1 Boring Old Man

NIH, FDA Toughen Rules on Reporting Medical Trials

The Chronicle of Higher Education

By Paul Basken

November 19, 2014

[behind pay-wall]

The Obama administration on Wednesday proposed new rules aimed at forcing researchers to publicly post details of medical trials involving human subjects, saying compliance to date has been woefully insufficient. For years, the government has required researchers using federal money, or seeking federal approval for a medical intervention, to announce the details of their trials in advance and post the results. But that hasn’t happened often enough, National Institutes of Health officials said. As evidence, they cited a study conducted at Yale University in 2012. Researchers studied a sample of trials using NIH money and found that fewer than half had results published within 30 months of the trials’ end.

"We as a community have a disappointing track record" of disseminating trial results, said Francis S. Collins, director of the NIH, in a briefing outlining the proposed new rules.

Registering trials in advance and reporting the results afterward are critical to ensuring the integrity of studies, protecting patients, and building awareness of the results, Dr. Collins said. Under a pair of related proposals announced by NIH officials, researchers will be given specific guidelines on which trials are covered by the rules and which penalties will be levied against researchers who fail to comply. The current law is unspecific, NIH officials said. That has left researchers uncertain ­— or able to claim uncertainty — about the law’s exact requirements.

Once the new rules take effect, "it will be a straightforward matter for us to be able to take compliance action," said Kathy L. Hudson, deputy director of science, outreach, and policy at NIH. The policy consists of two sets of complementary rules, one largely covering medical-trial results presented to the U.S. Food and Drug Administration as part of a drug-approval process, and the other covering research financed by the NIH.

In the case of the FDA, violations would lead to civil penalties. In the case of the NIH, researcher noncompliance could lead to the withholding of grant money, and loss of future agency support, Ms. Hudson said. "We’re certainly going to be taking that into account as we decide about future grant awards," she said of researcher-compliance records. The rules were issued with the expectation that they will take effect after a 90-day period of public comment…

HHS and NIH take steps to enhance transparency of clinical trial results

National Institute of Health

News Release

November. 19, 2014

The U.S. Department of Health and Human Services today issued a Notice of Proposed Rulemaking [NPRM], which proposes regulations to implement reporting requirements for clinical trials that are subject to Title VIII of the Food and Drug Administration Amendments Act of 2007 [FDAAA]. The proposed rule clarifies requirements to clinical researchers for registering clinical trials and submitting summary trial results information to ClinicalTrials.gov, a publicly accessible database operated by the National Library of Medicine, part of the National Institutes of Health. A major proposed change from current requirements is the expansion of the scope of clinical trials required to submit summary results to include trials of unapproved, unlicensed, and uncleared products.

“Medical advances would not be possible without participants in clinical trials,” said NIH Director Francis S. Collins, M.D., Ph.D. “We owe it to every participant and the public at large to support the maximal use of this knowledge for the greatest benefit to human health. This important commitment from researchers to research participants must always be upheld.”

ClinicalTrials.gov currently contains registration information for more than 178,000 clinical trials and summary results for more than 15,000. These numbers include trials that are not subject to FDAAA. Among the primary benefits of registering and reporting results of clinical trials, including both positive and negative findings, is that it helps researchers prevent unnecessary duplication of trials, particularly when trial results indicate that a product under study may be unsafe or ineffective, and it establishes trust with clinical trial participants that the information from their participation is being put to maximum use to further knowledge about their condition.

Developed by NIH in close coordination with the FDA, the proposed rule details procedures for meeting the requirements established by FDAAA to improve public access to clinical trial information. FDAAA and the proposed rule apply to certain interventional studies of drugs, biological products, and devices that are regulated by the FDA, but, generally, not to phase 1 trials of drugs and biological products and small feasibility studies of devices. The proposed rule specifies how data collected and analyzed in a clinical trial would be required to be submitted to ClinicalTrials.gov. It would not affect requirements for the design or conduct of clinical trials or for the data that must be collected during clinical trials.

“This proposed rule would close an important gap, making additional information about clinical studies of investigational drugs, medical devices and biological products available to the public,” said FDA Commissioner Margaret A. Hamburg, M.D. “It would help eliminate unnecessary duplicative trials, advance biomedical innovation, and provide the public with a much richer understanding about the clinical trials for these products.”

Notable changes from current requirements and practice that are outlined in the proposed rule include:

1. A streamlined approach for determining which trials are subject to the proposed regulations and who is responsible for submitting required information.
2. Expansion of the set of trials subject to summary results reporting to include trials of unapproved products.
3. Additional data elements that must be provided at the time of registration [not later than 21 days after enrolling the first participant] and results submission [generally not later than 12 months after completion].
4. Clarified procedures for delaying results submission when studying an unapproved, unlicensed, or uncleared product or a new use of a previously approved, licensed, or cleared product and for requesting extensions to the results submission deadline for good cause.
5. More rapid updating of several data elements to help ensure that users of ClinicalTrials.gov have access to accurate, up-to-date information about important aspects of a clinical trial.
6. Procedures for timely corrections to any errors discovered by the responsible party or by the Agency as it processes submissions prior to posting.

Read a summary of the proposed changes here.

Sharing and Reporting the Results of Clinical Trials

JAMA

by Kathy L. Hudson, PhD and Francis S. Collins, MD, MPH

November 19, 2014

[full text on-line]

NIH and FDA Toughen Rules for Reporting Clinical Trial Results

Pharmalot: WSJ

by Ed Silverman

November 19, 2014

[full text on-line]

Proposed rules will vastly expand trove of clinical trial data reported in U.S. database

Science: Science Insider

by By Jocelyn Kaiser

November 19, 2014

[full text on-line]

Back in the 1980s when psychiatry [and psychoanalysis, and medicine, and American culture] was undergoing big changes, the trajectory of my life changed and I found a place out of the flow that I really liked. It was more than a refuge or a sanctuary, it was just as interesting as I could’ve imagined. I’ve said it here a lot, but I had no idea how cloistered it was, and I’ve used the Rip Van Winkle analogy to the point of monotony. Today, I worked in the clinic where I volunteer – a plenty busy day. But it’s always the same. When I work as a psychiatrist/doctor, I don’t get into the tangles I can get into thinking about the things I write about.

I just looked over the comments, and I appreciate the input. I wasn’t kidding that I need to put the blog in the background and learn some new stuff for a big project. But I think I also need to think some about what that comment space is about. I haven’t really done that. I enjoy reading what people have to say, and there are lots of times when what I write about has been shaped by what I read there, but most of my energy goes into the content and topics I’ve followed.

The Internet is something new. I am a not-so-closet nerd and was on the Internet World Wide Web right after Al Gore Tim Berners-Lee invented it. I built an early site, The Way of Javascript, that was a tutorial that taught the first language that took the technology beyond just documents with links as it might be done by a Zen Master. Grand fun. And that was only 20 years ago. But the on-line interpersonal world hasn’t been a part of my life with its Avatars, Archetypes, infinite recesses, and the not so Zen Ways of Social Media. So I think I’ll just let that space and its vicissitudes simmer for a bit while I do this other thing, and see what bubbles up. If I’m to provide such a space, I guess it’s my responsibility to know what it’s for…

As some of you know, a group of us are on a RIAT [restoring invisible and abandoned trials] team that has spent the last year working on the first shot at an independent team analyzing and reporting on someone else’s Clinical Trial. It has been a great learning experience for me, and has been the reason for so many posts about how trials work and my monotonous slides:

On the day there was a bruhaha in the comments, I had learned that there was much to do in a tight time-frame. Emails were buzzing across oceans and I was all caught up in those things, so I missed what was going on in my own back yard. When I say tight time-frame, I should say tight time-frame for me. My place in this hinges in part on my previous training in math and statistics [which ended the same year the first PC was built – 1974]. So every new task has a learning curve that’s long and tedious – catching up with newer statistical methodology and doing it using modern software [mainly the latter]. When I was doing it the first time, data was on punch-cards and software was something you wrote yourself [also on punchcards].

Blogging is too much fun for me. I really enjoy having a piece of my day where I take something and research it a bit, then my dogs and I go out on the porch or one of those park benches in this beautiful Fall and compose what I want to say, write it down, then come back and format it as a post. It’s something a busy practitioner never really gets to do. But right now, I’m going to have to take something of a break and hit the books [AKA Internet] to learn some new stuff. I know what it is, and what it’s for, but I don’t know how to do it in practice or how to format the data or set up the equations, etc. If I keep having blogging fun, I won’t get the job done. So expect only occasional and brief content from me for the next month or so while I take a refresher course. Feel free to talk among yourself in the comments.

EMA’s Release of Regulatory Data: Possible Fall out for Journals and Research Synthesis

On 2 October the European Medicines Agency’s [EMA] published the final version of its policy on prospective release of clinical study reports [CSRs] of trials submitted by sponsors in support of Marketing Authorisation Applications [MAAs]

PLOS: Speaking of Medicine

By Tom Jefferson

November 3, 2014

[full text on-line]

I have summarized its content and made preliminary comments here

The policy
In brief, from 1 January 2015 the proactive policy will join the current reactive policy and allow prospective access to incomplete CSRs at two levels: a “viewer” level of access and a “researcher” level. The former will allow on-screen viewing only with a simple registration procedure, while the latter will require proof of identity but allow download and OCR searches to be carried out on CSRs. Prospective seems to mean two things: after a regulatory decision has been taken, pharma will format and write CSRs for direct web posting, and once you have obtained access credentials, you will not have to ask every time you want a CSR and wait some months [and in some cases be turned down].

Its meaning
The practical importance of the policy hinges on the dawning realization of the difference in accuracy, completeness and trustworthiness of published versions of trials compared to their CSR counterparts. Trials may not be published, some may not even be registered [especially the older ones] posing decades-old problems for readers, users and, from my point of view, evidence synthetisers. Reporting bias [cherry picking] is the broad term which encompasses the scores of different types of bias present in publications. The range from the well-known publication bias to the less known swamping bias [when important information on a trial is missed amidst a sea of other information]. CSRs in theory cut through all this by presenting exhaustive structured narratives and results of trials. This is essentially part of what regulators see.

The policy has some as yet unclear legal aspects and sets out equally unclear rules for redaction of CSRs [based on the preservation of commercial interests and protection of participant privacy]. It also does not explain why some parts of the CSRs will not be released.

The proactive EMA policy will provide an easily accessible window to look at CSRs. When you read the statements “placebo controlled” or “matching placebo” or “double blind” in a journal article you can now go and check if that is really the case. And if, for example, the certificate of analysis¹ is missing from the CSR that you are accessing, you can ask EMA why that is so, introducing an unheard of degree of accountability.

An ever growing body of scientific evidence shows that journals do not give the whole story [although some go to extraordinary lengths].  This point reflects simple arithmetic: the ratio of CSR pages to publication pages for the same trial can be as much as 8000 to 1.  To maintain their credibility journals will have to either provide access to CSRs, or stop publishing trials altogether and offer commentaries on trials only. One further option, that of asking for the complete CSR to be made available for each trial on submission, is also at present unrealistic, as current peer reviewers are unskilled in making sense and reviewing a CSR, especially if time constrained. My experience also tells me that every trial should be looked at in the context of the whole trial programme, for example to avoid a piecemeal approach to the assessment of potential harms.

There may be other scenarios such as slowing the rate of publication of trials to allow thorough review of the linked CSR, the growth of a skilled cohort of well-paid peer reviewers or the publication of structured summaries linked to CSRs on the EMA webpage or a combination of these.

Evidence synthesis
Accessibility of CSRs, although not a panacea for reporting bias, should also improve the reliability of research synthesis. As more information on the planning, intended and real conduct of the trial will be available, a good review will be the one that searches regulatory and pharma websites, reconstructs and presents the whole trial programme of interest and includes and reviews CSRs. A good review will also contact the trials sponsors to obtain confirmation that there are no invisible trials and trawls through registers, black and grey literature to check that this is so.

But all this will take a lot of time and require skills and tools to be developed. Businesses which produce reviews in months will require years to do the same, or fall behind.

It is likely that the whole infrastructure to produce synthesis studies will have to change and become much more professional, flexible and intensive, or fall behind. For the record, I don’t believe in automatic methods of data extraction to facilitate dealing with CSRs, but perhaps I am too old-school and will be proved wrong.

So, increased accountability should work for everyone and should keep CSR writers on their toes, open regulators to being quizzed, revolutionise publishing and produce better synthesis assessments.

I’m aware that an argument broke out in the comments that stepped outside the little box above the comments section – went interpersonal. It has happened before, which why that box says what it says. The first time, the circumstances were unusual. It was someone in town who discovered I had a blog and inserted himself into the comments as if it were a hot-line to my home. I shut down the blog [off the air…]. When I returned, I held and moderated all the comments. My models were Danny Carlat and Soulful Sepulcher who had done that for years for the same reason. Ultimately they left the public stage. After a time, the assault was over and I stopped. I didn’t like doing it. I don’t live at the computer and often compose with a primitive device, so it meant a lot of "checking in."

Time passed, and there came a period with multiple commenters who preached." I wrote them, asking them to stop, and they either did or moved on – all except one who escalated. It wasn’t that his views were the main problem, it was that he was dominating the space and insisting on agreement. I said that, even gave my alternative views and he escalated. I finally bannned him [a limit… last paragraph]. He found my home email address and made his closing argument. When I occasionally comment elsewhere, he often chimes in with another version of the story. I lost a lot in that episode. A number of very thoughtful commenters who didn’t feel safe and moved on. I hear from them from time to time, but it’s not the same as when they were adding input and perspective frequently.

In my life, I ran a number of therapy groups and groups of other kinds. The solidest line of thinking I ever read was written by Winfred Bion, a British Kleinian Psychoanalyst who was, as is common in that set, a lunatic who spoke in very peculiar ways. But his theories on the behavior of unstructured groups is as solid a piece of evidence-based-medicine to me as Vitamin C cures Scurvy. He says that people in groups are all frightened at some level, and that fear mobilizes aggression [in all of us]. At some point in a group’s history, the aggression will rise to the surface. Actually, it is in part because people feel safe enough to let it. One common solution is for the group to find a shared enemy, and the group organizes around opposition to that shared enemy. Think Klan. Think Nazi. Think tree-hugger. Think political party. Think Cult. We’ve all been in such groups. Group members are safe with each other guaranteed by the presence of a common enemy. Such a group can never change.

Another possibility is that the aggression can be mobilized inside the group, among members. A group leader can’t keep that from happening. It’s human nature. And people begin to take sides. There’s often a scapegoat, a person who is seen as the problem, and the group points towards that person. They have to shape up or ship out. It may be a weak link. But it may also be a strong link. Here, the group leader needs to do a difficult thing – keep the group from disintegrating or from killing [extruding] the scapegoat [whether they deserve it or not]. Success in that endeavor leads to the leader becoming the target. The leader is in charge, so fix it! The double bind is that the leader is only human and knows he/she can’t resort to murder – having just prevented several. He/she can’t change people, so he/she becomes the target. Weak. Playing favorites. No real leader at all. Safety was only an illusion. I once watched a perfectly competent Full Professor who ran a Resident’s Group be fired by the Group itself, and later censured by the University – which he left. His error? He thought he could fix it. He originally had given me the Bion book, but I don’t think he’d read it, at least not the last chapter. There’s only one outcome that ever works. The leader is no longer the leader, but survives and becomes just another vulnerable member. The safety of the group becomes the valued property and responsibility of the group itself. And safety without a shared enemy is the only viable principle for groups to remain healthy, creative, and endure. You saw the movie already. The Wizard of Oz. And that outcome is never guaranteed.

I haven’t really thought of the regular commenters as a group, but now that I think about it, you are. Steve said it best. I went back and reread all the comments for several months and this isn’t the first tit-for-tat. When it happens, I wince. Sometimes I turn off the comments. But mostly I wince. I’m not going to play wizard, spank anybody. Fire anybody. In a couple of emails, it was suggested that I’m protecting a "pal" – Dr. Carroll. We are pals, but he doesn’t need me to protect him. There was also a hint of the League of Arrogant Male Psychiatrists idea in there. I hate those people too. This bruhaha makes me aware of how much I value the input from everybody currently commenting. You have shaped and occasionally changed my own opinion. I don’t mean to be drippy, but I’m genuinely honored you chose this space to think out loud in. Here’s my contribution to the theme of safety. I just explained a psychoanalytic principle of Group Psychology out loud on this blog. After 34 years of being ridiculed for even thinking about such things, I just don’t do that – ever – except with safe colleagues. While I don’t plan to continue doing that here, I must feel at least safe enough to reveal the part of being a psychiatrist that has most preoccupied and mattered to me throughout my career.

When Sigmund Freud was in his 30’s, a young neurologist, he began to try to connect what he knew about the brain and what he saw in human behavior. The end of the 19th Century had seen a flowering of knowledge about the brain anatomy, micro-anatomy, and their correlation with the neurological syndromes. He wrote it as a treatise in 1895 he called The Project for a Scientific Psychology. Soon thereafter, he gave up trying to map behavior and psychic phenomena to the Brain, developing instead a system to define the structure of the Mind. Concurrently Emil Kreapelin in Germany and Eugene Bleuler in Switzerland were building diagnostic classifications of the Mental Diseases – primarily the Psychoses. In 1913, Karl Jaspers wrote his General Psychopathology proposing a fundamental distinction among the ¹Brain Diseases, ²Major Psychoses, and ³Personality Disorders:

Mental disorders as “brain diseases” and “Jaspers’ legacy

by MARIO MAJ

World Psychiatry. 2013 12:1-3.

…In this context, the basic heterogeneity of mental disorders should not be overlooked. “Contemporary neo-Kraepelinian American psychiatry … practices as if there were biological commitments to over 300 DSM-defined entities, while the biological model may apply only to a few mental disorders, for instance, “schizophrenia, manic-depressive illness, melancholic depression and obsessive-compulsive disorder”. These recent statements resonate with Jaspers’ classification of mental disorders into three groups — cerebral illnesses [such as Alzheimer’s disease], major psychoses [such as schizophrenia and manic-depressive illness], and personality disorders [including neurotic syndromes and abnormal personalities] — which are “essentially different from each other” and not equally amenable to biological research [those of the third group may just represent “variations of human nature”]…

The DSM-II revision was unpopular from the start, particularly in the Midwest [Saint Louis] where there was a movement to establish a more medical based biological psychiatry [the NeoKraepelinians]. In 1970, Eli Robins and Samuel Guze published Establishment of Diagnostic Validity in Psychiatric Illness: Its Application to Schizophrenia laying out their approach to diagnostic validation. Then in 1972, Washington University senior resident John Feighner, under the tutelage of the Saint Louis group, published the Feighner criteria [Diagnostic Criteria for Psychiatric Research]. Robert Spitzer, tasked with the next DSM revision, used the Feighner Criteria as the starting place for his RDC [Research Diagnostic Criteria: Rationale and Reliability], an NIMH/APA project that produced the DSM-III in 1980. The DSM-III was a radical change, organized by phenomenological criteria without reference to etiology – atheoretical. Robert Spitzer lead a further revision in 1987 [DSM-IIIR] and Allen Frances produced rhe DSM-IV in 1994. Both of these revisions were refinements – variations on the DSM-III theme of atheoretical phenomenology.

By the turn of the century, mainstream, academic, and organized psychiatry were focused on psychopharmacology and neuroscience research – what had formerly been called Biological Psychiatry. David Kupfer and Darrel Regier set out in 2002 to produce a DSM Revision with the clinical syndromes keyed to biologic parameters – a paradigm shift. But by 2011 after a $25M effort, Kupfer and Regier had to announce that the attempt had failed [Neuroscience, Clinical Evidence, and the Future of Psychiatric Classification in DSM-5]. The biological correlates just hadn’t materialized. In the quest for the big shift, they had not done much revising and the changes they did make had been heavily opposed by both Drs. Spitzer [DSM-III & DSM-IIIR] and Frances [DSM-IV] and many others. Then the Field Trials were disappoimting with Kappa values in the range of the DSM-II. So the DSM-5 Revision was released in a cloud of controversy. One conclusion clear outcome of that process was that the clinical syndromes as defined did not map onto the neuroscience findings or the effects of the widely used drugs.

The aim of the RDoC initiative is to accelerate the pace of research that translates basic science into clinical settings by understanding the multi-layered systems that contribute to mental function. The RDoC approach emphasizes neurodevelopment and environmental effects, in keeping with modern views about the genesis of mental disorders. “The RDoC unit is the culmination of over five years of effort from the institute and members of the research community,” said RDoC unit Director Bruce N. Cuthbert, Ph.D., who has served as coordinator of the RDoC working group since its inception. “We will now have four full-time staff to coordinate the program and enhance communication with scientists and the public as RDoC grows.” “RDoC represents a significant paradigm shift in the way we think about and study mental disorders,” said Thomas R. Insel, M.D., director of NIMH. “The RDoC approach cuts across traditional diagnostic categories to identify relationships among observable behavior, neurobiological measures, and patient self-report of mental status.”

Most of us sort of know what the RDoC is not. It’s not based on the traditional medical method of using signs and symptoms organized into syndromes that point to an underlying disease entity. Like Dr. Kupfer’s failed attempt to add "Cross Cutting Dimensional Diagnoses" to the DSM-5, it focuses on phenomena that transcend traditional categories. But the RDoC goes much further by ignoring diagnosis as we know it altogether. So what is it?

Research Domain Criteria [RDoC]

The Research Domain Criteria [RDoC] project implements Strategy 1.4 of the 2008 NIMH Strategic Plan: “Develop, for research purposes, new ways of classifying mental disorders based on behavioral dimensions and neurobiological measures.” RDoC attempts to bring the power of modern research approaches in genetics, neuroscience, and behavioral science to the problems of mental illness, studied independently from the classification systems by which patients are currently grouped.

The approach provides a framework to develop hypotheses and evaluate results from studies that investigate the mechanisms of psychopathology. The heart of RDoC is a matrix of functional dimensions, grouped into broad domains such as cognition and reward-related systems, examined across units of analysis ranging from genetics and circuit activity to psychology and behavior. Emphasis is placed upon the developmental trajectories through which these functions evolve over time, and the interaction of neurodevelopment with the environment. RDoC research starts with basic mechanisms and studies dysfunctions in these systems as a way to understand homogeneous symptom sets that cut across multiple disorders, rather than starting with clinical symptoms and working backwards.

We have established a multi-study database [RDoCdb] with subject-level data from RDoC research so that accumulating knowledge can be further investigated to identify trans-diagnostic mechanisms. The RDoC Discussion Forum invites input from the scientific community. We expect that the efforts of all involved in RDoC will encourage new ways to think about diagnosis and yield novel treatments and preventions.

Even a brief scanning of the tables reveals how very different the elements are from any existing system.

The RDoC has a Workgroup and a Unit, sub-Workgroups, the Matrix, a Database, and a granting mechanism. By keying future NIMH projects to the RDoC, they hope to populate their database and begin to correlate these basic measurable brain functions with the units of analysis [genes, molecules, cells, circuits, physiology, behavior, self-reports, and paradigms]. How this is exactly going to happen remains somewhat mysterious to me. Obviously, this is part of the NIMH push to quickly develop new treatments, drugs – and their hope is that the drugs, existing and future, will map onto these basic functions, unlike their independence from the traditional clinical symptoms and syndromes.

I don’t know enough neuroscience to evaluate how likely their constructs and sub-constructs are to represent discrete elements of brain function – implemented by genes, circuits, molecules, etc. Nor do I know how they intend to measure many of these parameters in reality. Like all the previous attempts, their assumptions are about the Brain [and not the Mind]. And this statement, "The RDoC approach emphasizes neurodevelopment and environmental effects, in keeping with modern views about the genesis of mental disorders", represents an opinion, stretched very thin after 35 years of disappointing research and theorizing.

Antidepressants’ Black-Box Warning 

– 10 Years Later

by Richard A. Friedman, M.D.

New England Journal of Medicine 2014 371:1666-1668.

[full text on-line]

• Case Reports: There are ample collections of case reports [SSRI Stories, Rxisk, etc] that document the syndrome of Akathisia with suicidal and homicidal thoughts and acts. And the most convincing evidence comes from personal encounter. Having seen such cases, I have no question that it is a very real phenomenon, though uncommon.
• Data from RTCs [Randomized Clinical Trials]: Meta-analyses, notably the FDA review by Hamads et al, find a small but significant increase in suicidality in the Clinical Trials of antidepressants in youth.
• Population Studies: The majority of authors who oppose or want to revoke the Black Box Warning base their arguments on the collection of population studies that come from a variety of sources. They show that the Black Box Warning did decrease anti-depressant prescription rates particularly in youth. Most of these studies show no real change in the overall rates of suicidal thinking or completed suicide.

Nevertheless, given the overall direction of these trends, it is critically important for primary care providers, who see and treat a substantial proportion of depressed patients, to know that the risk posed by untreated depression — in terms of morbidity and mortality — has always been far greater than the very small risk associated with antidepressant treatment. We need to better educate physicians, to help them understand that although they cannot ignore that small risk, they can safely manage it by carefully monitoring their patients, particularly children and adolescents, during pharmacotherapy.

What should the FDA do in light of these observational data? Given that the agency’s 2007 modification of the black-box warning has not been sufficient to prevent what seems to be a chilling effect on depression treatment — perhaps the mere presence of a warning speaks louder than any clarification it may contain — I believe it’s unlikely that further modification would be helpful. I would therefore argue that the FDA should consider removing the warning entirely…

Well, I wasn’t «chilled» by what I recalled of that paper Friedman is talking about, by Lu et al, so I went back for another look. I still wasn’t impressed that the Black Box Warning had that big an effect. I noticed that their graphs were drawn on different scales for adolescents, young adults, and adults. So on a lark, I graphically transposed the antidepressant usage onto a single graph with a unified scale, and look what happened…

compared to this [a bit of presentation  bias  trickery at work in my humble opinion].

The dip in prescriptions for adolescents was not so impressive after all! And as I look at those changes, they’re exactly what I would predict [and want] from the Warning. In all three cases [adolescent, young adult, and adult] it’s not so much that prescription rates even fell, they stopped rising [recall that it’s a percentage scale]. That’s expected, rational, careful – good for them. So back to the thread, I’m really not «chilled» now.

This is my biggest pet peeve with the KOL set. They talk as if a diagnosis of depression means the patient should be on antidepressants. Where did that ever come from? That’s not even true for adults – and it’s absolutely not true for adolescents. These drugs are just not that powerful. And, by the way, they’re still prescribing a whole lot of antidepressants for kids. So Dr. Friedman’s [and other anti-Black-Box-Ninjas’] argument that we need to get rid of the Warning so that Primary Care Doctors won’t be afraid to give these deprived teens antidepressants is unsupportable and totally irrational from any direction I know. Shame on him for even making the suggestion.

The FDA Warning on Antidepressants and Suicidality
– Why the Controversy?

by Marc B. Stone, M.D.

New England Journal of Medicine 2014 371:1668-1671.

[full text on-line]

Psychiatry, The Pharmaceutical Industry, and The Road to Better Therapeutics

An Editorial

by H. Christian Fibiger

Schizophrenia Bulletin. 2012 38[4]:649–650.

[full text on-line]

Psychopharmacology is in crisis. The data are in, and it is clear that a massive experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years. Indeed, despite enormous effort, the field has not been able to escape the “me too/me [questionably] better” straightjacket. In recent years, the appreciation of this reality has had profound consequences for innovation in psychopharmacology because nearly every major pharmaceutical company has either reduced greatly or abandoned research and development of mechanistically novel psychiatric drugs. This decision is understandable because pharmaceutical and biotechnology executives see less risky opportunities in other therapeutic areas, cancer and immunology being the current pipeline favorites. Indeed, in retrospect, one can wonder why it took so long for industry to abandon psychiatry therapeutics. So how did we get here and more importantly, what do we need to do to find a way forward?…

^{Click the graphic for the article}

I wrote "an honest assessment of the current era" when I read Dr. Fibiger’s article in 2012 and "a wise voice" when I reread it this week. I want to clarify that it’s that paragraph up there [minus the last sentence] that I was talking about. In what follows, he gets into "find a way forward" too quickly when what we need to figure out is "how did we get here." In my opinion, his problem with sustained wisdom is in "more importantly," revealing that you can take the boy out of industry but you can’t take the industry out of the boy may be an operative principle clouding his subsequent wisdom. What’s important to me [and us] is where in the hell have we been?

As much as I’m obviously in love with that graph, there’s something important that it doesn’t show – Clinical Trials. Clinical Trials proving efficacy [lite] were added to the mix in 1962 as a reform measure – including efficacy with safety in the FDA’s task list for approval of a drug. The Clinical Trial Industry blossomed later – 1980s? While there are many things one can say about that change, the one I’m focused on right now is the ability of a Clinical Trial to detect much smaller differences – even clinically insignificant differences. We don’t need Clinical Trials for Morphine [antiquity] or Penicillin [1928] or Thorazine [1950] or Valium [1960]. They obviously have strong effects – no statistics required. But for many medications, the math is necessary.

Finally, a personal observation of my own. The pharmaceutical industry in the 1960s and early 1970s that I met as a young Internist and the contemporary pharmaceutical industry I now write about seem like different species to me. I’ve never been personally much involved with industry, but from my perspective, the deceitful practices I write about here were not there at an earlier time. And in the interim, I was in a situation where I had little interest or contact, so I can’t really comment on the process of change. I can only say that the change seems striking to me.

This is the trend line from the top graph expressed in a different way. To get an NDE to take to market costs me 94 times as much in contemporary dollars in 2010 as it cost me in 1950. And that 2010 NDE is backed only by statistical evidence from a Clinical Trial rather than evidence that can be seen from across the room as in 1950 – so my lackluster 2010 drug that it costs me 94 times as much to get hold of is up against a robust 1950 drug [and, by the way, they’re not nearly so many of those NDEs around any more – except maybe out of reach in the top of the tree].

I’m sure we’re not out of drugs forever, but we’ve sure picked the low fruit, and then worked our way pretty far up the tree. A bit of mold on a petri dish kills staphylococcus; a new TB drug perks the depressed guys on the Chest Ward; a tweaked antihistamine that shuts down psychotic symptoms – that kind of serendipity is taken. And the hard work with similar compounds or similar pathways added some value, better tolerability. But the odds of an antipsychotic that isn’t neuroleptic are approximating zero. The same for an antipsychotic that improves negative symptoms. Many of us think that the symptomatic improvement of depressive affect may not have a much higher mark, particularly in patients with life/mind/social problems that transcend their biology. And how much more mileage is there in the war on serum lipids? This graph implies to me that we’ve passed the point of diminishing returns – probably even overshot:

^{Click the graphic for the article
Edited for clarity}

We’ve mined our current science, and we don’t really know if there’s a new next science that will add very much, at least any time soon. That’s what the PHARMA laboratories say and have been saying. I’ve had trouble giving their assertion proper valence because I’ve become so used to looking for the tricks in their words that I seem to have glossed over the main message [and there have been tricks enough to justify my skepticism!]. This next graph is from Janet Woodcock, MD Director, Center for Drug Evaluation and Research – FDA called "Today’s Biomedical Innovation: Lost in Translation?" In this slide, she makes clear that the PHARMA spending has not fallen off as much as the public spending – approaching close to $ 80 B/year:

^{Reformatted for clarity}

In the summer of 2011, PHARMA essentially exited CNS Drug development [suddenly, last summer…] and the DSM-5 Task force was forced to admit that its planned biologically based DSM-5 was being scrapped for lack of evidence. Speeches were given; meetings were held [APF Convenes Unique Pipeline Summit], rants were ranted [Are future psychiatric treatments doomed?].  The neuroscience base was stalled along with drug development. Dr. Insel had long tried to keep the NIMH focused on biological research and treatments, and the NIMH went into high gear. The slide above is parodoxical in that it shows that the PHARMA resources far exceed the NIH Budget. The party line was that industry had stuck with ‘me-too’ drugs and that the NIMH needed to pick up the ball and intensify its drug research endeavors with creativity and innovation. Both Drs. Woodcock [top slide below] and Insel [bottom figure below] showed us how hard and expensive it was for PHARMA to develop a new drug. Notably, neither pointed out that their figures came from ‘the end of the line’ – when there were ‘slim pickings’ [see the first graph above]. Both saw the development of new molecules as the job of academic researchers, someone else who fell down on the job:

They were joined in this rhetoric by former NIMH Director, Stephen Hyman [hope and hype…]. Now it’s two years later and the NIMH leads us ahead with an RDoC [Research Domain Criteria] and an NCATS [National Center for the Advancement of Translational Science] with all kind of new, innovative, novel strategies [see rather than micromanage…].

Psychiatry, The Pharmaceutical Industry, and The Road to Better Therapeutics

An Editorial

by H. Christian Fibiger

Schizophrenia Bulletin. 2012 38[4]:649–650.

[full text on-line]

Psychopharmacology is in crisis. The data are in, and it is clear that a massive experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years. Indeed, despite enormous effort, the field has not been able to escape the “me too/me [questionably] better” straightjacket. In recent years, the appreciation of this reality has had profound consequences for innovation in psychopharmacology because nearly every major pharmaceutical company has either reduced greatly or abandoned research and development of mechanistically novel psychiatric drugs. This decision is understandable because pharmaceutical and biotechnology executives see less risky opportunities in other therapeutic areas, cancer and immunology being the current pipeline favorites. Indeed, in retrospect, one can wonder why it took so long for industry to abandon psychiatry therapeutics. So how did we get here and more importantly, what do we need to do to find a way forward?

The discovery of all three major classes of psychiatric drugs, antidepressants, antipsychotics, and anxiolytics, came about on the basis of serendipitous clinical observation. At the time of their discoveries, the mechanisms by which these molecules produce their effects were unknown, and it was only later that antipsychotics were shown to be D2 receptor antagonists, antidepressants monoamine reuptake inhibitors, and anxiolytics GABA receptor modulators. It is interesting and perhaps instructive to consider whether any of these classes of drugs could have been discovered by current drug discovery strategies. For example, what genetic or preclinical data exist that point to the D2 dopamine receptor as a likely target for antipsychotic activity? Presently there are no genetic data that suggest that this receptor is expressed or functions abnormally in psychotic disorders. And without the benefit of the prior clinical validation, it is difficult to see how preclinical data alone would point to the D2 receptor as an interesting potential target for the treatment of psychotic disorders. The same can be said for monoamine transporters with respect to depression where, like psychosis, there are no animal models based on disease pathophysiology and no compelling preclinical data pointing to these as potential targets for antidepressant drugs. This raises a troubling question: if in retrospect the three major classes of currently prescribed psychiatric drugs would likely never have been discovered using current drug discovery strategies, why should we believe that such strategies are likely to bear fruit now or in the future?…

There are likely additional potentially productive ways to get psychiatric drug research and development back on track but a few things are now clear: [1] what the field has been doing for the past 3 or 4 decades has failed to generate effective, mechanistically novel psychopharmaceuticals, [2] the pharmaceutical industry is now well aware of this fact and has therefore greatly reduced investing, and [3] there is no choice but to make changes in how we approach the study of disease mechanisms, drug discovery, and development in psychiatry. This will require major investments in neuroscience research, humility in the face of our ignorance, and a willingness to consider fundamental reconceptualizations of psychiatry itself. It will be a long, important, and exciting march.

Department of Psychiatry, University of British Columbia Vancouver, B.C., Canada. Subsequent to his academic career, Dr Fibiger was Vice President of Neuroscience at Eli Lilly and Company, Vice President of Neuroscience at Amgen, and Senior Vice President and Chief Scientific Officer at Biovail Laboratories International.

All of these people [Insel, Hyman, Woodcock, Fibiger] and the collective APA hierarchy [APF Convenes Unique Pipeline Summit] seem to be desperately looking for a way to redirect our efforts at any cost to keep the dream alive, including reshaping psychiatry and psychiatric diagnosis [again!]. I find myself in a more pragmatic frame of mind as one might expect from my background. I think slim pickings are slim pickings. I doubt that there are magical drugs just around any corner waiting to be harvested by these new approaches. I now believe PHARMA gave it the old college try and "it is clear that a massive experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years." They are the best financed act in town with a bevy of the best scientists available. They are surely the most motivated – finding silver bullets is their only reason for being. I’m sure that PHARMA would love to find better drugs than they’ve offered us recently. They’d much rather build their brand and fill their coffers from genuine breakthroughs than slithering around marketing the weak [and sometimes toxic] sisters they’ve sent our way [lying about their safety and efficacy]. But they can’t find those wonder drugs – and they could’ve bought a small country for what they spent on looking.

Pharma Fails to Keep R&D Spending Commitment to Canada

Pharmalot

By Ed Silverman

Oct 24, 2014

Seventeen years ago, the government of Canada and the pharmaceutical industry struck a bargain. The country would extend patents for medicines and, in return, drug makers committed to spend 10% of their revenue on R&D in Canada. But it has not worked out that way and a public policy row has broken out over the extent to which the agreement may have denied Canadians speedier access to lower-cost generics. Why? Industry spending has fallen short of the mark every year for more than a decade. Last year, for instance, the amount of revenue dedicated to R&D activities in Canada was, collectively, 5.4% among drug makers with operations there, or $652 million, according to a recent report from the Patented Medicine Prices Review Board, a government agency.

The last time the pharmaceutical industry spent the agreed upon 10% of revenue on R&D work was in 2002. Since then, the amount of spending has declined each year. And when factoring in all drug makers, including those without operations in Canada, the portion of industry revenue spent last year on R&D was 4.5%. R&D spending was highest in 1997, when it reached 12.9% of revenue [see Table 16]….

^{adapted from [Table 16]}