Life Is Not A Randomized Double Blind Controlled Clinical Trial

Or  what is wrong with placebo controlled clinical trials and transparency?

I was in an imaginary meeting with a bunch of Internists and Psychiatrists.  We were debating the available and meager literature on the use of trazodone for sleep.  We got into one of my favorite topics - the double blind placebo controlled trial and that catch all "Evidence based medicine."  The dialogue went something like this:

Internist:  "The evidence from double blind placebo controlled trials is weak for trazodone....."

Me:  "Do I need a double blind placebo controlled trial to tell me to prescribe trazodone for sleep?"

Internist: "Are you saying you don't need evidence.  Oh wait, I was at a conference where the head of the society stood up and and gave evidence that clinical trials have their limitations.  Like they are subsequently proven to not be true...."

Me:  "That is not what I am talking about.  I am talking about all of the hype out there that only 40% of people recover from antidepressants or that they are no better than placebo........"

Internist: "But you do have the algorithmic approaches that show...."

Me:  "Yada, yada, yada - for every algorithm, there is somebody with a meta-analysis to show it is wrong.  No I am talking about the ridiculous notion that psychiatrists could stay in business or want to stay in business if only 40% of the people they treat got better.  If that was true I would have become a recluse 20 years ago and just walked away."

General laughter

Internist: "I would kill for a 40% response rate for some of the problems that I treat."

And so on........

This informal conversation among colleagues is illustrative of the recent arguments that focus on physicians and generally psychiatrists more than other physicians that treatments are ineffective.  They are based on an oversimplified view of placebo controlled clinical trials and conflict of interest.  Many times there are no clear points of demarcation between what is a scientific issue (the technical aspects of the clinical trial) and the ethical issue (conflict of interest issues that may compromise the scientific results).   You can read all about current technical problems with clinical trials, like the common observation that there is a lack of generalizability to clinical populations compared with the highly selected and trial sample that in the case of psychiatry generally has much milder forms of the illness being studied.  Here are a few of the concerns that I don't see being discussed anywhere, especially when it comes to clinical trials of psychiatric interventions:

1.  The crude state of clinical trials:  Clinical trials in psychiatry are tremendously unsophisticated. The trial result generally depends on rating scale or clinician global rating scale results that grossly oversimplify the condition and measure parameters that are irrelevant in clinical settings.  The best example I can think of is depression rating scales that list DSM criteria for depression and then apply a Likert dimension to those symptoms.  In clinical practice it is common to see hundreds of patients with the same score on this scale who have a full spectrum of disability from absolutely none to totally disabled.  Which population might be more likely to exhibit an antidepressant effect?  It is also common to see medically ill patients with insomnia who may score as mildly to moderately depressed who are physically ill and not depressed at all.   The same problems exist with clinical trials of schizophrenia, anxiety and Alzheimer's disease.   When this weak technology is combined with a selection process that eliminates clinical populations with the most severe illness, it should not be surprising that any treatment being studied has a weak effect.

2.  A weak clinical trials data base:  One of the clarion calls of so-called evidence based medicine is the Cochrane Collaboration.  I have looked up hundreds of their reviews and the majority of those reviews of both medical and psychiatric studies is: "insufficient results and methodologically unsound".  I suppose it is good to have somebody make that statement, but if you have proclaimed that you are an evidence based physician - you have nothing to go on.  In fact, at some point you stop going to Cochrane because the results are fairly predictable.   Even in the case where you have a result does it apply to the patient you are seeing?  I don't see many Cochrane studies depressed patients that have right bundle branch block, ventricular premature contractions, or complex atrial fibrillation - all common patients seen in clinical practice.  How many more research papers do I have to read that conclude that "more research is needed" while continued inadequate trials are being published and analyzed by Cochrane?  From the current trends and political correctness of evidence based medicine this will go on forever.  The practical aspects are the very large costs of trials.  That is the real reason that pharmaceutical companies (Big Pharma) sponsor these trials.  The political system in the US has decided to farm out clinical trials to private for-profit companies in the exact manner that the US government has farmed out management of the entire health care system.  In these systems Big Pharma absorbs a disproportionate amount of criticism relative to managed care companies.  Managed care has equated "medically necessary" care with care that can be provided in the form of a pill.

3.  The politicalization of clinical trials:  No clinical trials of psychiatric medications can be done these days without an eye to the politically relevant dimensions.  A new antidepressant needs to get as many FDA approved indications as possible in order to beat the political restrictions of utilization review by managed care companies.   That would include indications not only for depression, anxiety, panic, and social anxiety but also chronic pain and possibly attention deficit-hyperactivity disorder (ADHD).  The best way to beat utilization review is to have the only FDA approved indication in the class.  That is also applied to atypical antipsychotics and that fact seems to escape the critics who focus on the number of prescriptions and what that implies.  Physicians are pawns in a game when there are no suitable tolerated medications for bipolar disorder depression and there are atypical antipsychotics for that indication.  These current political factors in clinical trials preclude a focus on cognition, functional capacity, and endophenotypes - all potentially much more valuable than a focus on diagnostic criteria or rating scales based on those criteria.

4.  A characterization that the average physician is ignorant - at best:  Any political movement is associated with ugly rhetoric.   There has clearly been an effort to stampede any physicians with reservations about evidence based medicine into a Neanderthal category.  The irony is that the criticism often comes from sources like managed care companies, medical certification authorities and the press (bloggers) - all entities with their own high levels of conflict of interest.  Common rhetoric used against psychiatrists has been: "You just don't want to be measured".  If the criticism originates from a government, managed care company or administrative authority there is often the attached explicit threat: "Those  days are over!".  The obvious implicit observation is that medicine and psychiatry is now being run by people who don't know anything at all about medicine and there is plenty of evidence on this blog to back that up.

Many critics seem to get a lot of mileage out of the position that they seem to be particularly anointed to criticize the field.   That seems especially true if they happen to be a physician as in: "My colleagues certainly seem to be a bunch of chumps and therfore can be rejected on a wholesale basis or of course listen to me for enlightenment".  I have never witnessed that level of incompetence in any group of physicians where I have practiced across multiple settings.

5.  The use of statistics for rhetorical purposes:  At this stage after reading research for that past 35 years, I am convinced that you can come up with a meta-analysis that will show whatever you want it to show.  Several years ago in the New England Journal of Medicine there was a study that looked at how well meta-analyses predict the results of available large scale clinical trials.  That study showed 2/3 times.  It is common to see a result and then see a meta-analysis that "disproves" the clinical trials result.  Nobody seems very interested in looking in detail at how sound that meta-analysis was.

Today we have a large number of questionably valuable clinical indicators or quality care markers that are often based on the political rhetoric of the government and managed care organizations.   They may be invalid on the face of it, but there is a second equally important aspect.   These same organizations have no valid approach to looking at the statistics of longitudinal data.  They will look at clinic results or even results from the same physician and convert them all to a numerator and a denominator.  Whether that fraction means anything or not is anybody's guess, but there is an administrator somewhere who will be happy to tell you all about it.

6.  False assumptions about the expertise of physicians:  Much of the rhetoric above is focused on physicians.   Psychiatrists as the most politically disenfranchised group are a frequent target.  In the past years we have endured the ideas that medical treatments being prescribed are ineffective and overprescribed.  That brings us full circle to the opening imaginary conversation.  Physicians are trained to focus on several goals including acute treatment, treatment of chronic problems, and providing care for the dying.  The psychiatrists and physicians that I have had the pleasure of working with have been highly effective is achieving those goals.  When I look at the modest results of poorly designed clinical trials all I can do is shake my head.  I would have quit a long time ago if my diagnostic or treatment capabilities were accurately described in clinical trials and most physicians would have.  Informed clinical treatment is a series of often rapid changes in course, rejecting poorly tolerated treatments and looking for things that work better along the way.  I can change the course of treatment depicted in a clinical trial in one day.  In the trial that result is carried to the end as a failure.  How is it that a clinical trial or this evidence would predict my treatment results by mean?  If a treatment is ineffective or not tolerated in my practice, I don't stop treatment and call that person an unsuccessful intent-to-treat subject.  I work with them to establish effective treatment - often in the same time frame as a clinical trial.  Is it quite literally absurd to suggest that clinical trials accurately describe what will happen in clinical practice and yet that is the state of discourse.

7.  The false promise of transparency:  Anyone who followed politics knows that disclosing potential conflicts of interest  is meaningless in the case of politicians.  The general idea is that politicians would refrain from either accepting money from sources where they are involved politically or just not be involved in that area of legislation.  In reality that does not happen.  Sometimes the politicians involved will speak out against any suggestion that there is a connection between the money they receive and their legislative record even when their activities are consistent with a financial conflict of interest.  The sunlight of transparency that many of the critics talk about simply legitimizes ongoing involvement in areas of potential conflict of interest.   Disclosure is a stamp of approval for involvement.  All of that can be researched on Congressional watchdog sites.   The new CMS web site that posts payments to doctors is hyped as a way to appease all of the critics who seem clueless about transparency.  For an eye opener take a look at their decision point on conflict of interest.  CMS seems much more charitable than the typical blogger, politician or journalist with this disclaimer:

"Sharing information about financial relationships alone is not enough to decide whether they’re beneficial or improper.  Just because there are financial ties doesn’t mean that anyone is doing anything wrong.  Transparency will shed light on the nature and extent of these financial relationships and will hopefully discourage the development of inappropriate relationships.  Given the complexity of disclosure and the importance of discouraging inappropriate relationships without harming beneficial ones, CMS has worked closely with stakeholders to better understand the current scope of the interactions between physicians, teaching hospitals, and industry manufacturers."

8.  A lack of appreciation of the regulatory environment:  In the rush to condemn Big Pharma and anyone associated with them, critics often have an idealized version of regulation in their minds.  If only they had access to all of the clinical trials data to analyze for themselves.  They would personally be able to hold Big Pharma's feet to the fire and only allow drugs to be approved that they deemed to be safe and effective.   They are smarter and more ethical than anyone doing the actual trials and certainly smarter than the regulators.  This is at the minimum a failure to recognize that pharmaceutical regulation is after all a political process.  Like all politically directed regulation there are broad goals of safety and efficacy but they are relative and the regulatory mandate takes that into account.  On this blog I have pointed out several cases of medications that not only I,  but the Scientific Committee employed by the FDA recommended against based on safety considerations, but that were approved by the FDA.   Many drugs that I approved as a member of a Pharmacy and Therapeutics Committee (P&T) were expensive but had minimal efficacy.  We approved it based on political considerations (small but vocal advocacy group and untreatable illness) rather than pure efficacy or safety considerations.  The regulatory environment is currently designed to get promising agents into the hands of clinicians for clinical use.  The limited exposure of patients in clinical trials means that rare but serious side effects will not be recognized until post marketing surveillance occurs.  Every person taking an FDA approved medication should realize that.  The regulatory process is not designed to provide perfect medications because there are none.

There is a lot more to say about this subject like a detailed analysis of how the politicalized version about how physicians work and think has nothing to do with the way physicians actually work and think.  But for today I am stopping here.

Life is not a randomized double blind controlled clinical trial and that is generally a good thing.

George Dawson, MD, DFAPA

GSK Eliminates Appearance of Conflict of Interest - Who Is Next?

Glaxo Smith Kline came out with a major announcement a few days ago.   It will no longer pay doctors to promote its drugs and it will no longer tie the compensation of its sales force to the number of prescriptions written by doctors who have been detailed about those drugs.  These are both standard practices in the pharmaceutical industry and this is the first announcement of its kind within the industry.  GSK will continue to to provide "unsolicited independent educational grants" to educational institutions or medical societies.  Pharmaceutical reps will be paid on the basis of technical knowledge and customer service rather than sales.  GSK has been fined heavily lately about promoting off label use of its products and is currently under investigation in China.

My immediate reaction to the piece was "good riddance".  For the past decade there has been no bigger issue in psychiatry than the appearance of conflict of interest with the pharmaceutical industry.  Psychiatry has been targeted more than any other medical specialty by prominent politicians, the news media, and even by psychiatrists themselves.  There are endless blogs and opinion pieces about how the practice of psychiatry has been defined by this appearance of conflict of interest.  There are several blogs out there that have gained prominence by endlessly reviewing all of these details. It has affected the way the APA does business.  It has affected the way local district branches do business.  In the end the politicians are grandstanding on it, because the PPACA (Obamacare) will apparently list any physician receiving money from a pharmaceutical company.  That was suggested as a motivating factor in the NY Times article.  Those public lists have existed in some states like the one I have practiced in for years.

To me the arguments have always come down to advertising and ethics.  From an advertising perspective would we expect people to be affected by product advertising?  Of course we would.  The buying habits of the American population are shaped by advertising.  Selling products is more of a science than people think.  The American public can easily change its buying habits and can purchase products that are unnecessary and will be discarded after a brief period of time.  They can also be sold on products like junk food that are unhealthy but designed to be sold in large quantities.  Advertising would not seem to be the ideal basis for marketing drugs to physicians, but with many new products  physicians are now bypassed and the drug is sold directly to the consumer.  If the epidemiology  of a particular problem like "low-T" is known, direct-to-consumer marketing probably leads to many, many more physician visits than a physician suggesting to their patient that they probably have primary or hypogonadotropic hypogonadism.  All a patient has to do is go to the web site and take a non-specific checklist quiz on the features of "low-T" and be in their doctor's office to get the levels done within a week.  Things will probably go a lot smoother without a physician intermediary in the loop and I am sure that much physician behavior will be shaped by the onslaught of men coming in to be tested for "low-T".  I know for a fact that psychiatrists are approached for this problem because of the overlap between the syndrome and depression.

Part of the advertising argument has always been that there are unconscious factors in play.  Really?  That is the basis for all advertising in general.  The main difference has been that pharmaceutical representatives have been schooled on the relationship aspects of the sale.  They have been taught that basically if a physician likes them or feels indebted to them for free food, trinkets like poor quality pens that never seem to write very well, a round of golf, or tickets to the Lakers game that they may be more likely to prescribe their product.  Most physicians were apparently naive enough to not realize that there was a huge marketing database out there that tracked their prescription writing to see if they were writing the required number of prescriptions for that product.  In the real heyday of marketing bonuses to physicians, companies would pay for travel to important meetings.

While the people focused on the advertising influence kept chipping away mostly at psychiatrists, they seemed to ignore two important developments that made detailing or selling to individual physicians much less relevant.  The first was restricted formularies.  I was on the Pharmacy and Therapeutics Committee (P&T) of one of the largest health plans in the state and an affiliated hospital for a total of 10 years.  During that time, the predominant factor in the decision about whether to put a drug on a formulary that would make it available to prescribing physicians was the cost.  There were very few instances where a drug was so unique that it was made available even if it was very expensive.  In those cases a drug might be available for an incurable illness that had a negligible benefit but it was included basically for public relations.  One of the other overriding themes of the P & T Committee was that all drugs in a particular class (like antidepressants) were equivalent and therefore the least expensive drug in the class could be substituted for anything else.  This potentially led to a lot of unnecessary chaos when medications fell out of favor due to pricing and patients needed to be shifted en masse to the least expensive drug.  It gave hospitals and health plans leverage in dealing with pharmaceutical companies, but in some cases the deals were complex.  As an example, in order to get a new blockbuster drug at a good price, the health plan would need to accept the same company's generic in a different class that had been removed because it was considered too expensive.  Over a decade ago, business entrepreneurs decided that there was money to be made rationing medications to health plan enrollees and now a lot of that is done by pharmaceutical benefit managers (PBMs).  PBMs are currently a multibillion dollar industry.

The second important development was generic drugs.  Practically all of the blockbuster psychiatric medications of the past two decades are now generic drugs.  Many generic drugs are easily affordable even as direct out of pocket purchases.  At that point they are no longer actively marketed by the pharmaceutical company that held the exclusive patents.  They are more likely to be the preferred drugs of PBMs and health plan formularies.  They are in that role because of a scientific approximation.  That approximation is that all drugs in a certain class, like antidepressants that have the same purported mechanism of action are equivalent and one can be substituted for another.  That is clearly false but it allows the health plan to to provide you with the least expensive medication or charge you a hefty copay for one that is not.  It also seems to not consider after market information that can even affect generic drugs.  The best example I can think of there is the FDA warnings on citalopram.  I would guess that despite the warnings, it remains a preferred drug by most health plans.  Health plans in general seem to be geared up to prescribe antidepressants at higher and higher rates.  I would take it a step further and venture a guess that most health plans have not taken a look at the data in their systems on whether or not they have observed problems related to the FDA warning on citalopram.

The ethical argument goes something like this.  Physicians should have the best interests of their patients in mind and an advertising based conflict-of-interest to prescribe a certain drug creates an ethical concern.  On the face of it, it seems like a straightforward argument.  But there are several problems with it.  For example, what is the direct evidence that this occurs - if any?  Is it really believable that a physician would prescribe a decidedly suboptimal medication to a patient based on schmoozing with a pharmaceutical representative?  There are often other factors in play.  It is common to treat people with chronic illnesses who have suboptimal response to the current therapy and who are looking for the "next biggest thing" to try.  A physician who has been detailed on the "next biggest thing" is likely to prescribe it if asked.  There is a similar dynamic with the issue of overprescribing in general.  If a patient persists in their request for an opioid, an antibiotic, a stimulant or any other drug are they likely to get it?  The recent declaration that the CDC initiative to decrease antibiotic prescribing has failed would suggest that they will.  Finally there is the dynamic of "see the doctor and leave with a pill."  There are any number of scenarios where medications are used in medical practice and other options are not even discussed.  The psychiatric cases are highlighted but it happens as frequently in cases of mild diabetes mellitus, back pain, chronic pain of various causes, hypercholesterolemia, mild hypertension and others.  Many people have described this as "the doctor was poised over his prescription pad" but the healthcare industry is set up to see people in brief medication focused visits and physician reimbursement is tied to it.   There are also patient related factors and a recent Tom Hanks interview is illustrative.  He was on a late night talk show discussing his recent diagnosis of diabetes mellitus and he said his physician told him that if he could get back to his high school body weight he probably would not have it.  His reply was: "Well I'm going to have Type II diabetes."

The ethical arguments, especially the ones I have seen constructed by physicians also ignore the general case of conflicts of interest at the professional level.  Practically every major university department allows its faculty to supplement their salaries by consulting in private industry.  In many cases that is a major source of additional income.  In some cases those professionals are involved in setting standards and their approach is much different than the wall that is currently being constructed between the medical profession and the pharmaceutical industry.  As an example, academic and industry professionals within the engineering profession are often on committees responsible for setting standards that govern all of the products within that industry.  Their approach is to include as many industry professionals as necessary rather than suggesting the academics can set the standards themselves.  Considering that pharmaceutical companies employ some of the top scientists in the world it would seem that medicine has a lot to lose if it goes along with the prevailing assumption.  The prevailing assumption is that physicians are powerless to stop prescribing expensive medications that are of questionable benefit for their patients based solely on advertising and no scientific merit.

I applaud the GSK decision even though the above cited factors would suggest that for most physicians it has only historical relevance.  I would encourage all of Big Pharma to adopt the same policies toward physicians.  But this doesn't really go far enough and it is basically a token gesture at this point.  To really make a difference I would suggest that they stop giving money to politicians.  GSK spent $1.9 million on candidates and $4.9 million in lobbying last year.  All of that money was directed at a few politicians.  It is a part of a massive industry wide contribution to politicians.  What do you think buys more influence, giving free pizza and pens to doctors or giving thousands to tens of thousands of dollars to politicians?

George Dawson, MD, DFAPA


Katie Thomas.  Glaxo Says It Will Stop Paying Doctors To Promote Drugs.  New York Times December 16, 2013.

Managed Care 101 – The Prior Authorization Hoax

As managed care organizations worked on how they could prioritize pricing over medical decisions they came up with various plans to “manage” how physicians prescribed medications.  I was a member of two Pharmacy and Therapeutics Committees (P & T) that  both had this as a goal.  One of those committees had a much stricter mandate in terms of saving money.  The basic strategy used by that committee was to place a drug “on formulary” or “off formulary”.  If it was “off formulary” it was not available to any doctors within the HMO to prescribe.

The idea that all drugs within a class that had the same purported mechanism of action ruled the day.  As an example, all of the selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine) would be considered equivalent medications and the committee would decide to place the least expensive ones on the formulary.  At the time, the major controversy was fluoxetine because there was no generic brand available and the company that produced it was notorious for not negotiating prices with hospitals and health care systems.  There was an eventual appeal by psychiatrists who presented to the committee on the unique qualities of fluoxetine.  At the time it was the only medication studied in adolescent depression for example.  Eventually a rule was passed that it was nonformulary for any physician who was not a psychiatrist.

The total cost of the drug was more of a consideration than the absolute price.  Very expensive drugs were approved that had questionable endpoints based on the fact that utilization would be low and that advocates for a particular untreatable illness would want it.  So the decision of the committee and their mandate was to reduce the use of relatively more expensive drugs that would be used fairly frequently.  In some cases, the off formulary drugs were available by “prior authorization” meaning that the prescribing physician needed to usually write up an appeal and fax it to the pharmacy or health plan and in some cases make additional calls.

The health care business has a long history of introducing layers and layers of management driven largely by the amount of money involved.  If you can successfully insert more management for even a small percentage of the available health care dollars you will potentially have a multi billion dollar business.   The management of pharmaceuticals is no exception and the Pharmacy Benefit Manager or PBM was born.  The task of the PBM like the task of a P & T Committee is to control the prescribing physician and force them to choose a medication based on the lowest cost.  Individual variation between patients and all of the other variables that physicians have to take into account do not matter.  If the physician or the patient thinks that they do – it will take a prior authorization for the alternate medication.  

The PBM model was designed from the outset to take a central role in the management of prescription drugs by replacing the relationship that the patient has with their health plan, their pharmacist, and even their physician.  How do I know this?  Take a look at their game plan from an internal memo in the diagram below.  This diagram was taken from an internal memo from over 15 years ago.  The structure depicted in the diagram is the system of care that exists today and the one that 95% of patient have their benefits managed through 

The prior authorization fallacy is essentially the same as the utilization review fallacy.  The most charitable interpretation is that it assumes that a person who is not necessarily a physician and who has no personal responsibility for your care can substitute their judgment based on a cost consideration.    

The diagram is also instructive in the way that the prescribing decision (and the dispensing decision) is trivialized as a "habit" rather than a decision that takes into account the evaluation and personal knowledge of the individual patient.

Today all physicians are routinely subjected to prior authorization procedures that waste significant amounts of their time and the time of their staff in order to make seem like the PBM decision has some degree of medical legitimacy.  The cost to medical practices is huge and completely unnecessary.  If PBMs are really businesses there is really no legitimate reason that they need to include physicians in their decisions of what medication should be covered.  They just need to plainly state that to their patients and deal with the public relations problems instead of wasting about one million hours of physician time per week.  In the weeks that follow I will demonstrate just how far this business plan has infiltrated medicine and psychiatry and what the response has been to date.

George Dawson, MD