I'm not the only skeptic. A paper just out in the American Journal of Psychiatry adds to growing case against contemporary antidepressant trials (almost all of which are industry-sponsored) and should give everyone cause for thought.
The article, Can Phase III Trial Results of Antidepressant Medications Be Generalized to Clinical Practice? A STAR*D Report, is one of the many spin-offs from STAR*D. STAR*D was a large and ambitious study designed to investigate the effectiveness of antidepressants in a realistic setting. The results were rather difficult to interpret (and some are yet to be published), but this report is certainly amongst the most interesting.One of the things that made STAR*D different from the average trial was the recruitment criteria. Most trials require a volunteer to tick numerous boxes before they can be enrolled - for example, it's common to exclude anyone showing signs of suicidal thoughts or behaviours, people with any problems other than depression, such as addictions, and anyone whose depression is rated as "insufficiently severe" using a depression rating scale such as the HAMD.
The majority, probably the vast majority, of people who suffer from depression don't fit such narrow criteria. So antidepressants end up being tested on no more than a small select group of the people who are likely to end up taking them when and if they hit the market. And because criteria can differ between trials, two trials might end up testing the same drug on two quite different types of people - although on paper they are both a trial of the drug for the exact same thing, "major depression".
To be fair, some criteria are necessary to protect the safety of volunteers (you don't want someone who is suicidal getting their hands on an experimental and potentially dangerous drug), but the whole situation is far from ideal. People have been complaining about it for a while. The new paper adds to the list of complaints. The authors took advantage of the fact that STAR*D did not have restrictive entry criteria, and simply compared those patients who did happen to fit the bill for a "typical" antidepressant trial vs. those who didn't.
First off, just under a quarter (22.2%) of patients met the typical criteria. That's really not very many. And, as you'd expect, this minority of patients were rather different from the rest. Amongst many other things they were slightly younger, a lot richer (mean monthly income $3050 vs. $2163), much less likely to be unemployed or to have no medical insurance, and less likely to be black or Hispanic (this was an American sample).
Such differences might seem unimportant - if someone is suffering from a disease, and they're given a medication to treat it, does the size of their paycheque really matter? Yes it could - the patients who met the criteria for a typical antidepressant trial reported on average more improvement, and fewer side effects, compared to the others. (They were all given citalopram, a popular and pretty decent SSRI).
Does this mean that rich white people really get more benefit from citalopram? Or do they just tend to report more benefit? Or do they experience larger placebo effects? It's impossible to say. The authors, who include some big names in antidepressant research, conclude that:
...a patient sample that meets the inclusion criteria for a phase III clinical trial is not representative of depressed patients seen in typical clinical practice, and phase III trial outcomes may be more optimistic than results obtained in practice.Although it's also possible that trial outcomes could be more pessimistic, in terms of finding smaller drug-placebo differences than they otherwise would. Only one thing is certain - antidepressant trials are far removed from the real world, and the results of such trials have to be taken with a large pinch of salt.
Wisniewski, S., Rush, A., Nierenberg, A., Gaynes, B., Warden, D., Luther, J., McGrath, P., Lavori, P., Thase, M., Fava, M., & Trivedi, M. (2009). Can Phase III Trial Results of Antidepressant Medications Be Generalized to Clinical Practice? A STAR*D Report American Journal of Psychiatry DOI: 10.1176/appi.ajp.2008.08071027
8 comments:
(you don't want someone who is suicidal getting their hands on an experimental and potentially dangerous drug)
So, a psychiatrist will wait until after it's been approved - based on testing which does not include suicidal people - and then experiment on his suicidal patients. But under less controlled conditions.
I can see a need to ensure an anti-depressant is safe and effective for non-suicidal depressed people before testing on suicidal people - but there's no way to avoid experimenting on suicidal people, except to abandon all efforts at treatment.
Well, quite. Although there is another fairly good reason not to include suicidal patients in clinical trials - it would be unethical to give them placebo (or a drug which may not work) when you could give them the best possible standard of care.
The problem is, if you follow this logic, nooone would know what the best standard of care for suicidal people is, because noone would ever study them. Especially given the real concerns that some antidepressants could make people more suicidal, this is a real problem.
Thank you for a very informative post. I think the study and your analysis gives us a bit better understanding of this complex problem.
"The problem is, if you follow this logic, nooone would know what the best standard of care for suicidal people is, because noone would ever study them."
Which is the problem pregnant women have.
Heh, I hadn't thought of that.
Although at least if there's a drug which works in other women but which has never been trialled in pregnant women, you can be fairly sure it will still work in pregnant ones. The main issue would be safety.
Whereas in the case of suicidal depressed people, it may well be that drugs which work in other depressed people don't actually work (and vice versa).
The Atrophy Of Objectivity
If I were to rate the corruptive tactics performed by big pharmaceutical companies during my intimate experience with them , the frequent and intentional strategy of implementing fabricated and unreliable results of clinical trials performed by others possibly tops the list.
By this atrophy of the scientific method absent of authenticity that has been known to occur, harm and damage is possibly done to the health of the public.
Most would agree that the science of research should be sound and as aseptic as possible- completely free of deliberate and reckless interference.
However, it appears, money and increased profits can be a catalyst for disregard for human health with the clinical trial process that is largely unregulated.
This is particularly a factor on post-marketing studies of various pharmaceutical companies, as some pharmaceutical corporations seem to be deliberately conducting nothing less than seeding trials- with about a 50 percent tax credit for these trial sponsors.
Trials that exist that are in fact pointless and void of scientific benefit.
Decades ago, clinical trials were conducted at academic settings that focused on the acquisition of knowledge and the completely objective discoveries of drugs and devices to benefit mankind.
Then, in 1980, the Bayh-Dole Act, Public Law 96-517,was created, which allowed for such places with their researchers to profit off of their discoveries that were performed for pharmaceutical companies and others in the past.
Furthermore, such academic institutions were coerced to license patented inventions to those pharmaceutical companies that will then commercialize these discoveries paid for in large part by the taxpayers who funded this research to a degree.
This resulted in the creation of for-profit research trial sites without any academic affiliation that are called Contract Research Organizations.
CROS utilize primarily community patient care clinics whose staff are absent of any research training compared with the former researchers that existed decades ago. They are regulated, so they say, by institutional review boards, or IRBs. Both are for profit and essentially cater to the sponsor of the clinical trial in which all are involved with manipulating.
Because of this structure, the clinical trial investigators of these pharmaceutical sponsored trials are likely novice compared with academic researchers.
This, of course, happens with intent by the sponsor who can and does control all aspects of the clinical trial protocol at the site locations of a clinical trial that the pharmaceutical company structures and even gives the trial the title they want for their marketing purposes.
These quite numerous CROS are in fact for- profit, with some CROs making billions of dollars a year, and this market continues to grow.
The trials conducted at such places again are sponsored by pharmaceutical companies that control and manipulate all aspects of the trial being conducted involving their particular drug chosen to be studied.
Etiology for their deception regarding this manipulation is because the pharmaceutical company that sponsors such a trial is basically creating a marketing tool for this drug of theirs to be studied in this manner.
This coercion is done by various methods of deception in subtle and tacit methods.
As a result, research in this protocol of the sponsor ensures favorable results of the sponsor’s medication that is involved in the clinical trial they clearly own.
These activities are again believed to be absent of true or applied regulation to any degree, and therefore have the autonomy to create whatever they want to benefit the pharmaceutical sponsor.
There likely is a collusive relationship between the sites, the CRO, and the sponsor, as this whole system is planned beforehand by the pharmaceutical sponsor of their clinical trial to again be utilized to increase the market share of the drug studied that they promote.
Guest authorship has been known to be aggressively recruited by sponsors by paying a known opinion leader to sign off on the completed clinical trial.
Furthermore, the pharmaceutical sponsor recruits investigators to be used for this function of what ultimately is a fabricated clinical trial protocol.
The trial manuscript and protocol design is prepared by those employed by the drug company sponsor upon specific direction of this sponsor on how this should be prepared.
The medical program coordinator of a particular sponsored trial is an actual employee of the sponsoring drug company.
This person also may act as the publisher, manuscript version reviewer, and the clinical trial director who works with the drug company’s hired CRO editors whose objectives are to benefit the sponsor.
Typical and ultimate cost of the final manuscript of the trial to the sponsor created by the hired CRO and the recruited ghostwriters exceeds 1000 dollars per page, some have said.
Merck engages in this behavior, which shocked many, as they were always viewed as an ethical pharmaceutical company that always placed patients over profits.
Apparently, this is no longer the case. There are other well known and large pharmaceutical corporations that consider this plan of action standard operating procedures to ensure growth of their drugs.
Further disturbing is that once the creation of the trials is completed, the research paper is often composed with specific directions by the sponsor to writers known again as ghostwriters.
These people are usually not identified and acknowledged by the sponsor, and may not be trained in clinical research overall, as they are simply freelance writers.
One does not need research training or certification in order to perform this function. Rarely do clinical trial ghostwriters question their instructions about their assignment, which is clearly deceptive and undocumented by the pharmaceutical sponsor.
Also, these hired mystery writers are known to make about 100 grand a year performing this deception full time.
This activity removes accountability and authenticity of the fabricated clinical trial even further.
The corruptive act is finally completed by the sponsor hiring again a known thought leader as an author to have their name be placed on the trial, while this hired author likely had absolutely no involvement with the trial, or even reviewing the trial is not asked or required by the hired author, others have said.
To have the trial published, the sponsor has been known to pay an obscure journal, and the sponsor bribes the journal in a few ways, such as the sponsor purchasing from a selected journal thousands of reprints of their study from the journal, for example.
Again, how often this process is performed is unknown, yet frequent enough to create hundreds of such false writers mentioned earlier and progressively growing research sites to receive the support the pharmaceutical industry.
So benefits of pharmaceuticals that are studied in such a malicious way potentially can harm patients and their treatment options along with clear safety risks as a result of this process.
The purchased reprints of the fabricated clinical trial are then bought by the sponsor of the study from the medical journal they hired to publish this trial.
The reprints are eventually distributed to the sponsor’s sales force to share the content with prescribers, with the sales force completely unaware about this manipulation that has happened with such a trial that benefits the drug they promote for their employer.
As a bonus, the sponsor may agree to pay the chosen medical journal to advertise their products to be placed in this journal as well.
Such misconduct discussed so far impedes research and the scientific method with frightening ethical and harmful concerns, as stated previously.
If so, our health care treatment options with drugs that are claimed to have benefits that are absent have now become unreliable in large part due to such corruptive situations.
Not to mention the absence of objectivity that has been intentionally eliminated with trials produced in this way.
More now than ever, meds are removed from the market or are given black box warnings due to the damaging effects of drugs approved by the FDA. We as citizens need to dig deep and ask why this is happening.
Transparency and disclosure needs to happen with the pharmaceutical industry for reasons such as this as well as many others, in order to correct what we have historically relied upon for conclusive proof, which is the scientific method.
More importantly, research should be conducted in a way that the sponsor cannot in any way interfere in such ways described in this article, which would require independent clinical trial sites with no involvement from the maker of the drug studied in a clinical trial.
And clearly, regulation has to be enforced not selectively, but in a complete fashion regarding such matters.
Public awareness would be a catalyst for this to occur, after initially experiencing a state of total disbelief that such operations actually are conducted by such people, of course.
We can no longer be dependent on others for our optimal health.
Knowledge is power, and is also possibly a lifesaver.
“Ethics and Science need to shake hands.” ……. Richard Cabot
Dan Abshear
Author’s note: What has been written was based upon information and belief.
Published on: www.brainblogger.com
And what to say about the RCT's for psychotherapy?? That's a bigger problem, I think. There can't even be a real placebo group.
But still, it is seen as the golden standard by CBT-specialists.
Anonymous - Good point. That's a whole other story... at some point I'll write about that.
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