you couldn’t make this stuff up…

Posted on Monday 24 November 2014

So remember Guido Rasi, head of the European Medicines Agency, the guy who has been the architect of their policy on Data Transparency? [see European Medicines Agency: a timeline…, game on…]:
Regulatory Affairs Professional Society
By Alexander Gaffney, RAC
14 November 2014

In a major development, the head of the European Medicines Agency [EMA], Guido Rasi, has been forced to step down by the EU Civil Service Tribunal after adjudicators found that the European Commission had improperly selected him in 2011. The case against Rasi’s appointment was filed by Emil Hristov, formerly with the Bulgarian Drug Agency and a member of EMA’s board, who maintained that EMA and the European Commission had improperly assembled a short list of candidates for the position of EMA’s executive director after the controversial departure of former executive director Thomas Lönngren in 2010. Hristov had applied to the position, but after reaching the interview process for the interview, was ranked last among eight candidates and was not selected to be on a "short list" of candidates presented to EMA’s Board of Directors as being the most suitable for the position. The assembly of that "short list" of candidates by a selection committee was improper, the court found, and the EMA board should have been able to consider the candidacy of Hristov, who they were familiar with.

Therefore, the selection of Rasi by the European Commission is to be annulled, the court ordered. The decision has immediately ramifications for EMA and Rasi, who has been removed from his position and replaced on an acting basis by Andreas Pott, now deputy executive director of EMA. “I note with regret today’s judgment by the European Union Civil Service Tribunal," said Professor Sir Kent Woods, chair of the Management Board, in a statement. "It is important to remember that the ruling is about a procedural formality. It is not a reflection on Guido Rasi’s competence or ability to run the Agency, something which he has done successfully since November 2011.”

Both EMA and the European Commission are scrambling to see if the decision can be overturned, they said. The departure of Rasi comes at a particularly tricky time for EMA, which is in the process of implementing a massive change in the way it treats clinical data transparency. Transparency has been one of the hallmarks of Guido’s tenure as EMA’s executive director, and his departure could very well derail some of his signature initiatives.
And he’s been quickly replaced…
Andreas Pott Again Tasked with Steadying EMA in Turbulent Times
Regulatory Affairs Professional Society
By Nick Paul Taylor
20 November 2014

Andreas Pott has a habit of being thrust into difficult situations. In 2010, Pott was appointed acting executive director of the European Medicines Agency (EMA) at a time when the regulator was dealing with allegations of conflicts of interest, disputes with the European Parliament and an early row over transparency. Now, Pott is once again in the hot seat during a period of turbulence at EMA. The factors behind Pott’s latest stint as acting executive director relate to the first time he took the role. Back then, Pott held the post during the protracted and messy transition between the reigns of Thomas Lönngren and Guido Rasi. Pott handed the position over to Rasi in late 2011. However, a tribunal has now ruled the European Commission [EC] failed to follow proper recruitment procedures, triggering the annulment of Rasi’s appointment.

Having been forced to remove Rasi from his post, EMA named Pott as acting director. Pott faces the task of implementing new clinical trial legislation, managing the ongoing dispute over data transparency and getting changes to medical device regulation underway. The fallout from disputes in the EC about the oversight of EMA and the resignation of the director-general for health could also affect the regulator. Pott has faced similar circumstances in the past. When Pott last served as acting executive director, he dealt with reports Lönngren was advising pharmaceutical companies, a request from a politician to fire an EMA expert, and a spat with the Nordic Cochrane Centre over the publication of clinical trial data, the Finnegan’s Take blog summarized in 2012. On that occasion, Pott held the post for one year. At this stage it is unclear how long his latest spell will last.
And if you want to read some historical pulp fiction [that happens to be true], don’t miss the Finnegan’s Take blog mentioned above. One might think these matters might be handled with a bit more decorum, but alas, scientists and regulators are people too. As best I can tell, this has little to do with Dr. Rasi, though who knows what’s coming next? It hasn’t made much difference at the EMA so far. Here are a few of last week’s and today’s releases from the EMA:
and an article from Ed Silverman:
Will this have an impact of the EMA Data Transparency policy? I don’t know. All speculations welcome…
Mickey @ 2:41 PM
Filed under: OPINION
promises, promises…

Posted on Sunday 23 November 2014

I didn’t know it when I started blogging, but this blog isn’t about psychiatry, it’s about honesty in medical science. And right now, for me that reduces down to what has come to be called Data Transparency. The reason for my sabbatical these last several weeks has to do with a project working with the actual raw data behind a published Clinical Trial – hopefully something that will become increasingly common in the future because it’s clear that the space between the Clinical Trials themselves and many published articles has remained corrupted in spite of 50 years of successive reforms.
 
Industry funded Clinical Trials are often called "research," but a better term is "product testing" since lucrative profits are on the line depending on the outcome. In theory. the Clinical Trial is heavily structured. A Protocol defines how it will be conducted and what endpoint parameters will be analyzed to reach the final conclusions. The Subjects and Investigators are blinded to the medications until the blind is broken at the end of the actual trial and the results are analyzed by the Authors according to the a priori Protocol specifications.

We all know, that’s not what happens. The results are turned over to the corporate sponsor who analyze the results and use medical writers to produce the article. In many cases, the physicians and other scientists on the Author By-Line are primarily a ticket into a peer-reviewed journal, and have little if any input into the actual production of the article. And since the reader of the article can’t see any of the process that goes into the creation of what they’re reading, the data can be subtly manipulated to accentuate the positive and eliminate the negative. It not only can happen, it has happened in epidemic proportions – yielding enormous profits and more importantly has resulted in doctors prescribing many ineffective or sometimes harmful medications. The time for simply decrying this state of affairs has long passed. It’s time to put a stop to it, but that’s proving to be a very thorny task.

Every solution to this problem starts with Data Transparency. Unless science at large has access to every part of that top figure, the problem will persist. And the industry that stands to gain has mounted a sustained resistance at every point along the road. Their public arguments are commercially confident information and patient confidentiality, but that’s simply a smoke-screen for their real problem. Without the cover of darkness, many of the medications released in recent decades wouldn’t have made it to first base. There’s nothing scientific about the idea that new drugs are better, or that new drug discovery can proceed at a predictable pace. "A good man drug is hard to find. You often always get the other kind." – wouldn’t be a bad theme song for this industry.

In this last year, Data Transparency has finally made it to the front burner. This time last year, the European Medicines Agency [EMA] was well on the way to a sweeping policy change with unrestricted access to the data submitted to them, but as the year progressed, that move has been systematically eroded primarily by a coordinated campaign by industry in spite of a growing clamor supporting Data Transparency. The policy as it now stands is a watered-down version of its original promise. Now. the NIH and FDA have initiated a new program [speaking of about time!…] – taking aim at the problem with another promise:
NIH Director’s Blog
by Drs. Kathy L. Hudson and Francis S. Collins
November 19, 2014

When people enroll in clinical trials to test new drugs, devices, or other interventions, they’re often informed that such research may not benefit them directly. But they’re also told what’s learned in those clinical trials may help others, both now and in the future. To honor these participants’ selfless commitment to advancing biomedical science, researchers have an ethical obligation to share the results of clinical trials in a swift and transparent manner.

But that’s not the only reason why sharing data from clinical trials is so important. Prompt dissemination of clinical trial results is essential for guiding future research. Furthermore, resources can be wasted and people may even stand to be harmed if the results of clinical trials are not fully disclosed in a timely manner. Without access to complete information about previous clinical trials — including data that are negative or inconclusive, researchers may launch similar studies that put participants at needless risk or expose them to ineffective interventions. And, if conclusions are distorted by failure to report results, incomplete knowledge can eventually make its way into clinical guidelines and, thereby, affect the care of a great many patients. Unfortunately, the timely public reporting of results has not been consistent across the clinical trials enterprise. For example, a recent analysis of 400 U.S. clinical trials found that even four years after the trials had been completed, nearly 30% had failed to share results by publishing in a scientific journal or reporting in ClinicalTrials.gov, a public database maintained by NIH.

Today, the Department of Health and Human Services [HHS] proposed a rule to require public sharing of key results — the summary data — from certain clinical trials of drugs and devices regulated by the Food and Drug Administration [FDA]. While such a mandate has been in place for several years, the proposed rule aims to clarify the requirements. Summary data would include: baseline characteristics of participants, primary and secondary outcome results, and information about adverse events. With a few exceptions, such results must be submitted to ClinicalTrials.gov within one year of the time when the trial completes collection of primary outcome data. But we at NIH are proposing to go one step further to address this important issue. Today, NIH released a draft policy for public comment to apply these data reporting requirements to all interventional clinical trials that it funds. We are committed to working with NIH-supported researchers and institutions to ensure the new responsibilities in this proposed policy are understood and any unanticipated obstacles are removed.

What all this really comes down to is trust. Clinical trial participants trust that the data they provide will be used by biomedical science to advance the health of many. Researchers seek to add to the body of biomedical knowledge and can respect this commitment by promptly sharing clinical trial data. There is also the important matter of public trust. American taxpayers trust NIH to be a good steward of their investment — and one way we can do that is to ensure that results of all our clinical trials are shared with the worldwide scientific community in an open and efficient manner. Data sharing is essential to turn even more scientific discoveries into better health at an even faster pace!
Unfortunately, the clinicaltrials.gov results database isn’t comprehensive [see bring on the hoops! at least the ones that matter]. But it’s a hell of a lot better than nothing, and this NIH proposal initiates something that has been woefully lacking – enforcement. Looking back through the history of all the many reforms attempting to keep this business of drug testing scientific and honest, it looks almost like a comedy of errors. I don’t think that’s right. Most of the reforms seem to me to be serious attempts at getting the drug testing on the right path. Two things have been missing. The first is obvious – enforcement. With clinicaltrials.gov, they had a very right idea, but there was essentially no enforcement. The drug companies and others just ignored the law. That’s the really important part of this move by the Dr. Collins [Director of the NIH] if he’s serious and follows through. The second thing is ongoing monitoring. This history has been written by many well-meaning congressmen, reformers, and agencies, but they haven’t stayed at it. Industry is always at it. So the crises pass and drug companies just keep on doing what they’ve been doing as soon as the dust settles. It’s time for a new clamor – enforcement and ongoing monitoring. Without those two things, it’s all just more empty promises…


What is the Results Database?
The ClinicalTrials.gov results database was launched in September 2008 to implement Section 801 of the Food and Drug Administration Amendments Act of 2007 [FDAAA 801] [PDF], which requires the submission of "basic results" for certain clinical trials, generally not later than 1 year after their Completion Date [see Primary Completion Date on ClinicalTrials.gov]. The submission of adverse event information was optional when the results database was released but became required in September 2009. Results information for registered and completed studies is submitted by the study sponsor or principal investigator in a standard, tabular format without discussions or conclusions. The information is considered summary information and does not include patient-level data. The results information that is submitted includes the following:
  • Participant Flow. A tabular summary of the progress of participants through each stage of a study, by study arm or comparison group. It includes the numbers of participants who started, completed, and dropped out of each period of the study based on the sequence in which interventions were assigned.
  • Baseline Characteristics. A tabular summary of the data collected at the beginning of a study for all participants, by study arm or comparison group. These data include demographics, such as age and gender, and study-specific measures (for example, systolic blood pressure, prior antidepressant treatment).
  • Outcome Measures and Statistical Analyses. A tabular summary of  outcome measure values, by study arm or comparison group. It includes tables for each prespecified Primary Outcome and Secondary Outcome and may also include other prespecified outcomes, post hoc outcomes, and any appropriate statistical analyses.
  • Adverse Events. A tabular summary of all anticipated and unanticipated  serious adverse events and a tabular summary of anticipated and unanticipated other adverse events exceeding a specific frequency threshold. For each serious or other adverse event, it includes the adverse event term, affected organ system, number of participants at risk, and number of participants affected, by study arm or comparison group.
ClinicalTrials.gov staff review results submissions to ensure that they are clear and informative prior to posting to the Web site. However, ClinicalTrials.gov cannot ensure scientific accuracy. Data providers are responsible for ensuring that submitted information is accurate and complete.


Commenting on the NPRM and proposed NIH Policy
The public may comment on any aspect of the NPRM or proposed NIH Policy. Written comments on the NPRM should be submitted to docket number NIH-2011-0003 at www.regulations.gov [not there as of today?] Commenters are asked to indicate the specific section of the NPRM to which each comment refers. Written comments on the proposed NIH Policy should be submitted electronically to the Office of Clinical Research and Bioethics Policy, Office of Science Policy, NIH, via email at:
mail: at 6705 Rockledge Drive, Suite 750, Bethesda, MD 20892, or by fax: at 301-496-9839. The agency will consider all comments in preparing the final rule and final NIH Policy.

UPDATE: This is the working link for comments:

Mickey @ 6:13 PM
Filed under: OPINION
speaking of about time!…

Posted on Wednesday 19 November 2014

I know I said that I was taking something of a sabbatical to finish up a project, but I broke that to post the Newsweek article last week [see about time…]. And I’m doing it again because this just came my way – and it’s huge!:
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…
Here’s the official press briefing:
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.
Here it is rolled out by the NIH top brass:
JAMA
by Kathy L. Hudson, PhD and Francis S. Collins, MD, MPH
November 19, 2014
Here is Ed Silverman’s take on it:
Pharmalot: WSJ
by Ed Silverman
November 19, 2014
And here’s the Science Insider:
Science: Science Insider
by By Jocelyn Kaiser
November 19, 2014
I’ve spent months following the European Medicines Agency [EMA] deliberations about Data Transparency in Clinical Trials. In fact, my project that takes me away from blogging is about that same issue. I know I’ve written about a lot of things along the way in these blogging years, but this is the most important issue in my own mind. Somewhere along the way, a conduit got opened and the medical literature became corrupted by industry and academic articles whose agenda were something other that the advancement of medical science. My specialty, psychiatry, was heavily afflicted – filled with jury-rigged experimercials and questionable Clinical Trial results, equally questionable review articles, and industry contaminated CME material, all of which were aimed at corporate profits, not doing the job of caring for the sick. If the NIH and FDA really do everything they say here, they would be starting a ball rolling down the rightest of hills to begin cleaning up this wrongest of circumstances. And speaking of about time, it’s long overdue – but a welcome move in the very rightest of directions…
Mickey @ 9:06 PM
Filed under: OPINION
about time…

Posted on Friday 14 November 2014

Mickey @ 4:12 PM
Filed under: OPINION
what it’s for…

Posted on Friday 7 November 2014

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…

Mickey @ 8:28 PM
Filed under: OPINION
something else…

Posted on Wednesday 5 November 2014

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].

Most of you don’t know this yet, but in retirement time can be infinite, or can fill up in ways you never imagined. I had already realized I needed to clear out some space for some intense learning time, so this is what I had planned to say:
    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.
But that seems a really odd thing to say in the present moment without explanation, though it’s still the truth. I doubt I’ll be able to stop my pre-sunrise routine of looking at what’s going on. But I’m going to have to forgo the later fun part, mentioned above. So I may just post articles or links, without much comment or research. Envision me at the computer looking at screens with too many greek letters with my eyes trying to cross. It may not be as hard as I think, but I won’t know that until I know it. Here’s what I would’ve thought about today:
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

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.
Mickey @ 9:06 PM
Filed under: OPINION
no wizard…

Posted on Wednesday 5 November 2014

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.

I can’t fix this [and shouldn’t]. If you want some resolution, I’ll be glad to pass any email addresses or messages along between any two of you if you both agree. Otherwise, I can only hope you remain valued contributers to this blog. And there’s something else – coming in the next post…
Mickey @ 4:15 PM
Filed under: OPINION
The Project for a Scientific Psychology – 2014

Posted on Sunday 2 November 2014

Emil Kraepelin, Karl Jaspers, Eugen Bleuler, Sigmund Freud, Adolf Meyers

from The Project for a Scientific PsychologyWhen 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:

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”]…

While Jaspers himself left Psychiatry for Philosophy, his three part system was followed by the American Psychiatris Association’s first Diagnostic and Statistical Manual [DSM] in 1952 with the section on personality disorders built on the ideas of Adolf Meyer who saw them as "reactions" to Life. In the next revision in 1968 [DSM-III], that third section was organized using the psychoanalytic theory.

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.

Darrel Regier & David Kupfer [DSM-5], Allen Frances [DSM-4], John Feighner, Robert Spitzer [RDC, DSM-III, DSM-IIIR]

As the time for the DSM-5 Revision to be released neared, Dr. Tom Insel announced that the NIMH was abandoning the DSM-5 and moving to it’s own embryonic classification system [Transforming Diagnosis] – the RDoC [Research Domain Criteria] – an initiative lead by Drs. Tom Insel and Bruce Cuthbert at the NIMH since in 2009:
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?

Tom Insel [Director NIMH] & Bruce Cuthbert [Director of Translational Research, NIMH]

Well, for one thing it is is the pair of Tables [Matrices] shown below [introduced in Director’s Blog: Transforming Diagnosis; by Tom Insel; April 29, 2013]. Explained here:
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.

I don’t really know what I think about all of this. Like the DSM-5 debacle, they persist in pursuing the idea that mental illness is all biologically determined rather than focusing on only those syndromes where that is likely, once again diluting the kind of directed research that might yield useful results. And it’s hard for me to shake the feeling that this effort is yet another desperate attempt to "realize the dream of Guze, Robins, and the neoKraepelinians" or Tom Insel’s dream that "psychiatry is clinical neuroscience" – and a way of diverting our attention away from the embarrassing collapse of the DSM-5 effort; the failure of the pharmaceutical industry to produce robust drug treatments [the empty pipeline]; and the widespread corruption and conflict of interest revelations in the academic pharmaceutical complex over the last five years. One would think this is a time for reflection and re-evaluation, rather than for racing down a new track full throttle…
Mickey @ 11:06 AM
Filed under: OPINION
unsupportable and totally irrational…

Posted on Friday 31 October 2014

by Richard A. Friedman, M.D.
New England Journal of Medicine 2014 371:1666-1668.
The core of this seemingly endless debate about the Black Box Warning revolves around a more fundamental question about the source of medical knowledge – observations made on  the collective? or on individual cases? Obviously the answer is some version of both, but this debate puts the subtilties of the distinction in bas-relief:
  • 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.
This debate is further complicated by controversy over the efficacy of antidepressant treatment in depressed children and adolescents. Only two of the SSRIs [Prozac and Lexapro] have been approved by the FDA  for the treatment of pediatric depression. And none of the RCTs [including those of these two drugs] have shown anything like a robust response in this age group:
Cochrane Systematic Reviews
by Sarah E Hetrick, Joanne E McKenzie, Georgina R Cox, Magenta B Simmons, and Sally N Merry
14 NOV 2012

… Based on 14 of the trials [2490 participants in total], there was evidence that those treated with an antidepressant had lower depression severity scores than those on placebo, however, the size of this difference was small. Based on 17 trials [3229 participants in total], there was evidence of an increased risk [64%] of suicide-related outcomes for those on antidepressants compared with those given placebo…

The argument mounted by people who support the Black Box Warning is simple, coming primarily from the case reports: The syndrome does occur and both doctors and patients need to know about it. It’s what the warning says:
The argument coming from the anti-Black-Box set is more complex. They propose that the Black Box Warning itself discourages doctors from prescribing and patients from taking antidepressants, so depressed youth are going untreated. In Friedman’s paper, he says:
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.
Then he concludes:
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…
The «chilling effect on depression treatment» punch line in this argument is hard for me to take, or for that matter, even follow. The notion that the antidepressant drugs are effective enough in pediatric depression to warrant Dr. Friedman’s «chill» is unsupported by anything I can see. And as for «the risk posed by untreated depression», those unmedicated subjects have actually been well studied themselves. They’re the Placebo Groups in each of those Clinical Trials.

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.

Note: Dr. Stone approaches this from a different angle in a companion piece, and makes some excellent points:
by Marc B. Stone, M.D.
New England Journal of Medicine 2014 371:1668-1671.
Mickey @ 4:14 PM
Filed under: OPINION
explain, not justify…

Posted on Wednesday 29 October 2014

In case it’s not apparent in these last two posts [sleep on it…, we’re all out of drugs…], I’ve had a change of heart. I’ll admit that my earlier interpretation of PHARMA pulling out of CNS Drug Development was that they were taking so many hits in the courtroom that they decided to throw in the towel. That may or may not be, but I now think even if it’s a factor, it’s an aside. On center stage is the main problem, well expressed by Dr. Fibiger:
An Editorial
by H. Christian Fibiger
Schizophrenia Bulletin. 2012 38[4]:649–650.

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?…
Here’s that graph again [for the third post in a row]:


Click the graphic for the article

Note: Recall that this graph is corrected for inflation and that it’s all drugs [New Drug Entities] not just psychiatric drugs.

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].

THIS IS A TEST:
Assuming the validity of my observation that the pharmaceutical industry had undergone a "dramatic" change in my medical lifetime [50 years], is there anything in this post that might explain why that happened?

Disclaimer: Please note that I said explain, not justify.
Mickey @ 5:18 PM
Filed under: OPINION