The Placebo Effect.

[Midpack]

Did anyone else see this segment on 60 Minutes last night? I was stunned, not by the effectiveness of anti-depressants specifically, but by how marginally effective drugs are FDA approved, put on the market and prescribed. WOW!

Per the FDA - if a drug proves effective in two clinical trials, it can be approved, even if the same drug has failed to provide better results than a placebo in ten other trials. Silly me, I just assumed to be approved, the drug would have to prove effective in a majority of the trials at the very least.

Some quotes (italics my remarks) that I can't get my head around, full video below.

Quote:

From the Dr taking the counterpoint in favor of marginally effective drugs. "Especially for the mildly depressed, using a different methodology, he finds that the drugs help 14 percent of those moderately depressed, and even more for those severely depressed. Thase: I wish our antidepressants were stronger. I hope we have better ones in the future. But that 14 percent advantage over and above the placebo is for a condition that afflicts millions of people, that represents hundreds of thousands of people who are better parents, who are better workers, who are happier and who are less likely to take their life." And 6 times as many who take anti-depressants without benefit, at what cost to all of us? Here he offers that anti-depressants are effective for moderately depressed patients in 14% of cases, and in his opinion that's worth the cost overall (an $11.3 BILLION dollar industry, how much of that provides an actual benefit?). WHAT??

Quote:

To approve any drug, the Food and Drug Administration merely requires that companies show their pill is more effective than a placebo in two clinical trials - even if many other drug trials failed. Brown: The FDA for antidepressants has a fairly low bar. A new drug can be no better than placebo in 10 trials, but if two trials show it to be better, it gets approved. Stahl (CBS): Does that make sense to you? Brown: That's not the way I would do it if I were the king. But I'm not. Dr. Tom Laughren, director of the FDA's division of psychiatry products, defends the approval process. Stahl (CBS): We're told you discard the negatives. Is that not right? Tom Laughren (FDA): We consider everything that we have. We look at those trials individually-- Stahl (CBS): But how are you knowing that the two positives deserve bigger strength in the decision? Laughren (FDA): Getting that finding of a positive study by chance, if there isn't really an effect, is very low. I mean, that's basic statistics and that's the way clinical trials are interpreted. A separate question is whether or not the effect that you're seeing is clinically relevant. Stahl (CBS): Okay. Is it clinically relevant? Laughren (FDA): The data that we have shows that the drugs are effective. Stahl (CBS): But what about the degree of effectiveness? Laughren (FDA): I think we all agree that the changes that you see in the short-term trials, the difference between improvement in drug and placebo is rather small. Stahl (CBS): It's a moderate difference. Laughren (FDA): It's a small, it's a modest difference. It's so modest - that in Great Britain the National Health Service decided to dramatically revamp the way these drugs are prescribed. It did so after commissioning its own review of clinical trials. Tim Kendall (UK NHS): We came to the conclusion that for mild to moderate depression, these drugs probably weren't worth having. Stahl (CBS): At all. Kendall (UK NHS): Not really.

Treating Depression: Is there a placebo effect? - 60 Minutes - CBS News

[TromboneAl]

Well, that's depressing.

Almost everyone underestimates the placebo effect.

I see the placebo effect as the main reason that many people believe in some treatments that that are not effective. Many say "Well, if it works, I don't care if it's a placebo effect." But placebos are unnecessarily expensive, and often don't continue to work for long.

Here's something that many people don't know. When I was in school, a result was considered statistically significant if the results would have occurred by chance less than 5% of the time. That means that 5% of studies will show a statistically significant result, when in fact the results are due to chance.

My distrust of drug companies just keeps growing.

[Midpack]

Quote:

Originally Posted by TromboneAl My distrust of drug companies just keeps growing.

And the FDA...they serve a true need, but I assumed they put the public good well ahead of the drug companies? Silly me.

Your tax dollars at work...

[JakeBrake]

Back in the '50's I participated in the national field trial for the Salk polio vaccine. It's too bad that all field trials are not that dramatically successful. They never told us who was injected with the real vaccine and who got the placebo, so I was vaccinated again after the field trial.

For those of you who have no personal memory of polio (thanks to the vaccine), trust me, polio is BAD.

[eytonxav]

Saw that last night, wow is right, its definitely scary what gets approved by the FDA. Aside from the Placebo effect, I ofter wonder how much can be cured with just good nutrition and exercise (anyone remember Adelle Davis, author of Lets Eat Right to Get Well).

[EvrClrx311]

curing ailments since 1969...

[Nemo2]

I always ask my doctor for the generic knock-off placebos....they're so much cheaper.

[Nords]

Quote:

Originally Posted by Midpack And the FDA...they serve a true need, but I assumed they put the public good well ahead of the drug companies? Silly me. Your tax dollars at work...

I think their "public good" comes from implementing a process and making sure that the substance doesn't actively kill people. You know, the "First, do no harm" part.

Then it's up to the drug researchers to shoulder the expense & risk of going from "pill v1.0" to "curing cancer".

So a drug's marginally effective-- is that worse than doing nothing? And then there's my favorite strawman analogy: "What if it's your mother?"

I've been following a surgeon who's invented a better mousetrap stent. This guy's a rock star at what he does, he's world-renowned among his fellow surgeons in this arcane specialty, he's been at it for over five years, and he's been bootstrapping & angel-funded for the last four years. It may take him another 2-3 years to complete the appropriate certifications in the U.S. and abroad. But the value of his company lies in taking this device through the R&D and the certification. J&J's not going to do it on their own, and they're not going to pay him a penny for the patents until he proves that it's more effective than existing stents. But he still won't cure heart attacks or stenosis.

His research is subsidized by the state of Hawaii, and 100% state tax credits are available to those who've invested. Is this a good investment? Too early to tell. Is it a waste of good taxpayer dollars? Not so far-- and what if your mother needs a better stent?

[Midpack]

Quote:

Originally Posted by Nords So a drug's marginally effective-- is that worse than doing nothing? And then there's my favorite strawman analogy: "What if it's your mother?"

I don't need a drug that has a 1 in 7 chance of being effective, neither does Mom. Anti-depressants are an $11.3B industry, is $9.7 BILLION of that essentially wasted?

I never would have dreamed our FDA would approve ANY drug that was more effective than a placebo in 2 of 12 trials, that was a revelation to me at least.

The top 20 big pharma companies are $500B in revenue. What percentage of that is wasted?

In the context of the recent thread about the much higher costs of healthcare in the US (without better results), and those who said we just can't reduce costs and maybe also cover the 50 million people with no health care insurance...

'We get what we deserve.'

[sengsational]

Along these lines, I always wonder how much more we would know about vitamins and suppliments if they were patentable or otherwise could justify the cost of double blind placebo controlled studies. Maybe the governments could spend money on something useful like that for a change. Nah, big pharma lobbiests wouldn't let it through. They won't want nearly free pills that are safer and more effective to take market share.

[Dawg52]

I saw the show. Very interesting. No telling how much money goes down the toilet on other types of drugs for mild conditions with little benefit.

[clifp]

Quote:

Originally Posted by Midpack I don't need a drug that has a 1 in 7 chance of being effective, neither does Mom. Anti-depressants are an $11.3B industry, is $9.7 BILLION of that essentially wasted? I never would have dreamed our FDA would approve ANY drug that was more effective than a placebo in 2 of 12 trials, that was a revelation to me at least. The top 20 big pharma companies are $500B in revenue. What percentage of that is wasted? In the context of the recent thread about the much higher costs of healthcare in the US (without better results), and those who said we just can't reduce costs and maybe also cover the 50 million people with no health care insurance... 'We get what we deserve.'

I also watched the 60 Minute's piece and it was an eye opener. I vaguely understood the FDA approval process as Nord's say the rule #1 is "do no harm" and for the most part the FDA does a pretty good job of doing that.

The "do good" bar is surprisingly low, and it sure depends on a the disease. 1 chance in 7 the drug will kill cancer is heck of lot more useful to patient than Prozac is to the guy who tell his therapist that he is depressed cause his girlfriend dumped him, he didn't get a promotion, his mom is sick, and his dog died. No doubt he is depressed but he'll probably get better treatment or no treatment. The fact that sugar pill worked virtually as well as anti-depressants was a surprise. I do think that the British are smart to stop wasting money by prescribing anti-depressants for mild cases. I also think we would be smart to give doctors lots of leeway to prescribe placebo for many ailments.

One of my favorite columnist the Atlantic's Megan McArdle had recent column

Quote:

The standard figure for drug discovery thrown around by the industry's most avid critics is the Light and Warburton estimate of roughly $43 million. Most serious analysts think that's way too low (I agree--their assumptions were bizarre, and their attempt to defend them in the comments to this Tim Noah piece is painful to read). The industry, and its supporters, prefer Joseph DiMasi's figure of around $800 million. But critics point out that it was derived using confidential data, which can't be verified, and they are very critical of the method, which includes opportunity costs--the returns that pharmaceutical firms didn't earn by spending the money elsewhere. Now along comes a new method, from Matthew Herper at Forbes. It uses only public, audited data, and it's breathtakingly simple: over a 15-year period, they divided each company's R&D spend by the number of drugs they got approved. The result: DiMasi is also way too low. For every approved drug, pharma spent between $4 billion and $11 billion on R&D. Yes, there's probably some wiggle room on the accounting, but not that much--your auditor is not going to let you reclassify your new delivery trucks, or a Human Resources SVP, as a research expense.

I have also been following the doctor that Nord's invested with. As Nord's say the guy is very good, and extraordinary frugal. Despite this and the fact that he is developing an improved Stent (a device not a drug which have simpler FDA approval process) I'm sure that will it cost well over $43 million to get it developed. This is assumed that it eventually gets approved that fact that many fail obviously drives up the cost.

I figure that medicine has a lot in common with investing. Much like active investing adds very little or even no value and for most people passive investing works well. A passive approaches to medicine often works pretty well , the body cures itself of most common aliments. This healing process works best if you engage the brain in thinking positive thoughts.

As a society we spend a fortune trying to "cure" common ailments like high blood pressure, mild depression, high cholesterol etc. We also spent a second fortune try to cure dying on 80 and 90 year old patient many of whom are ready to go.

[Bluemoon]

I wonder if hypnosis could be used to tell someone that they will be cured in X amount of time. Would that work the same as a placebo would?

I suffered from clinical depression and if the symptoms got worse an increase in my medication dosage counteracted the symptoms. Of course since I was not in the mildly despressed group a placebo supposedly wouldn't work for me.

If the FDA and drug company tests are so accurate why are so many drugs withdrawn from the market years after they are approved due to complications from side effects (including death)?

[clifp]

Quote:

Originally Posted by Bluemoon I wonder if hypnosis could be used to tell someone that they will be cured in X amount of time. Would that work the same as a placebo would? I suffered from clinical depression and if the symptoms got worse an increase in my medication dosage counteracted the symptoms. Of course since I was not in the mildly despressed group a placebo supposedly wouldn't work for me. If the FDA and drug company tests are so accurate why are so many drugs withdrawn from the market years after they are approved due to complications from side effects (including death)?

The 60 Minutes piece did point out that the drugs were relatively more effective the more severe depression. Still even for severe depression in some cases placebo worked as well as a drugs.

I have no idea if hypnosis works or not. I will say despite the much deserved criticism of modern medicine, I have more confidence in it because they actually attempt to use data to make decision.

IMO virtually all of the alternative medicine makes use of the placebo effect. They string together a bunch of anecdotes and feature them in their marketing material, while burying the "not FDA approved disclaimer" as obscurely as legally permissible.

[Wendy]

An interesting discussion about my former industy.

The 60 Minutes story came as no surprise since researchers still don't really know how SSRIs (modern anti-depressive drugs) work, or even understand all the factors involved in depression itself. The placebo effect is a major factor in this disease, more so than some others.

Nords is correct that the FDA's main mission is to evaluate the risk-benefit profile of new drugs. So why do some new drugs end up being so dangerous?

1: Very rare side effects don't show up in the relatively small groups of patients tested in clinical trials.

2: Patients in trials are carefully selected and monitored. "Real world" use of drugs is often suboptimal.

3: Sometimes drug co's conceal negative safety data from the FDA during the approval process. (eg, Vioxx)

As to why the FDA approves drugs with marginal efficacy, the fact is that some patients may benefit from a new drug even if most don't, and doctors (and patients) like having this choice. From a cost perspective this is wasteful, which is why the UK and other countries restrict the number of new drugs they will pay for. In the US, insurance companies may do this, but for the most part patients have access to anything as long as they pay (more) for it.

The holy grail of new drug development would be to determine exactly which patient subgroups can benefit from a particular drug, like we see with some cancer drugs that are tailored to patients with specific genetic profiles, for example. It doesn't matter if a drug is only effective in 17% of all patients, if you fall into the group for which it works 99% of the time.

[haha]

Quote:

Originally Posted by Wendy An interesting discussion about my former industy. The 60 Minutes story came as no surprise since researchers still don't really know how SSRIs (modern anti-depressive drugs) work, or even understand all the factors involved in depression itself. The placebo effect is a major factor in this disease, more so than some others. Nords is correct that the FDA's main mission is to evaluate the risk-benefit profile of new drugs. So why do some new drugs end up being so dangerous? 1: Very rare side effects don't show up in the relatively small groups of patients tested in clinical trials. 2: Patients in trials are carefully selected and monitored. "Real world" use of drugs is often suboptimal. 3: Sometimes drug co's conceal negative safety data from the FDA during the approval process. (eg, Vioxx) As to why the FDA approves drugs with marginal efficacy, the fact is that some patients may benefit from a new drug even if most don't, and doctors (and patients) like having this choice. From a cost perspective this is wasteful, which is why the UK and other countries restrict the number of new drugs they will pay for. In the US, insurance companies may do this, but for the most part patients have access to anything as long as they pay (more) for it. The holy grail of new drug development would be to determine exactly which patient subgroups can benefit from a particular drug, like we see with some cancer drugs that are tailored to patients with specific genetic profiles, for example. It doesn't matter if a drug is only effective in 17% of all patients, if you fall into the group for which it works 99% of the time.

Excellent post, and this point to can be gernalized to some faults inherent in the current infatuation with Evidence Based Medicine. Groups are made op of sub-groups, and a number of subgroups can cancel each other out giving negative trial results, while some subgroups may be helped a great deal.

Ha

[Wendy]

Glad it was helpful!

Drug co's do put subgroups into their clinical trials, but deciding on these groups involves some educated guesses as well as a trade-off between more data vs. longer and costlier trials. Once a drug is approved, the company may continue testing to identify the best patient populations, which in turn might increase use.

There are few disease now for which we know enough about patient genotypes/ phenotypes to prescribe the "best" drug the first time. Most chronic, common diseases seem to be treated with a more empirical approach: give the patient a course of drug A, and if that doesn't work, try drug B, then C, etc.

And that's why everyone wants a wide choice, vs. just having drug A as an option.

[Midpack]

Quote:

Originally Posted by Wendy An interesting discussion about my former industy. The 60 Minutes story came as no surprise since researchers still don't really know how SSRIs (modern anti-depressive drugs) work, or even understand all the factors involved in depression itself. The placebo effect is a major factor in this disease, more so than some others. Nords is correct that the FDA's main mission is to evaluate the risk-benefit profile of new drugs. So why do some new drugs end up being so dangerous? 1: Very rare side effects don't show up in the relatively small groups of patients tested in clinical trials. 2: Patients in trials are carefully selected and monitored. "Real world" use of drugs is often suboptimal. 3: Sometimes drug co's conceal negative safety data from the FDA during the approval process. (eg, Vioxx) As to why the FDA approves drugs with marginal efficacy, the fact is that some patients may benefit from a new drug even if most don't, and doctors (and patients) like having this choice. From a cost perspective this is wasteful, which is why the UK and other countries restrict the number of new drugs they will pay for. In the US, insurance companies may do this, but for the most part patients have access to anything as long as they pay (more) for it. The holy grail of new drug development would be to determine exactly which patient subgroups can benefit from a particular drug, like we see with some cancer drugs that are tailored to patients with specific genetic profiles, for example. It doesn't matter if a drug is only effective in 17% of all patients, if you fall into the group for which it works 99% of the time.

Nice post! I was just surprised that drugs with such a low probability of success were being approved, just another area where I am naive. I would think Doctors and patients would be entitled to know what these probabilities were from actual trials. I assume some drugs are highly effective (call it over 80%) and which are not. Then we can evaluate based on cost and prob of success whether to try a drug and/or whether to continue with it after the first Rx. Not to disparage drug companies, but they probably like the status quo. It gives them incentive to spend R&D $ knowing the drug will be "FDA approved" if it's at all effective, no matter how marginally. What am I missing?

[Wendy]

Quote:

Originally Posted by Midpack What am I missing?...I would think Doctors and patients would be entitled to know what these probabilities were from actual trials.

Potentially missing the fact that drugs that are only marginally effective will lose market share = decreased sales = less profit when more effective drugs are available.

Data on trials used to support FDA approval are in the prescribing information, and something your doctor *should* know before prescribing. It's available to anyone but difficult for the average layperson to decipher. It's good to be an informed patient and do your research on a drug (via the internet) before speaking to (or challenging) your doc, but be prepared for pushback. Certainty, ask her why she's prescribing the new expensive wonder drug vs. the old cheap generic; docs are pretty used to that by now.

But a more cynical question might be, how do you and your doc learn of all the failed trials that the FDA didn't use for the approval? That's a subject of much debate now, and some recent efforts by the FDA to force drug co's to disclose all the pre-approval data, not just the favorable stuff.

[Nords]

Quote:

Originally Posted by clifp Despite this and the fact that he is developing an improved Stent (a device not a drug which have simpler FDA approval process) I'm sure that will it cost well over $43 million to get it developed. This is assumed that it eventually gets approved that fact that many fail obviously drives up the cost.

When it gets FDA approval, I'm going to buy some sheet metal and tin snips at Home Depot. I can pick up a set for you, too, and we'll have a stent-making party!