio-protective effect because we know that it prevents clotting, even without an indication a physician would prescribe ASA knowing that is the effective therapeutic intervention he wants for the patient. The same goes for stroke, an MD would prescribe ASA to prevent clotting as a risk for stroke patients as well, despite it not having an indication for that use.

What we sometimes have in cases like these type uses are retrospective trials, which go back and look at cardiac patients who used ASA and patients who used the NSAID for RA vs. cardiac and RA patients who did not..and look at the statistical outcomes to see if there was a risk reduction in cardiac events or pain/inflammation for those who did use the drug vs. those who did not. Although, these studies could not be used to gain FDA approved indications, they would have significant clinical impact with clinicians and on their prescrribing habits. Especially if they demonstrate statistical and/or clinical significance between those who did use the product vs. those who did not.

I suppose what I am really saying is that an FDA approved use for a product as effective and safe, provides assurance clinically about safety and efficacy, which is what the clinician needs to feel comfortable about using it for diseases similiar to the approved indication even if the controlled trials may not have been done. Even side effects can be beneficial, at times, for a mfgr. Take for instance Rogaine, it was developed to treat high blood pressure but a side effect was hair growth. Due to the tremendous hair loss market potential i.e. ROI, mfgrs did do the trials to prove efficacy and gain FDA approval. However, even when trials are not done for FDA approval, due to the cost involved...clinically they can be highly effective and have lots of use based on the clinical outcomes the physician has with his/her patients.

So, I am not sure how a more stringent 'efficacy' policy would beneficially impact the present situation, which works very well based on the clinical outcomes the physician sees with his patients.

In terms of the 'optimal drug' policy. There are lots of pharmacoeconomic studies out there on diseases state management done for HMO's and to establish which products a insititution will have on their formulary. Those studies generally focus on cost-effective therapy for the a specific population.
Clinicians do not need to sort through lots of data as there are numerous reviews, and evidence based medicine data which serves as a guideline.

What physicians seldom have is head to head comparisons of one drug vs. another in terms of efficacy, safety and cost. However, the reality is that if the drug has a significantly better safety or efficacy profile, the physician generally can assess that from his clinical experience. One other thing to keep in mind is that no drug works for every patient, so even if a product is highly effective, the patient may have an underlying health issue that precludes them from using the product as indicated or there could be hypersensitivities to the product.

If we as consumer(s) want head to head comparisons, in terms of policies...my suggestion which was mentioned in a prior post, is that we have a surcharge for FDA drug approval that goes to fund comparative testing of approved agents in the same therapeutic class, that could be performed by NIH, post marketing. Because it would be government tested the data could not be controlled by the mfgr.

Honestly, though it is not that big of deal, clinically, given that physicians routinely know which agent is effective in their patient just by their own clinical assessment.

It is only when the market is really large that pharmaceutical mfgrs attempt to create 'wedge clinical' issues to be competitive in the market place that such issues come up. And they are generally around safety issues.

For example in the 80s the most prescribed agent for hypertension was a drug called aldomet, and it's closest competitor was minipress. When minipress wanted to gain more market share, they went after the side effect profile of aldomet and said that it caused impotence...they captured the market...not on efficacy, but most male physicians did not feel was 'best' to prescribe aldomet to their male patients, despite it being just as effective.

Another example would be Tagamet and Zantac. Tagamet completely revolutionized how ulcers were treated and had a monopoly in the marketplace until Zantac came along. Zantac, was not demonstrated to be more effective than Tagamet...but Zantac had far fewer drug interactions than Tagamet..making it a much safer drug in terms of clinical use..since doctors need not worry about what other meds their patients were taking when they prescribed Zantac.

So, efficacy is seldom the issue when drugs in a therapeutic class are compared...the reason being that both received FDA approval for efficacy. Generally, subsequent agents in the class have better safety profiles since that is an incentive for the FDA to approve the product for the indicated use, despite their being other products on the market already which are just as effective.

Posted by: elrapierwit on April 26, 2006 at 10:00 AM | PERMALINK

I stand corrected on Aspirin. I am in the device field and am clearly out of my league when it comes to drugs on this stream. You should listen to elrapierwit, who has a much better understanding about drugs. And he should, he prescribes them. And I shouldn't have used the word 'benign' for aspirin. I have a warped concept of 'benign' coming from the surgical field. What we consider to be benign surgery is, in fact, quite dangerous. We can lose a patient in even the simplest of surgeries. I tend to forget that because my job is to make surgery safer, so I think in terms of relative improvements, not absolutes. Keep in mind, we sometimes literally fillet our patients in my business. And by fillet, I mean neck to pelvis, all the way to the spine. Ouch! This is rare, but it does happen.

Posted by: tom on April 26, 2006 at 2:39 PM | PERMALINK

Thanks again for the responses. This is probably the most informative comments thread i've been part of :)

Posted by: MattXIV on April 26, 2006 at 6:36 PM | PERMALINK

You should listen to elrapierwit, who has a much better understanding about drugs. And he should, he prescribes them.
Posted by: tom on April 26, 2006 at 2:39 PM

You know, Tom...that is false. I am uncertain why you are asserting that I prescribe drugs. I have not stated, implied nor inferred such.

Posted by: elrapierwit on April 26, 2006 at 6:41 PM | PERMALINK




 

 

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