1 Boring Old Man

1. Suicidal patients were excluded from the C.A.F.E. study. Dan was admitted with expressed homicidality. In psychiatry, there is no distinction between suicidality or homicidality that I’ve ever heard. Commitment laws invariably say "dangerous to self or others" in one breath. The lectures have titles like "The Lethal Patient." The claim that he was eligible because he was only homicidal is clinically absurd.
2. Dan was declared incompetent and involuntarily committed, but within days allowed to enter a voluntary drug study in lieu of going to the State Hospital. Another absurdity.
3. The outcome parameter for C.A.F.E. was voluntarily continuing the medication, yet Dan’s conditions for avoiding institutionalization were that he stay on the medication. That invalidates any reason for him to be in the study – need I say absurd once again?
4. In the treatment center where he was staying, the staff saw little to suggest any improvement. Dan’s mother increasingly worried about Dan’s clinical state and yet was told he was doing fine. Then at six months, his involuntary commitment was extended for another six months, the duration of the clinical trial. Further absurdity.

This case has lingered for a decade, becoming a cause célèbre and it’s not because the facts of the case are unclear. It’s because the doctor involved, the chairman of his department, the medical school, and the university itself have resisted every attempt to have an independent investigation of this specific case – in spite of the efforts of Dan’s family, the bioethics department at the university, the university senate, and the scientific community at large. The university senate’s vote to investigate was turned into an investigation of the clinical trial conditions now rather than when Dan was still alive in spite of their clearly stated wishes. Carl Elliot has amassed an impressive dossier on this case [Fear and Loathing in Bioethics]. But beyond that, there’s plenty of other evidence on his site that the Markingson’s case isn’t an exception, but simply the loudest example from a program that shouldn’t be allowed to continue operating as it stands.

Conclusions: Olanzapine, quetiapine, and risperidone demonstrated comparable effectiveness in early-psychosis patients, as indicated by similar rates of all-cause treatment discontinuation.

Obtaining that statement and this graph for the AstraZeneca marketing department to counter the other studies showing up Seroquel® [quetiapine] as a weak sister was the goal of the C.A.F.E. study. How can I say that without even being tentative? It’s easy, AstrZeneca said it themselves. Back in 1997, Andrew Goudie, a researcher who had previously worked on Seroquel® wrote Jeffrey Goldstein of the AstraZeneca’s R&D section requesting funding for a further study. In the return email, Goldstein made their policies very clear:

 

Flash: see the press release from the Nordic Cochrane center et al: Backpedalling on EMA’s “proactive publication of clinical-data” draft policy…

Well, today is International Clinical Trials Day once again – celebrated from all sides of the controversies.The AllTrials campaign has a new video about Data Transparency:

… while Clinical Research Organizations have many things planned around the world. I’m spending the afternoon celebrating by going over Clinical Report Forms from an old trial that was misreported. My favorite part of the festivities is a simulated ClinicalTrials.gov write up for James Lind‘s first ever clinical trial on Scurvy in 1747 – Study of the Effects of Multiple Medicines on Scorbutic Sailors Upon The High Seas.

When I think back to 1963 when I started medical school, I never thought about clinical trials. To be honest, I didn’t really know what they were. I learned pharmacology as a discipline much like chemistry where the mechanism of drug action was front and center. In an Internal Medicine Residency, that continued and the use of drugs was based on more apprentice learning and practical experience. Drugs that had a small or variable effects were not prominent on my [or anyone else’s] radar. The focus was on treating the [very] sick, learning how to use toxic chemicals safely. Like saving the life of a patient with septic shock with Kanomycin without ending up with a live, but totally deaf patient. In those days, the class of a drug mattered more that the particular member of the class. I always used Digoxin in heart failure because I knew how to dose it in the various situations where it was called for. A good friend always used Digitoxin because that’s what he learned with. The old doc in the clinic used Digitalis leaf, one step removed from the aboriginal who discovered that chewing certain leaves treated his dropsy. We all did fine and never argued about the choice.

A Psychiatry residency was my first encounter with the endless discussion of small differences among members of a class of drugs. On the in-patient unit, there were a lot of discussions about the differences among the [first generation] neuroleptic drugs and the [tricyclic] antidepressants. I’m a good boy so I learned what I was taught and used the drugs accordingly. But I’ll admit that privately, early on, I didn’t see that much difference. At first, I think I thought that since there were so few drugs available, Psychiatrists needed something to talk about. Later, I came around to seeing that there were side effect differences that were important – though I continued to think that there was a lot more talk than was warranted.

I met Clinical Trials late in my career, actually when I began to wake up to their corruption – after I retired. I’m afraid my old Internist Chauvinism reared its ugly head when I realized that these differences among drugs was being measured with statistics, because the actual differences were so slight. Antipsychotics were like the drugs of my youth. They worked, but they could be plenty toxic and needed to be treated with much respect. Antidepressants were "light and variable" [and toxic], so I mostly stayed away from them when I practiced. When I started looking at the RCTs [Randomized Clinical Trials], I saw what small differences there really were, and how vulnerable these trials were to the analysts who converted the results into papers in a journal. But that’s old news.

Are KOLs drying up? Praise be

Hooked

by Howard Brody

May 14, 2014

Back in 2011 I heard from Cutting Edge Information on the subject of key opinion leaders [KOLs]:

http://brodyhooked.blogspot.com/2011/06/keeping-kols-fat-and-sassy-these.html

I figured that once I outed them on this blog, they would know better than to send me any more e-mails, but apparently they are still at it; the cold-call e-mail that’s reprinted below arrived this week. The content would seem to suggest that Pharma firms are having greater difficulties finding “Key opinion leader” physicians [aka shills] due to the increased transparency requirements of the pending Sunshine Act. If this is the case, then of course it is what I have been advocating for years. I read both the e-mail and the attached detailed brochure but could not find a figure as to the actual cost of this 179-page report, so you’ll have to contact Cutting Edge Information directly if you want to buy a copy. [I have a feeling there might be some sticker shock]…

He goes on to reproduce their email, brochure, and a link.

Addressing Physician Needs through Customer-Centric Commercial Strategies: Many medical device and pharma sales forces are adopting more customer-centric approaches. These commercial models move away from purely product-driven conversations to focus on — and meet — physicians’ and patients’ needs while educating them on key products. Customer-centric sales representatives must work to bring value to their target physicians and patient populations. Many teams focus on finding best-fit product solutions for specific practices. Teams also seek out opportunities to package these products with value-adding materials such as education- and support-based websites or applications…

A few years back, I wrote a post [rip van winkle… ] in which I analogized myself to Rip Van Winkle, Washington Irving’s fictional character who slept for forty years and awoke to a world he didn’t understand. I claimed that my cloistered practice had been a similar hibernation, and that the psychiatry of today was unrecognizable to me. At the time, even I thought I was being melodramatic with that analogy, but now I think I was right after all. But it’s not just psychiatry, it’s Medicine in general. I’ve finally gotten old enough to be visiting doctors myself, and the taint I’ve written about in psychiatry is everywhere.

This Cutting Edge Information company basically functions by taking every aspect of running a pharmaceutical company and surveys the whole industry, collecting the various companies’ ways of approaching the problems, then puts together documents and presentations to sell. It’s marketing research on marketing, and they thrive on attempts to curb the out of control industry marketing techniques. Each new regulatory hurdle is just another market for their materials about how to get around it. Think I’m kidding, just dance around in their site for a while – at least for as long as you can tolerate their strange jargon.

And at the risk of beating a dead horse, Cutting Edge Information has nothing to do with whether the drug in question is any good, or if it’s safe – just how to sell more of it. And since they’ve discovered that their bottom line is total pills sold, they’re getting into the medication compliance business.  In psychiatry, we’re also well aware of how LCM [Life Cycle Management] as in indication sprawl, patent extension, dissuading generics, patenting XR versions or nearby chemical clones, have all have become routine practices.

A remote desktop is a single window whose contents can’t be removed or operated on by any other program in your computer. So everything you do has to be contained within that single window, and any operations have to be done by the limited software provided inside that window. It’s a royal pain in the ass to try to work with the thousands of pages in a clinical trial in that environment. As part of a group trying to vet Paxil Study 329 using this tool, I can personally attest to the fact that it’s an obstruction extraordinaire. It’s like going to sea to see the world in a submarine looking through a periscope.

see also Welcome to Troy, Ombudsman concerned about change of policy at Medicines Agency as regards clinical trial data transparency, EMA policy on publication of and access to clinical-trial data]. Here’s a memo from Peter Doshi and Tom Jefferson that reviews the story:

Simply put, this is just yet another trick to maintain ownership of data for no rational reason. The only purpose is to maintain control, and the only reason to do that is to be able to cheat, and cheat they did in spades. Did AbbVie withdraw their suit by extracting this deal from the EMA? My guess would be that the answer is "yes". These people don’t know how to do anything by playing it straight. Fiona Godlee probably said it right [a sticky wicket…]:

"Unless we can find a solution to the commercial incompetence problem, we have to recognize that the pharmaceutical industry has an irreducible conflict of interest in relation to the way it represents its drugs, in science and in marketing. And unless we can resolve this in a way that is more in the public interest and in patients’ interest, I would argue that drug companies should not be allowed to evaluate their own products."

How Being a Doctor Became the Most Miserable Profession

The Daily Beast

April 14, 2014

A former student of mine, a cardiologist, was seeing me on a consultation because of an abnormality in a test. The question was, "Did I need a cardiac catheterization?" I knew I didn’t. I expect the referring doctor knew I didn’t. The cardiologist quickly knew I didn’t. He also knew that I blogged about the excesses of the pharmaceutical industry. I have a surprisingly respectable LDL ["bad cholesterol"]. Yet he said meekly, "How do you feel about Statins?" I answered, "Not big on them." But he persisted, "We like to see the LDL under a hundred in people with risk factors." I won’t go on, but I felt sorry for him. Like most doctors, he’s surrounded by Guidelines, Managed Care contracts, Medicare rules, etc. The original test was probably not really necessary, nor was the referral, nor would’ve been the Statins. But that’s the way it goes these days [No, I’m not on Statins].

This weekend at a neighborhood Bar-B-Q, I was talking to a neighbor who has a weekend place near where I now live. He’s an Ophthalmologist and I was talking to another friend’s daughter whose job is helping doctors learn to use electronic medical records. The Ophthalmologist laughed and told us that his group [twenty doctors] has 250 employees most of whom are involved with filing insurance and keeping up with the ever changing guidelines on electronic medical records. etc. etc.

I could go on like this for hours, but will spare you. It’s not whining, it’s the truth about practicing medicine right now. I’ve been exceedingly lucky in my life, and missed a lot of the misery that has developed since I reported to medical school in 1963. I changed to a specialty by choice that actually was one of the few that allowed me to evade the misery. That wasn’t the reason I changed, but just blind luck. I didn’t have much in the way of financial ambition and, again by luck, neither did my wife. I had a decent reputation when I left academia so I had a steady referral base for the years I practiced. In retirement, I work for free as a volunteer. Doctors who work for free can practice without the modern strangle-holds. I’m a lucky guy, still glad I went to medical school.

What needs to happen to ensure that ‘treatment’ is front and center in america’s ongoing conversation on mental illness

PhRMA

by Thomas Insel

We need a new generation of treatments for mental disorders. With current medications for schizophrenia, bipolar disorder, and depression, many people get better, but too few get well. And for many mental disorders, such as post traumatic stress disorder [PTSD], anorexia nervosa, and the core symptoms of autism, we lack effective medications altogether. The public health need is undeniable: neuropsychiatric disorders are the largest source of medical disability in the U.S. with onset before age 25 in 75% of affected people.

In the absence of predictably effective treatments, trial and error with current medications remains the standard of care. Since it takes several weeks for antidepressant and antipsychotic medications to reduce symptoms, trial and error often means weeks of needless suffering. In the absence of compelling evidence for choosing a specific treatment, polypharmacy, for better or worse, is now the norm for treating mental disorders. Unfortunately, multiple medications increase the risk for adverse events, and this approach has generally not been proven more effective than giving a single medication…

But we also need better therapeutics. The recent progress in genomics [common variants found in schizophrenia and rare variants in autism] is beginning to define the biology of mental disorders. The discovery of rapidly acting antidepressants [treating depression in 6 hours instead of 6 weeks] reveals unexpected opportunities for treatment. And results from clinical trials with both psychosocial and neuromodulatory treatments demonstrate that psychiatric symptoms are, in fact, highly responsive to intervention, including interventions that tune specific brain circuits. The public health need is great and the opportunity for progress is clear. But it is equally clear that there will not be a magic bullet for schizophrenia or autism or anorexia nervosa. The future for treating mental disorders belongs to networked solutions that combine medications, technology, and psychosocial treatments.

Intellectual Property Protections Are Vital to Continuing Innovation in the Biopharmaceutical Industry

PhRMA

Biopharmaceutical research companies operate under a challenging business model: For every 5,000 to 10,000 experimental compounds considered, typically only one will gain Food and Drug Administration [FDA] approval, after 10 to 15 years of research and development costing an average of $1.2 billion, based on a 2007 study. The few successes must make up for the many failures. In fact, only two out of every 10 medicines will recoup the money spent on their development.

Drug research and development leads to the discovery of tomorrow’s life-changing and life-saving new medicines. Biopharmaceutical intellectual property [IP] protections, such as patents and data protection, provide the incentives that spur research and development. They help ensure that the innovative biopharmaceutical companies that have invested in life-saving medicines have an opportunity to justify their investments. Intellectual property protections also help companies secure the resources for future investments in research, giving hope to patients who await tomorrow’s innovative medicines.

The existing framework of intellectual property policies—including the recently amended patent law and the inclusion of 12 years of data protection for innovative biologics in the health reform law—are necessary to support future R&D investment . These policies provide incentives that spur biopharmaceutical innovation, leading to new treatments and eventually generics—and biosimilars.

How and Why IP Protection Works

There are three key elements for an effective intellectual property system:

It must provide fair and effective incentives for innovation
It must provide innovators certainty regarding their rights
It must offer patent holders strong enforcement tools for defending infringed patents

Without intellectual property rights, competitors could simply copy biopharmaceutical innovations as soon as they were proven safe and effective, offering their own versions without investing the time and money to develop the medicines. Innovators in the biopharmaceutical industry could lose the ability to recoup their substantial investment in new drug development, making it more challenging to find funding.

Reasonable intellectual property protection is essential to sustain the U.S. biopharmaceutical sector’s continuing investments in new research and development. At the most fundamental level, IP rights give America’s biopharmaceutical research companies a chance to fund research into new treatments for our most costly and challenging diseases.

Read More

PhRMA 2014 Special 301 Submission — PhRMA has submitted it’s 2014 Special 301 Submission with the aim of protecting innovation and intellectual property around the world
Note to Media on Elected Officials Support for 12 Years of Data Protection in TPP –Read letters from various members of Congress supporting intellectual property protections in TPP

There was a time when the pharmaceutical industry would have been seen as a support industry for doctors and patients in their quest for improved health. The same for the medical device makers, medical insurance providers, and hospital corporations. But now things seem to have become reversed, with doctors being seen as the distribution system for these industries’ products and patients as consumers. Likewise, organizations like the NIMH and the APA were to assist doctors and patients in their quest for health – but now they have taken on the role of defining how doctors practice, what diagnostic system to use, and have generated guidelines for treatment – paying homage to and dependent on the makers of treatments and the purveyors of medical care with a lousy track record by any standard.

I realize that nosing around the NIMH RAISE Project is a little different than many of the things I write about here. Usually, I’m rooting around looking for corruption peeking out from behind the spin. But here, I’m looking for something else. I want these early psychosis programs to work. A career of seeing what the psychosis of young adults we call Schizophrenia can do to a life has been difficult. The medications available can eliminate the most troubling symptoms but they’ve been overutilized and are no long term solution. And I’m sure that the place to to start is early – before the psychosis erupts if possible, but certainly as soon as it shows its head. I had such a case [1. from n equals one…], and I’m convinced that the course of the illness can be altered. But, thus far, no one has been able to construct a viable  program that endures. There are all kinds of initiatives around the world trying right now – notably Dr. McGorry’s program in Australia [which gets mixed reviews]. RAISE is apparently our current shot, and I want it to be more than simply another well-intentioned-but-likely-to-fizzle program going large prematurely.

Recovery Act Funds Will Support First Phase of Project

NIMH Science News

July 21, 2009

The National Institute of Mental Health [NIMH] is launching a large-scale research project to explore whether using early and aggressive treatment, individually targeted and integrating a variety of different therapeutic approaches, will reduce the symptoms and prevent the gradual deterioration of functioning that is characteristic of chronic schizophrenia. The Recovery After an Initial Schizophrenia Episode [RAISE] project is being funded by NIMH with additional support from the American Recovery and Reinvestment Act [ARRA]. RAISE is a model example of how money from the Recovery Act can accelerate science related to public health problems and potentially benefit those citizens most in need…

RAISE will test approaches that involve intervening immediately upon first diagnosis, systematically incorporating the range of options that are now available in a more piecemeal fashion to people with schizophrenia. These options include medications, psychosocial treatments, and rehabilitation, including teaching patients and families how to manage the disease. The hope is that such a coordinated approach tailored to each individual and sustained over time may make lasting differences in the acceptability of treatment and overall function…

Two research groups will work in parallel to develop and test potential intervention approaches. One group will be led by John M. Kane, M.D., of the Zucker Hillside Hospital, Feinstein Institute for Medical Research, Manhasset, N.Y. The second group will be led by Jeffrey Lieberman, M.D., of the Research Foundation for Mental Hygiene, Inc., New York City. The research teams feature national and international collaborations, with treatment to be delivered in up to 30 clinical sites across the United States. Recovery Act funds will underwrite the initial two phases of the trial, during which the investigators will refine the interventions with input from stakeholders and conduct a feasibility study to demonstrate that each intervention can be fielded in real world community treatment settings and be evaluated in a randomized clinical trial design. With long-term funds committed by NIMH to complete these phases plus a full-scale clinical trial, funding for the study is $40 million…

NIMH RAISE Project Makes Progress as Teams Refine Research Approaches

NIMH Science News

August 9, 2011

Researchers continue to make progress in the NIMH Recovery After an Initial Schizophrenia Episode [RAISE] Project, which seeks to intervene at the earliest stages of illness in order to prevent long term disability. Recent refinements to the two RAISE studies will ensure that RAISE continues efficiently, and generates results that will be relevant to consumers and health care policy makers.

The RAISE Early Treatment Program [ETP], led by John Kane, M.D., of the Feinstein Institute for Medical Research in Manhasset, NY, is now conducting a full-scale, randomized controlled trial comparing two different ways of providing treatment to people experiencing the early stages of schizophrenia and related disorders. Both types of treatment emphasize early intervention but feature different approaches for initiating and coordinating care. Treatment may include personalized medication treatment, individual resiliency training, and supportive services, such as family psychoeducation and education or employment assistance. A total of 34 study locations are scattered throughout the nation and are currently recruiting patients. ETP plans to recruit at least 400 patients for the study for up to two years of treatment and evaluation.

The RAISE Connection Program [Wayback Machine], led by Susan Essock, Ph.D., of Columbia University, will identify ways to effectively integrate a comprehensive early intervention program for schizophrenia and related disorders into existing medical care systems, as well as how such programs benefit individuals receiving multi-element treatment. With the goal of recruiting up to 100 participants in Baltimore, Md., and New York City, the Connection Program will provide participants with individually tailored medication treatment, illness management strategies, education or employment assistance, supportive services for participants and their families, and follow-up care for up to two years. The Connection Program will also carefully document what is needed to implement the key aspects of the intervention in a community setting. If the program proves successful, the information generated will be a resource for state administrators who may wish to incorporate the intervention as a core component of their health care system.

The ETP and Connection Programs aim to improve our knowledge of effective intervention approaches and increase the likelihood of rapid adoption and implementation of a multi-component treatment package for the early stages of schizophrenia. The two studies have the shared goals of improving clinical outcomes for patients and informing health care providers and payers of what could and should be done to avoid the long-term disability currently associated with chronic schizophrenia.

NIMH’s Dr. Robert Heinssen Receives Special Presidential Commendation from APA

NIMH Science News

April 23, 2014

The National Institute of Mental Health [NIMH] congratulates Robert Heinssen, Ph.D., recipient of the 2014 Special Presidential Commendation from the American Psychiatric Association [APA]. Dr. Heinssen serves as Director of the Division of Services and Intervention Research at NIMH. He has been recognized by the APA for championing research on early psychosis and translating it into policy and programs for clinical implementation as a new standard of care. The Special Presidential Commendation ceremony is part of the APA Annual Meeting in New York, with the presentation to Dr. Heinssen taking place at the Convocation of Distinguished Fellows on May 5, 2014.

Dr. Heinssen has played a key role in the development of the NIMH research project, Recovery After an Initial Schizophrenia Episode [RAISE]. This groundbreaking project seeks to fundamentally change the trajectory and prognosis of schizophrenia through coordinated and aggressive treatment in the earliest stages of illness. RAISE is designed to reduce the likelihood of long-term disability that people with schizophrenia often experience. It aims to help people with the disorder lead productive, independent lives. At the same time, it aims to reduce the financial impact on the public systems often tapped to pay for the care of people with schizophrenia.

Learn more about the RAISE project as well as the two NIMH-funded research teams that have developed interventions that can be tested in real-world treatment settings and be readily adopted and quickly put into practice. Dr. Lisa Dixon of Columbia University developed the RAISE Connection Program [Wayback Machine] and Dr. John Kane of the Feinstein Institute for Medical Research has developed the RAISE Early Treatment Program.

The Blockbuster Drug Comes to an End

Forbes

by Matthew Herper

04/06/2011

Geraldine Ferraro died from the rare blood cancer multiple myeloma on Mar. 26 after an 11-year battle. Breakthrough medicines kept the former congresswoman alive, but by 2007 she was worrying about their cost. The medicine she was taking at the end of her life cost 16 times more than the one she took when she was first diagnosed. That reflects the transformation of the drug business over the last decade: from pills taken by millions of people to expensive medicines taken by very small numbers of people. This strategy maintains earnings in the face of fewer new drugs. In November Lipitor, the last branded drug among the 15 most used medicines in the U.S., goes off patent, marking the end of the blockbuster era.

hat tip to Jamzo…  

note that there are no psychiatric drugs on that top ten list

It’s possible that some of the insanity of the PHARMA invasion of Medicine may finally be abating.

How evidence-based medicine is failing due to biased trials and selective publication

by Susanna Every-Palmer and Jeremy Howick

Journal of Evaluation in Clinical Practice. 2014 May 12. [Epub ahead of print]

[full text on-line]

Evidence-based medicine [EBM] was announced in the early 1990s as a ‘new paradigm’ for improving patient care. Yet there is currently little evidence that EBM has achieved its aim. Since its introduction, health care costs have increased while there remains a lack of high-quality evidence suggesting EBM has resulted in substantial population-level health gains. In this paper we suggest that EBM’s potential for improving patients’ health care has been thwarted by bias in the choice of hypotheses tested, manipulation of study design and selective publication. Evidence for these flaws is clearest in industry-funded studies. We argue EBM’s indiscriminate acceptance of industry-generated ‘evidence’ is akin to letting politicians count their own votes. Given that most intervention studies are industry funded, this is a serious problem for the overall evidence base. Clinical decisions based on such evidence are likely to be misinformed, with patients given less effective, harmful or more expensive treatments. More investment in independent research is urgently required. Independent bodies, informed democratically, need to set research priorities. We also propose that evidence rating schemes are formally modified so research with conflict of interest bias is explicitly downgraded in value.

hat tip to pharmagossip…   

Evidence based medicine: what it is and what it isn’t

It’s about integrating individual clinical expertise and the best external evidence

by David L Sackett , William M C Rosenberg , JA Muir Gray , R Brian Haynes , and W Scott Richardson

British Medical Journal. 1996 312:71-72.

[full text on-line]

Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice… By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests [including the clinical examination], the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens…

Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough. Without clinical expertise, practice risks becoming tyrannised by evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual patient…

Evidence based medicine is not “cookbook” medicine. Because it requires a bottom up approach that integrates the best external evidence with individual clinical expertise and patients’ choice, it cannot result in slavish, cookbook approaches to individual patient care. External clinical evidence can inform, but can never replace, individual clinical expertise, and it is this expertise that decides whether the external evidence applies to the individual patient at all and, if so, how it should be integrated into a clinical decision. Similarly, any external guideline must be integrated with individual clinical expertise in deciding whether and how it matches the patient’s clinical state, predicament, and preferences, and thus whether it should be applied. Clinicians who fear top down cookbooks will find the advocates of evidence based medicine joining them at the barricades…

Some fear that evidence based medicine will be hijacked by purchasers and managers to cut the costs of health care. This would not only be a misuse of evidence based medicine but suggests a fundamental misunderstanding of its financial consequences…

Evidence based medicine is not restricted to randomised trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions… It is when asking questions about therapy that we should try to avoid the non-experimental approaches, since these routinely lead to false positive conclusions about efficacy. Because the randomised trial, and especially the systematic review of several randomised trials, is so much more likely to inform us and so much less likely to mislead us, it has become the “gold standard” for judging whether a treatment does more good than harm…

If EBM were the revolutionary movement it was hailed as, we would expect more than benefits demonstrated in specific cases. We would expect population-level health gains, such as those that occurred after the introduction of antibiotics, improved sanitation and smoking cessation. Unfortunately, there is little evidence that EBM has had such effects.

The story so far suggests improved patient outcomes and EBM’s ability to identify superior treatments to replace less effective alternatives. However, the reality is different. Ten years after atypicals had saturated the market, large independent trials known by the acronyms CATIE [Clinical Antipsychotic Trials of Inter- vention Effectiveness], CUtLASS [Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study], and EUFEST [European First Episode Study] have demonstrated that the atypical agents are in fact no more effective, no better tolerated and are less cost effective than their typical predecessors.

In relation to depression, independent meta-analyses pooling unpublished as well as published data now show that SSRIs are no more effective than placebo in treating mild-to-moderate depression, the condition for which they have been most commonly prescribed

So how is it that for over a decade we were convinced by the evidence into thinking these treatments were superior? How could there have been ‘an evidence myth constructed from a thousand randomized trials’ and how did we fall for it?

It is beyond the scope of this paper to discuss practical solutions in great detail, however, we make the following suggestions:

1. The sensible campaign to formalize and enforce measures ensuring the registration and reporting of all clinical trials [see http:// www.alltrials.net/] should be supported – otherwise trials that do not give the answer industry wants will remain unpublished.
2. More investment in independent research is required. As we have described, it is a false economy to indirectly finance industry-funded research through the high costs of patented pharmaceuticals.
3. Independent bodies, informed democratically, need to set research priorities.
4. Individuals and institutions conducting independent studies should be rewarded by the methodological quality of their studies and not by whether they manage to get a positive result [a ‘negative’ study is as valuable as a ‘positive’ one from a scientific point of view].
5. Risk of bias assessment instruments such as the Cochrane risk of bias tool should be amended to include funding source as an independent item.
6. Evidence-ranking schemes need to be modified to take the evidence about industry bias into account. There are already mechanisms within EBM evidence-ranking schemes to up- or downgrade evidence based on risk of bias. For example, the Grading of Recommendation Assessment, Development and Evaluation [GRADE] system allows for upgrading observational evidence.

I really have a distaste for grant applications. I did some when I was an NIH Fellow in the bronze age and much later wrote periodic training grants. I get it why one has to fill out all that stuff and look endlessly at the endless guidelines, but getting it doesn’t erase the tedium of doing it. I am discovering that reading such things is an equally odious task, having tried yesterday to make some sense out of the NIMH RAISE Studies I mentioned earlier [a fabrication?…]. While I’m at it, I apologize for the disjointedness of that last post. I started out with something in mind, but every time I looked something up, some new confusion reared its head. So the post wandered as I wandered from place to place trying to figure things out. This post is a second look at the material from that post.

First off, I declare that I’m a supporter of both the efforts to identify people who are going to have psychosis in advance, though I question whether the existing methods being proposed are on the right track. And I also believe that early intense intervention in FSE [First Schizophrenic Episode] is an imperative. So my interest in the RAISE Programs isn’t antagonistic, I just want to be sure that what’s being proposed is rational and likely to get us somewhere useful. So first, here is what I could find out about the grants:

2009, A Remarkable Year For NIMH

NIMH Director’s blog

By Thomas Insel

December 29, 2009

From the extraordinary funding opportunities presented by the passage of the American Recovery and Reinvestment Act of 2009 [Recovery Act] to significant new investments in research and resource infrastructure — this has been a remarkable year for our Institute. I would like to reflect with you on how the work of 2009 has prepared us for the year ahead…

Finally, I would like to highlight a research project launched this year that seeks to fundamentally change the way schizophrenia is treated: the Recovery After an Initial Schizophrenia Episode [RAISE] project. The RAISE project, which is also supported through Recovery Act funds, will develop and test innovative and coordinated intervention approaches in the early stages of the illness when symptoms may be most responsive to treatment. The study is designed to alter the long-term disability that can result from schizophrenia and help ensure that people with the disease can lead productive, independent lives. Importantly, the interventions being tested will be designed from the outset to be readily adopted in real-world health care settings and quickly put into practice.

^{[reformatted to fit]}

OD stands for Office of the Director, in this case I presume that the Director is allocating the funds from the American Recovery and Reinvestment Act [ARRA]. An Aside: This was the stimulus money after the Great Recession of 2008, I can’t resist showing their prediction graph from that time with what actually happened added [in red].

So with the ARRA windfall, Dr. Insel funded two RAISE [Recovery After an Initial Schizophrenia Episode] grants: RAISE Connection [271200900020C-1-0-1] and RAISE ETP [271200900019C-0-0-1]. Dr. Jeffrey Lieberman was Principle Investigator on RAISE Connection – a two site effort looking to recruit >370 subjects. It looks as if they planned to have two treatment arms assigned randomly at both sites. Dr. John Kane [1][2] was the Principle Investigator on RAISE ETP with 33 sites with a projected enrollment of >400 also with two arms, but each site was assigned to a specific arm. While the NIMH grant description for both was the same, the clinicaltrials.gov descriptions differed and they followed a remarkably different revision history.

And these are the two studies that were implemented from these grants:

1. Behavioral: Multi-element, team-oriented treatment
   Arm Label: Team-based treatment:
   Participants will receive treatment and services based on their needs coordinated by a small team that is led by a clinical coordinator. Services that are available to the participants include social skills training, medication treatment to address symptoms, education and employment advising, and substance use treatment.
2. Behavioral: Connections to community-based treatment and services
   Arm Label: Facilitated community-based treatment:
   A care specialist will work with participants to identify and link to treatment and service options that are available in the community. These options can include finding a therapist, obtaining ongoing medication treatment to address symptoms, joining a support group, and getting a job coach.

• Dr. Lieberman was replaced as the responsible party by Susan Ellis PhD.
• The target enrollment was dropped from 370 to 80, and shortened.
• The active comparator was dropped [now only one arm]:
  "The Connection Program aims to to assess the effectiveness of a Team-based intervention for individuals with a first psychotic episode, observing outcomes over time for our study participants. When tracking outcomes, the Connection Program will make comparisons with what is known about the natural history of untreated first episode of psychosis as well as usual care outcomes from other experimental studies…"
• The study was logged in as recruiting again.
• Obviously, it was no longer randomized or blinded as there was only one group.

RAISE ETP [Extended Treatment Program]: Clinical Trial NCT01321177 was registered on January 27, 2011 with two arms:

1. Behavioral: Integrated Treatment
   Arm Label: Integrated Treatment:
   Integrated program of treatments and services delivered by a coordinated team of providers that includes:
   • education about schizophrenia and its treatment for the participants and their family members
   • medication for symptoms and preventing relapse that uses a computerized decision support system
   • strategies for managing the illness and building personal resilience
   • help getting back to school or work using a supported employment/education model
2. Behavioral: Connections to community-based treatment and services
   Arm Label: Facilitated community-based treatment:
   A care specialist will work with participants to identify and link to treatment and service options that are available in the community. These options can include finding a therapist, obtaining ongoing medication treatment to address symptoms, joining a support group, and getting a job coach.
Standard mental health treatments and services offered at the local agency that may include:
• medication for symptoms and preventing relapse
• psychosocial therapy which may include a range of behavioral treatments and supportive services
• Case management

It was logged as recruiting on 03/22/2011 and as Active, not recruiting on 12/27/2012.

If you’ve made it through this tediousness, you can see that something fairly dramatic happened along the way. RAISE Connection got off to the first start but shortly after they started recruiting, they stopped. Then a few months later, it was as if it just shut down. There was a new P.I.; they dropped the Active Comparator; they radically downsized the projected enrollment; then sauntered along with changing investigators and sponsors; and they ended up with only 65 subjects. At the same time RAISE Connection went on ice, RAISE ETP got started and barreled ahead full bore. I can locate nothing that tells me what happened, but I think it matters some. RAISE Connection was awarded ~$10 M and basically shut itself down when RAISE ETP got started. So I think it’s legitimate to ask, Where did that $10 M go?

Portions of this report have been drawn from the final reports of the RAISE Connection Program [Contract No. HHSN271200900020C] and interim progress reports of the RAISE Early Treatment Program [Contract No. HHSN271200900019C]. We thank the following subject matter experts for their careful review of this document, insightful feedback, and helpful editorial suggestions: Lisa Dixon, Susan Essock, and Howard Goldman [RAISE Connection Program]; John Kane, Nina Schooler, Delbert Robinson, Jean Addington, Mary Brunette, David Penn, and Patricia Marcy [RAISE Early Treatment Program]; Kristin Cadenhead, Barbara Cornblatt, Keith Nuechterlein, Diana Perkins, and Scott Woods. Finally, we thank Patrick McGorry [AO, M.D., Ph.D, FRCP, FRANZCP] for generously sharing resources developed in Australia to support broad implementation of evidence-based treatment approaches for FEP, as well as lessons learned from the national roll out of coordinated specialty care programs in that country.

Dr. Insel’s blog post, Director’s Blog: From Research to Practice, focused of the rapidity of the NIMH translation of the RAISE Connection study to the SAMSA Block Grants for the States to implement FSE/FPE programs. This is a relative huge initiative similar to the EPPIC program in Australia. First off, the RAISE Connection study is absolutely nothing to write home about, and we don’t have access to "the final reports of the RAISE Connection Program … and interim progress reports of the RAISE Early Treatment Program" to allow us to know if the results of these programs justify their being a template for such a major undertaking. It might be the greatest idea in the world or it might be a major dud and a massive waste of resources.