The Double Blind Randomized Placebo Controlled Clinical Trial [RTC] is such a standard methodology that it’s hard to realize that it even had an origin – more like something that came to us as the glaciers receded. But that’s not even close. It came to us in that era of bomb shelters, hula-hoops, hot-rods, and rock-and-roll we now call the "fifties." Dr. David Healy tells us about it in a new post, The Tragedy of Lou Lasagna, the third in a series that started with Not So Bad Pharma and April Fool in Harlow [see also there, it’s solved…, hearing voices… and something essential betrayed…]. The RTC came as part of a reform movement that was also the the birth of clinical pharmacology that put the "D" in our FDA [Food and Drug Administration]. The champion was named Dr. Lou Lasagna.
Post-war 1950s America was on a roll: cars, television, advertising, and drug discovery was in the mix – psychopharmacology, antibiotics, wonder drugs. Dr. Lasagna was in the middle of things – introducing informed consent, the placebo effect, randomized clinical trials. At the end of the fifties, the Kefauver Hearings had tried to introduce sweeping reform of the abuses of the pharmaceutical industry, but floundered at the hands of the lobbyists with Dr. Lasagna advising, testifying, and publishing on the side of reform [sound familiar?]. But when the Thalidomide scandal broke, Kefauver’s bill was revived, rushed through Congress, and the FDA was tasked with certifying not only safety, but also efficacy. The wording that went into the legislation was, “Adequate and well controlled studies carried out by experts with scientific training” [adequate being a compromise between preponderance and substantial].
This when translated into practice came to mean two placebo controlled trials. The wording came from Lasagna.
Dr. Healy documents Dr. Lasagna’s fall from the spotlight first by having lobbied for Thalidomide before the scandal, and later by supporting other industry causes – becoming seen as a "a business-friendly conservative." So having championed the Clinical Trial into prominence, Lasagna later had reservations:
Lasagna’s misgivings:
Despite being the poster boy of the new science of drug evaluation, Lasagna had deep misgivings about the 1962 regulations. Thirty years later he said: “in contrast to my role in the 1950s which was trying to convince people to do controlled trials, now I find myself telling people that it’s not the only way to truth.
“My favourite quotation was taken from Austin Bradford Hill’s Heberden Lecture in 1965: “If one came to the conclusion that the only way to find out the truth about a medication was to use a controlled clinical trial, it would mean not that the pendulum had swung too far but that it had come completely off its hook”. “In another part of the paper [Hill] comes up with something else that I have been trying to sell to people with not an awful lot of luck. What he said was that a controlled trial does not tell the physician what he would like to know which is how do I know in advance without engaging in trial and error which antidepressant is better for Mr Jones or Mrs Smith. That’s what doctors and patients would like to know. We don’t do that”.
Hill and Lasagna had similar roles in the US and UK but Hill hadn’t enshrined clinical trials in legislation or in a bureaucratic apparatus. Lasagna had and could see the problems.
I’ve only hit the high points of this story as told in Dr. Healy’s post. It’s always instructive to look into the history of such things – the political wheeling and dealing, the lobbying, the compromises, and how contemporary issues of the day [Thalidomide, Marilyn Monroe’s suicide] come together to create such a written-in-stone mandate. From today’s vantage, there’s plenty to question about every step of the process.
My own beefs about the RTC culture that developed are multiple. The Clinical Research Industry that developed uses recruited subjects which hardly mirror the treatment seeking patients psychiatrists deal with in their offices. The RTC aims at statistical results rather than clinically significant results. The methodology of analyzing the data allows for a seemingly infinite variety of techniques to distort the reports. And the requirement for two positive studies allow for throwing out unwanted results from efficacy evaluations by simply not reporting negative trials. The net effect is that this seeming scientific reform can and has been distorted beyond anyone’s imagination. Those are the pieces that Ben Goldacre and the Data Transparency movement are setting out to make right. Data Transparency addresses a lot of those ills.
Data Transparency does not address the problem of the use of recruited patients. It doesn’t necessarily address the problem of statistical versus clinically relevant efficacy. But Dr. Healy is after bigger game than simply the misuse of scientific analysis in clinical trials. He is questioning the whole of elevation of the clinical trial to the position of the final word in medicine. We’ll be hearing more from him about that as his series progresses.
What I would say about all of this is simple: of course the clinical trial data is not the gold standard – the patient in front of me wasn’t in it. I would say the same thing about the deification of the DSM diagnostic categories – my patient wasn’t in the field trials either. 
Those things are in "the cloud" along with everything else I’ve ever learned along the way, and everything the patient has learned along the way. The clinical issue in our meeting is to come up with the best path for the patient with the time and resources at hand. Accurate clinical trials are sometimes a big help, but clinical trial results hardly make clinical decisions or define a clinician. The scheme below might make an iPhone App, but it’s not clinical medicine:
What about Science-Based medicine which incorporate basic science into the practice of medicine?
Alain
All medicine does that in my book.
You’d be correct except for alternative (or is it integrative) medicine, the like which is funded by the NCCAM but the problem is more because of evidence based medicine which place RCT at the top of the food chain and basic science at the bottom of the ladder. SBM place a greater emphasis on prior probability and the correct application of basic science in determining if a clinical trial is appropriate (one wouldn’t expect a clinical trial of reiki for ears infection to have a high prior probability).
I agree that basic science prior might not have a big effect on me too drugs but I guess that’s the failure of being more creative and find alternative modality to lab rat studies to test antidepressant and other me too drugs.
Alain
“But you have to be very cautious about how you extrapolate from what happens to some cells in a dish on a laboratory bench to the complex system of a living human being, where things can work in completely the opposite way from what laboratory work would suggest.” p94 “Bad Science” Ben Goldacre
Good for Ben. That’s right…
Some food for thought:
http://www.pmean.com/07/PostModernAssault.html
http://www.sciencebasedmedicine.org/index.php/how-do-you-feel-about-evidence-based-medicine/
http://www.bmj.com/highwire/filestream/393069/field_highwire_article_pdf/0/1618.full.pdf
I don’t think that Drs. Goldacre and Chalmers are wed to the tranditional RCT as we know it as much as they envision this:
“‘In an ideal world, wherever possible, we could be gathering anonymised outcome data and comparing this against medication history, making exceptions only for those who put their anxieties about privacy above the lives of others . . . In an ideal world, wherever a patient is given any treatment, and there is genuine uncertainty about which treatment is best, they would be simply and efficiently randomised to one treatment, and their progress monitored. In an ideal world, these notions would be so routinely embedded in our notion of what healthcare looks like that no patient would be bothered by it.’”
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0050882/
“Q: While reading Bad Pharma, I couldn’t help but think that we will look back at the way medicine is practiced today in the same way we look at something like bloodletting now.
A: That’s right. There’s this great line from Muir Gray (chief knowledge officer of the National Health Service in the UK) about John Snow, the great-grandfather of epidemiology who spotted the cholera epidemic in London. Gray says that in the 19th century, we made huge leaps in medicine with clean, clear water. In the 21st century, we’ll make the same leaps with clean clear information. That is where the action is. People will look back and say, ‘What on earth were you doing? Why were you relying on small crappy trials in unrepresentative patients? How could you expect to know what the true benefits of your treatments were? You must all be out of your mind.’
Q: So what will this revolution in medicine look like?
A: I think we have failed at getting a competent information architecture for evidence-based medicine. So many of these problems are only problems because medicine isn’t very good at finding out what works, bringing all the evidence together, and then making sure we get that information to the right person—the doctor, the patient—at the right time. If we were good at synthesizing and disseminating evidence to clinicians, marketing would be irrelevant. The only reason it matters that the majority of continuing medical education for doctors is funded by the pharmaceutical industry is because there’s no other better way of disseminating information to clinicians. Similarly, the problems of clinical trials being done in small numbers of unrepresentative people, comparing new treatments against nothing instead of the currently best-available treatment—all those problems should really be solved by embedding randomized controlled trials into everyday, routine clinical practice. You can run trials comparing one statin against another for almost no cost, using (National Health Service) electronic health records. If we did that, frankly, the fact that industry wants to fund trials against nothing—it would become irrelevant.”
http://www2.macleans.ca/2013/02/05/talking-with-ben-goldacre-about-his-new-book-bad-pharma/
They are not fans either of small crappy trials with unrepresentative patients. They do not want pharmaceutical companies to have a hegemony on how trials are run.
From the first link there is this:
” On the other hand, a clinician may try this new therapy without any intention of studying it, merely because he believes it will benefit his patients. In that situation, trying the new therapy is not research, the trial does not need IRB approval, and consent may be obtained in a manner governed only by the risk of malpractice litigation.
It would seem that the patients in the second situation (non research) are at much higher risk than are the patients in the first situation (being part of formal clinical research). Furthermore, the physician in the first situation seems more ethically admirable. The physician in the first situation is evaluating the therapy, whereas the physician in the second situation is using the therapy based on his or her imperfect hunches. Nevertheless, because ethical codes that seek to protect patients focus on the goal of creating generalizable knowledge, they regulate the responsible investigator but not the irresponsible adventurer.’”
I do not believe this is a simple debate.
There are 3 statements from your posts that have recently been coming to mind:
“Make the clinical trial world play it straight, and, by the way, don’t over-value clinical trials. There, it’s solved…”
“I was thinking about clinical judgement. In some of the comments, there’s a somewhat predictable dichotomy. Clinical judgement as medical imperialism, shooting from the hip versis clinical judgement as the highest order patient focused wisdom. I know that I way overstated that – the right of literary device.”
Drs. Goldacre, Chalmers, and colleagues hope to turn the whole of medical practice into a clinical trial patterned on first principles (embedding randomization, blinding, …etc) rather than on the industrial model currently in place.
If there is uncertainty then it seems they would prefer to have a random assignment made and the result monitored. Rather that the physician and patient together make a decision. This is not a crazy idea. It may not be the right idea. It does not seem that Dr. Healy is sufficiently distinguishing this idea from the idea of the traditional RCT. There is a real discussion to be had on the utility of embedding a more trial like structure into n of 1 clinical assessment. And, a question of individual vs systemic benefits.
Perhaps call it a discussion of balancing the Art with the Embedded Trial?
One of the interesting points they make that if a physician wishes to do n of 1 experiments on their patient with an FDA approach treatment that’s one thing, but if you actually wanted to study the outcome more systematically than with a case series then the task is made much more regulated and onerous.
All systems can be co-opted and corrupted. While Dr. Healy is making some enormously important points about the role of RCTs, how that has evolved, and how they have been misused, I do not think he is doing justice to the sophistication of the positions about trial approaches of Goldacre and Chalmers.
To me, there are some less clear cut and more interesting debates to be had.
I am also reminded of a last quote from one of your posts:
“The medical literature that practitioners traditionally counted on is now too contaminated to trust. A lot of things have gotten off the track in psychiatry, and I want to help find out how that happened. And there are plenty of complaints about the field other that the ones I address – some valid and some not. This is not an open forum for that discussion. There are bloggers who do answer general questions or engage arguments, and others who use a blog as a form of social media like facebook or twitter. Those are all choices to make, but they’re not mine.”
I continue to look forward to the thoughts you choose to share, whether or not they happen to touch upon anything in this comment. There isn’t really a comparable resource out there.
This is an area where pharmacologists could do work worthy of their education, and worth getting higher degrees for. Much of what a drug does is due to the chemistry of the drug which pharmacologists are more likely to understand than doctors. Additional studies carried out by pharmacologists on a more select group of patients— like patients already taking a drug for whatever they’re taking it for— could tell doctors a lot more about how a drug behaves and perhaps how it behaves in different people toward different goals.
It’s kind of suspicious that pharmacologists that are a major part of the developing process of drugs, are not a major part of further testing, evaluating, and educating about these drugs. There could be a partnership between prescribers and pharmacologists that could not only inform, but monitor, and report effects of the drugs, which, in the context of chemistry, could create a very useful feedback loop for doctors and patients and the drug companies that are finally getting sued for the negative effects and bogus uses of their drugs.
Alain,
There is some sound science behind integrative medicine.
Go to –
http://www.vitasearch.com
Type in keyword ‘depression’ to find over 1,100 studies (use other keywords to search by health condition).
Also, the Germans have done some good scientific resarch on herbs.
Herbs are prescribed in Germany like drugs here in the U.S.
Their ‘Commission E’ has a list of ‘approved’ herbs for various health conditions. –
http://cms.herbalgram.org/commissione/index.html
There is also some sound scientific research in neurofeedback, acupuncture and other areas.
Be well,
Duane
Another good source – PubMed – Dietary Supplement Subset –
http://ods.od.nih.gov/Research/PubMed_Dietary_Supplement_Subset.aspx
Duane
Oh dear God, D&R! I’ve had pernicious anemia (which was diagnosed as Depression) and last year had a B-12 deficiency (even though I eat red meat and drink milk). And I have MS.
Why did I have no idea that pernicious anemia is an autoimmune disease? You’d think a doctor would tell you that. The GP I had when I had anemia didn’t talk much— better have this talk with the doc I have now. I’ve often craved B-12, especially the sublingual version and have suspected from time to time that I’m one of those people who don’t absorb it properly. I’ve read speculation that difficulty absorbing B vitamins can result in mood disregulation.
Now I find out that I B-12 deficiency over the long term can result in irreversible nerve damage. And I have MS. Oh well, I’m reading some advice on the link you gave and will try to take a more structured and educated approach to supplements— which means keeping records. Blech. Oh well. I do think supplements are helping to ward off fatigue and brain for right now. Or not. Hard to tell.
Allergies, pernicious anemia, and MS. Could one or two things be at the root of all of these? At least two of those can easily be mistaken for mental disorder.
How many psychoactive drugs rob a body of vitamins and minerals?
Wiley,
I hope you find some answers.
A link to find a doctor –
http://discoverandrecover.wordpress.com/find-health-care-provider/
My apologies, for the number of comments.
Also, it was not my intent to promote my website, only to send a link to Wiley to help, if possible.
Duane