a long hot summer…

Posted on Wednesday 9 July 2014

Further discussion required on wording and practical arrangements
European Medicines Agency
Press Release
09/07/2014

The Management Board of the European Medicines Agency [EMA] has postponed formal adoption of the policy on publication of clinical trial data to its 2 October 2014 meeting. Further clarifications on wording and practical arrangements will be discussed by Board members, who have confirmed their general support to the overall aims and objectives of the policy, including the more user-friendly amendments proposed by EMA Executive Director Guido Rasi that would allow data to be downloaded, saved or printed for academic and non-commercial research purposes.

Further to the agreement reached with the European Commission in accordance with Article 80 of Regulation [EC] No 726/2004, the Board was not able to conclude on the final wording of the policy through a written procedure. Members of the Board have offered additional valuable contributions which will now be considered and addressed in the next few weeks, with a view to reaching final agreement at the next Management Board meeting in October.

The Agency welcomes this additional round of joint reflections and respects all opinions, as well as the views expressed by several Member States, which largely reproduce the complexity of the debate on both political and technical aspects which have emerged during the previous general and more targeted consultation phases. In the last 12 months the Agency has attempted to strike a balance between proactive data disclosure, the absolute need to protect personal data and the concerns relating to the protection of commercially confidential information.

The Agency management remains committed to introducing this additional measure towards transparency as soon as possible, so as to enhance citizens’ awareness and confidence in the EU authorisation system for medicinal products. The Agency has also underlined several times that the new policy, if approved, will be without prejudice to the provisions of Regulation [EC] No 1049/2001 on access to documents and the new clinical trial Regulation [EC] No 536/2014, which will become applicable in 2016 at the earliest and, as also noted during the debate, will apply to clinical trials conducted in the European Union.

The Agency management is conscious that any delay prevents citizens, and in particular academics and non-commercial researchers, from enjoying the benefits of proactive publication of clinical trial data for a further period. The Agency will continue to work with the Management Board and the European Commission ahead of the 2 October meeting to ensure that members receive the clarifications requested and to facilitate the adoption of the policy.
Pharmalot
By Ed Silverman
July 9. 2014

Drug makers and academic researchers will have to wait a little longer for the new policy on disclosing clinical trial data from the European Medicines Agency. The regulator has postponed formal adoption of the policy until its next board meeting on October 2, according to a statement issued today. Why? The EMA did not offer many specifics, other than to say its board was unable to reach agreement on final wording, although board members have “confirmed their general support to the overall aims and objectives of the policy.”

This is the second time that approval has been delayed in two months and one source indicated there may be disagreement among member states. The continual delays come amid controversy over the direction the EMA has taken in finalizing its stance toward the disclosure of clinical trial data, a hot-button issue for the pharmaceutical industry. Disclosure has been a contentious topic following scandals over safety or effectiveness data that was not publicly shared. The EMA had publicly committed itself to ensuring trial data is accessible and easily analyzed. And its public statements suggested the pharmaceutical industry would be required to release significant amounts of data, including clinical study reports, which collect and summarize trial data.

For their part, however, drug makers maintained that the EMA sought to go too far in releasing data that could contain trade secrets or compromise patient privacy. In fact, two drug makers – AbbVie and InterMune – went to court in hopes of preventing the agency from releasing data about some of their drugs. Those cases were recently settled. Last month, though, the EMA began circulating its draft policy and was accused by some academics and policy makers of doing an about face in the wake of the settlements. European Ombudsman Emily O’Reilly claimed the agency revised its policy to adhere to the “wishes” of the pharmaceutical industry and she is now reviewing redacted records from those court cases for clues to the EMA change in policy. Despite such impressions, the EMA attempted yesterday to reassure its critics that the policy will lead to greater transparency and, in particular, noted that access to documents will be permitted under freedom of information requests in keeping with European Commission regulations. The EMA also reiterated its willingness to allow data to be downloaded, saved or printed, a restriction that was unexpectedly included in the draft policy, but removed last month amid the burst of criticism.
I’m actually neither surprised nor disheartened. Literally Billions of Dollars, Pounds, and Euros are riding on this decision, and we would be naive indeed to think that this could happen without a fight. Had there been true data transparency, the last twenty-five years might have been very different, particularly in psychiatry. The Clinical Trials of the SSRIs and Atypical Antipsychotics might have looked very different if we had the opportunity to thoroughly evaluate them. And that’s also true of many of the general medicine "blockbusters" [> $1B/year]. So I wouldn’t be terribly surprised if another suit popped up along the way. And I wonder how solid that 2 October deadline will turn out to be. We can almost be guaranteed that some PhRMA/EFPIA workgroup is very busy at work even as I write this, jockeying for position. Remember this [a closing argument…]. A long hot summer up ahead…
Mickey @ 5:27 PM
Filed under: politics
antipsychiatry sentiment…

Posted on Wednesday 9 July 2014

As with benzodiazepines in the 1980s, the UK is prescribing SSRI antidepressants at a staggering rate – and to no good effect
The Guardian
by Peter Gøtzsche
30 April 2014

We appear to be in the midst of a psychiatric drug epidemic, just as we were when benzodiazepines [tranquilisers] were at their height in the late 1980s. The decline in their use after warnings about addiction led to a big increase in the use of the newer antidepressants, the SSRIs [selective serotonin re-uptake inhibitors]. Figures released by the Council for Evidence-based Psychiatry, which was set up to challenge many of the assumptions commonly made about modern psychiatry, show that more than 53m prescriptions for antidepressants were issued in 2013 in England alone. This is almost the equivalent of one for every man, woman and child and constitutes a 92% increase since 2003.

The problem is that many of these drugs simply do not work as people suppose. The main effect of antidepressants is not the reduction of depressive symptoms. They are no better than placebo for mild depression, only slightly better for moderate depression, and benefit only one out of 10 with severe depression. In around half of all patients, they cause sexual disturbances. The symptoms include decreased libido, delayed orgasm or ejaculation, no orgasm or ejaculation and erectile dysfunction. Studies in both humans and animals suggest that these effects may persist long after the drug has been discontinued. The US Food and Drug Administration has shown that antidepressants increase suicidal behaviour up to the age of 40, and many suicides have been reported even in healthy people who took the drugs for other reasons [for example, for stress or pain]. Another report also said that, among people over 65, antidepressants are believed to kill one out of every 28 people treated for one year, because they lead to falls and hip fractures. Indeed, it is not clear whether antidepressants are safe at any age.

My studies of the research literature in this whole area lead me to a very uncomfortable conclusion: the way we currently use psychiatric drugs is causing more harm than good. We should therefore use them much less, for shorter periods of time, and always with a plan for tapering off, to prevent people from being medicated for the rest of their lives.
The Lancet
by David J Nutt, Guy M Goodwin, Dinesh Bhuqra, Seena Fazel, and Stephen Lawrie
May 27, 2014

Psychiatry is used to being attacked by external parties with antidiagnosis and antitreatment agendas. However, the recent disclosure that a doctor [Professor Peter Getzsche] had joined a new group, the Council for Evidence-based Psychiatry, whose launch was accompanied by newspaper headlines such as "Antidepressants do more harm than good, research says" and "Psychiatric drugs are doing us more harm than good" in The Times and The Guardian plumbs a new nadir in irrational polemic. What is especially worrying is that this doctor is a co-founder of the Nordic Cochrane collaboration, an initiative set up to provide the best evidence for clinical practitioners. What is the truth about antidepressant efficacy and adverse effects, and why would Professor Getzsche apparently suspend his training in evidence analysis for popular polemic?

Of course, all active drugs have adverse effects, but for the new antidepressants these are rarely severe or life-threatening, even in overdose situations. Indeed, the new antidepressants, especially the selective serotonin reuptake inhibitors, are some of the safest drugs ever made. In our experience, the vast majority of patients who choose to stay on them do so because they improve their mood and well·being rather than because they cannot cope with withdrawal symptoms when they stop. Many of the extreme examples of adverse effects given by the opponents of antidepressants are both rare and sometimes sufficiently bizarre as to warrant the description of an unexplained medical symptom. To attribute extremely unusual or severe experiences to drugs that appear largely innocuous in double-blind clinical trials is to prefer anecdote to evidence. The incentive of litigation might also distort the presentation of some of the claims.

Whatever the reasons, extreme assertions such as those made by Prof Gøtzsche are insulting to the discipline of psychiatry and at some level express and reinforce stigma against mental illnesses and the people who have them. The medical profession must challenge these poorly thought-out negative claims by one of its own very vigorously.
I picked these two articles because at first reading they seem like antipodes – two diametrically opposed takes on the same thing. Dr. Peter Gøtzsche has become a lightning rod for criticism since writing Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare, a book whose very title makes his position clear to all. And yet his conclusion doesn’t strike me as particularly radical – more like good advice:
    …the way we currently use psychiatric drugs is causing more harm than good. We should therefore use them much less, for shorter periods of time, and always with a plan for tapering off, to prevent people from being medicated for the rest of their lives.
He doesn’t argue that the drugs shouldn’t be used. He says that they are overused, and reaffirms that depressions are time limited, so the use of the medication should be time limited. His recommendation for tapering is rooted in clinical observation. Withdrawal symptoms are common and are frequently misinterpreted as returning depression. We regularly see people who have been on antidepressants for years, afraid to stop as if some underlying depressive something-or-another will raise its ugly head. So in spite of Dr. Gøtzsche’s confrontational style, his actual recommendations seem "evidence-based" to me.

Dr. Nutt’s reply to Dr. Gøtzsche is pretty much standard fare for him – forever championing the notion that there’s too much attention paid to adverse effects of the psychopharmacologic drugs. Three years ago, he made a similar speech to the Royal College of Psychiatry, No Psychiatry Without Psychopharmacology, that vilified Dr. David Healy as a "scaremonger" in an opening slide:

I had decided to skip Dr. Nutt’s article [Attacks on antidepressants: signs of deep-seated stigma?], but yet I kept it around. I looked at it periodically and was never quite able to close it. So here it is over a month after it was published. These are the phrases that linger:
    Psychiatry is used to being attacked by external parties with antidiagnosis and antitreatment agendas. However, the recent disclosure that a doctor [Professor Peter Gøtzsche] had joined a new group, the Council for Evidence-based Psychiatry, whose launch was accompanied by newspaper headlines such as "Antidepressants do more harm than good, research says" and "Psychiatric drugs are doing us more harm than good" in The Times and The Guardian plumbs a new nadir in irrational polemic..

    … and at some level express and reinforce stigma against mental illnesses and the people who have them. The medical profession must challenge these poorly thought-out negative claims by one of its own very vigorously.
Several things. I don’t much mind Peter Gøtzsche’s style. He goes after mammography with the same passion [see the video in a major force…]. His conclusions seem right as rain to me, so he can rant all he wants. The antidepressants are unquestionably overused; people are on them too long [and hard to get off]; and I’ve come to believe that they should always be tapered. Solid points. And as for Dr. Nutt’s implication that it represents an attack on psychiatry, I didn’t think of that when I read what Gøtzsche had to say. He says, "the way we currently use psychiatric drugs," and I take him literally as meaning "we doctors." And he’s right from where I sit. Most of the overuse of antidepressants I see is by primary care physicians [though there aren't  many psychiatrists around here in rural Georgia]. So I guess I see Dr. Gøtzsche as an acquired taste – not for everyone. But I don’t particularly think of him as attacking psychiatry as a medical discipline.

On the other hand, there are some things about this piece by Dr. Nutt that do bother me. In fact, most of what he writes bothers me. I think it dredges up my memories of the conflicts of the late 1970s. Dr. Szazs monotonous definitions of disease requiring some biological marker [the Myth of Mental Illness] and the neoKraepelinians going him even one step further by saying "The focus of psychiatric physicians should be on the biological aspects of illness" and then sliding over the years to Tom Insel’s "Psychiatry is a Clinical Neuroscience Discipline" version. I guess they all feel like dogmatic pronouncements or injunctions – but they’re really just opinions. I was personally comfortable with the more traditional Doctors take care of sick people. That’s who came to my office, and that’s what I did. Sickness came long before any biological understanding was around. We started with just "Do no Harm" and that’s where we’re still supposed to be. So my complaint is that besides Dr. Nutt’s pharmaphillia, and his neoKraepelinian bio-dogma, I think he perpetuates what seems to me a false dichotomy, one that goes back into the dawn of our history.

But if that were all, I would’ve probably just sent this article to cyberspace. It’s this part that kept it around:
    … and at some level express and reinforce stigma against mental illnesses and the people who have them. The medical profession must challenge these poorly thought-out negative claims by one of its own very vigorously.
I recalled something similar from Dr. Lieberman [Psychiatry: Nothing to Be Defensive About]:
    I recently wrote an article for the Scientific American blog that explores how stigma and antipsychiatry sentiments fuel prejudice against our field and our patients. But I think it’s also important to note how the unwillingness of the public and pundits to accept psychiatry as a scientific discipline and full-fledged medical specialty perpetuates the false dualism of the mind and the brain — attempting to transport psychiatry back to the Cartesian philosophy of the 17th century…
I don’t question that there is still a stigma with mental illness, though less than there used to be. And I don’t question that there are anti-psychiatrists or people who question psychiatry as a medical specialty. But I think that in this case, Dr. Nutt and Dr. Lieberman are misappropriating those things to keep from looking in the mirror. If Peter Gøtzsche is making his complaints as a veiled attack on psychiatry as a medical specialty, I sure can’t see it. And I read him as a patient advocate. I frequently make the same comments about not overprescribing antidepressants, using antidepressants in a more time limited way, warning about the dangers, and tapering these drugs. And I’m neither an antipsychiatrist nor prejudiced against mental patients. I’m saying those things because the antidepressants are used too often, too long, too casually, and stopped too abruptly. I resent him imputing other fantasied motives to people that disagree with him. And his maximizing efficacy and minimizing adverse effects is no different from people who do the opposite. There’s a rational place in the middle. I would propose that the Dr. Nutts and Dr. Liebermans of the world do no one any favors by making these defensive and externalizing kind of comments. They actually cause a lot of the antipsychiatry sentiment they seem to think they’re fighting against. That’s not Peter Gøtzsche’s doing…
Mickey @ 1:47 PM
Filed under: politics
part four: the answers?…

Posted on Tuesday 8 July 2014

Families that communicate with Double Binds create children who often spend an inordinate amount of time in their lives trying to find solutions to problems that really have no solution [part one: the bind…]. To review the elements of a Double Bind: [1 & 2] Two mutually exclusive commands ["lose weight" and "clean your plate"]; [3] the injunction that you have to act; [4] the prohibition against addressing the impossibility of the situation. What does a "healthy" person do in that circumstance? In the words of the ancients, they "go between the horns." Said in other ways, they deny that [1 & 2] are the only possibilities; they break rules [3] and [4] by talking about the impossibility of the task, that neither action is correct [in this case, "silence is not golden"]. In the real world, the problem needs to be reframed in a more realistic way to look for solutions.

In the case of the challenging/disruptive intellectually impaired child, the Hamlet question, "to prescribe antipsychotics, or not to prescribe antipsychotics" is hardly the right way to formulate the clinical problem. Probably the first order of business is to explore the situation of the specific patient and the specific caregiver and the specific living situation to see if one can figure out what’s so upsetting, what’s wrong? Sometimes it’s something you can’t do anything about, but often it is amenable to change. Mentally retarded people are just like the rest of us – just less able to figure out and communicate what needs to be dealt with. Trying to control behavior with medication if there is ongoing conflict is a dubious enterprise. You end up with a sleepy conflicted person.

The next thing that comes to mind is that such things are rarely acute problems that need to be solved in a single visit. The challenging/disruptive behavior is usually chronic and deserves more than a one-shot decision – so there really is no requirement to act immediately – prescription or otherwise. And as for medication, we really don’t know the answer as to whether psychoactive medications like antipsychotics or anxiolytics are helpful in these situations [part two: the dogma…, part three: the questions…] – when or if to use them. We do know that the Dogma that they are helpful is not based in science.

But we also need to consider the situation I described earlier [part one: the bind…]:
    So you’re a doctor and a parent/caregiver brings a mentally retarded child to see you who is oppositional/challenging/disruptive in the waiting room and in your office. Then you look at the child’s parent/caregiver and you see a person hanging on by a thread, on the edge of tears, spent from dealing with this child. Maybe it’s a Foster Parent, one you already know to be a real trooper, about to give up return the child to DFCS…
This situation is one of the consequences of what’s been wrong in psychiatry and mental health care in general as it has evolved in recent decades. It’s a common problem and what people do has been heavily influenced by the short-session ways of managed care or the pill for every ill meme of the pharmaceutical industry. We ought to be ashamed of ourselves for going along with this superficial approach to something that can be a compelling 24/7 problem for both the patient and the parent/caregivers. In my opinion, this is actually an example of a major failing of our National Mental Health Institute – taking on the real world problems of mental health workers and families with impaired children. A few well designed retrospective and prospective, unbiased studies could provide all the answers needed to give our Double Bound doctor and his patient[s] a path to follow that actually goes somewhere. And this is not just a problem for the biomedical among us. It’s time for the behaviorist or the social worker to get into the act too. Tyrer et al say:
    "Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population."
While I agree with them, they are still constrained by too limited a question, "to prescribe antipsychotics, or not to prescribe antipsychotics." What is the right thing to do in this situation? Where can the caregiver/parent turn to best approach the problem? What’s wrong with medication? What are the alternatives? I’m no fan of guidelines because they are so vulnerable to bias, but this may well be a situation where a well thought out white paper might really help.

We’re still in the midst of a climate that has been pervasive for much too long – the fantasy that we’re going to knock the ball out of the park, crack the great riddles of the causation of mental illness, figure out the brain. Our National Institute of Mental Health is currently obsessed with discovering new treatments to make up for the deficiencies of the ones we currently have. The solutions remain in the as-yet-unrealized future. Dr. Insel’s NIMH is now saying that future NIMH Clinical Trials will need to contain probes that look for etiological clues – "a focus on learning more about the disorders, as well as the mechanisms of intervention" [time for a sabbatical…].

But what about the treatments we’re currently using? One would have to have been in a prolonged coma state not to know that many of our current practices and beliefs about psychoactive medications have been heavily shaped by influences that don’t have to do with patient care – the profit motives of PHARMA, the cost-cutting motives of third party carriers. Medical science has been clearly twisted to serve both masters. It seems to me that the onus falls on the National Institute of Mental Health [and our professional organizations] to investigate problems like the one addressed in Tyrer et al’s editorial. It’s time to stop simply decrying over-prescribing, and provide some solid evidence-based science to the practitioners who sit in their offices seeing patients.

Writing a prescription may well be the solution to the physician’s discomfort at being in a Double Bind in a given session. In fact it probably will solve the problem of that moment. But a frank discussion of the downside of that option, at least long term, might be a much more effective use of the time and open the door to a more productive approach. It may well turn out that there are situations where the use of medication may be medically sound rather than just a momentary solution, but that’s the kind of thing that requires solid research with follow-up, and right now it’s just not available. The pharmaceutical companies can’t be expected to do this kind of study. That’s why we have a publicly funded NIMH, to help us answer this kind of everyday question. The answers? Not yet…
Mickey @ 6:00 AM
Filed under: politics
part three: the questions…

Posted on Monday 7 July 2014

As for efficacy, Tyrer et al say [see part one: the bind…]:
    What is the evidence for the benefits of these drugs in the treatment of challenging behaviour? Virtually none. Almost all the evidence in favour comes from small trials conducted by drug companies. Yet it would be perverse if doctors continued to prescribe these drugs, knowing about their adverse effects, if they were entirely without efficacy, and many claim that they cannot care adequately for their patients without the option of drug treatment…
In 2012, a Cochrane Systematic Review [not limited to children with mental retardation] found only eight studies of a quality to include – seven with Risperdal® and one with Seroquel®:
by Loy JH, Merry SN, Hetrick SE, and Stasiak K.
Cochrane Database of Systematic Reviews. 2012 9:CD008559 .

BACKGROUND: Disruptive behaviour disorders include conduct disorder, oppositional defiant disorder and disruptive behaviour not otherwise specified. Attention deficit hyperactivity disorder [ADHD] is frequently associated with disruptive behaviour disorders. The difficulties associated with disruptive behaviour disorders are demonstrated through aggression and severe behavioural problems. These often result in presentation to psychiatric services and may be treated with medications such as atypical antipsychotics. There is increasing evidence of a significant rise in the use of atypical antipsychotics for treating disruptive behaviour disorders in child and adolescent populations.
OBJECTIVES: To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths.
SEARCH METHODS: We searched the following databases in August 2011: CENTRAL… MEDLINE… EMBASE… PsycINFO… CINAHL… ClinicalTrials.gov… Australian New Zealand Clinical Trials Registry… CenterWatch… and ICTRP…
SELECTION CRITERIA: We included randomised controlled trials with children and youths up to and including the age of 18, in any setting, with a diagnosis of a disruptive behaviour disorder. We included trials where participants had a comorbid diagnosis of attention deficit hyperactivity disorder, major depression or an anxiety disorder…
MAIN RESULTS: We included eight randomised controlled trials, spanning 2000 to 2008. Seven assessed risperidone and one assessed quetiapine. Three of the studies were multicentre. Seven trials assessed acute efficacy and one assessed time to symptom recurrence over a six-month maintenance period.We performed meta-analyses for the primary outcomes of aggression, conduct problems and weight changes but these were limited by the available data as different trials reported either mean change scores [average difference] or final/post-intervention raw scores and used different outcome measures. We also evaluated each individual trial’s treatment effect size where possible, using Hedges’ g.For aggression, we conducted two meta-analyses. The first included three trials [combined n = 238] using mean difference [MD] on the Aberrant Behaviour Checklist [ABC] Irritability subscale. Results yielded a final mean score with treatment that was 6.49 points lower than the post-intervention mean score with placebo [95% confidence interval [CI] -8.79 to -4.19]. The second meta-analysis on aggression included two trials [combined n = 57] that employed two different outcome measures [Overt Aggression Scale [modified] [OAS-M] and OAS, respectively] and thus we used a standardised mean difference. Results yielded an effect estimate of -0.18 [95% CI -0.70 to 0.34], which was statistically non-significant.We also performed two meta-analyses for conduct problems. The first included two trials [combined n = 225], both of which employed the Nisonger Child Behaviour Rating Form – Conduct Problem subscale [NCBRF-CP]. The results yielded a final mean score with treatment that was 8.61 points lower than that with placebo [95% CI -11.49 to -5.74]. The second meta-analysis on conduct problems included two trials [combined n = 36], which used the Conners’ Parent Rating Scale – Conduct Problem subscale [CPRS-CP]. Results yielded a mean score with treatment of 12.67 lower than with placebo [95% CI -37.45 to 12.11], which was a statistically non-significant result.With respect to the side effect of weight gain, a meta-analysis of two studies [combined n = 138] showed that participants on risperidone gained on average 2.37 kilograms more than those in the placebo group over the treatment period [MD 2.37; 95% CI 0.26 to 4.49].For individual trials, there was a range of effect sizes [ranging from small to large] for risperidone reducing aggression and conduct problems. The precision of the estimate of the effect size varied between trials.
AUTHORS’ CONCLUSIONS: There is some limited evidence of efficacy of risperidone reducing aggression and conduct problems in children aged 5 to 18 with disruptive behaviour disorders in the short term. For aggression, the difference in scores of 6.49 points on the ABC Irritability subscale [range 0 to 45] may be clinically significant. For conduct problems, the difference in scores of 8.61 points on the NCBRF-CP [range 0 to 48] is likely to be clinically significant. Caution is required due to the limitations of the evidence and the small number of relevant high-quality studies. The findings from the one study assessing impact in the longer term suggest that the effects are maintained to some extent [small effect size] for up to six months. Inadequately powered studies produced non-significant results. The evidence is restricted by heterogeneity of the population [including below average and borderline IQ], and methodological issues in some studies, such as use of enriched designs and risk of selection bias… Further high-quality research is required with large samples of clinically representative youths and long-term follow-up to replicate current findings.
Nothing much to write home about there – confirming Tyrer et al’s point that although the use of antipsychotics in intellectually impaired kids with challenging/disruptive behavior is near "Dogma," it’s not "evidence-based Dogma." It’s just what "doctors-habitually-think-Dogma." So all the questions remain unanswered:
  • Are [Atypical] Antipsychotics effective in managing challenging/disruptive behavior in intellectually impaired children? or for that matter, children with other non-psychotic diagnoses? Short term? Long term?
  • What is the incidence of various Adverse Effects using [Atypical] Antipsychotics in intellectually impaired children? or again, children with other non-psychotic diagnoses? Short term? Long term? Are these drugs actually harmful?
  • What are alternative recommendations for managing challenging/disruptive behavior in retarded children? or children with other non-psychotic diagnoses? Short term? Long term?
The ubiquitous influence of the pharmaceutical industry and the cost-cutting restrictions of managed care have had an enormous influence on the way we approach issues like this over the last fifty years. The editorial by Tyrer points out that the use of antipsychotics [I would add particularly Atypical Antipsychotics, particularly Risperdal®] is based on a belief that has achieved the level of Dogma, but the basis for that belief is hardly confirmed by the available scientific record. The problem their editorial addresses – the use of antipsychotics in mentally retarded children – seems to me to encompass an even greater domain than they mention i.e. Autism, primary behavioral problems, whatever-the-Biederman-Bipolar-kids represented, other non-psychotic conditions. And the answer to the question "What is the best practice response, if any, to challenging/disruptive behavior in children with intellectual impairment?" is actually unknown, as is specifically "What is the place of antipsychotics, if any?"

Parenthetically, I marvel at how a study like Aman et al’s [Risperidone Disruptive Behavior Study Group] Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Disruptive Behaviors in Children With Subaverage Intelligence can have such a large effect over the years. It was a small industry run study that was part of a failed attempt early on get approval for the behavioral management of mentally retarded children. It was reincarnated as a justification for using antipsychotics in kids with "super angry/grouchy/cranky irritability" that came to be called Bipolar, at least for a time. And here fifteen years later, it remains as 1/7th of the literature suitable for the Cochrane meta-analysis.

I’m aware that I put more emphasis on the impact of PHARMA on this prescribing practice than Tyrer et al. I don’t think that’s because I’m some kind of wild-eyed activist. I think it’s because I heard it in person with my own ears when I went to the J&J/TMAP trial in Austin in January 2012 [State of Texas and Allen Jones v. Janssen et al]. If you find yourself doubting that influence, I’ve posted the transcripts of that trial. I would recommend reading the testimony of sales rep Tiffany Moake and particularly sales manager Tone Jones [here and here]. I can pretty much guarantee that you will come around to my view before you are halfway through.
Mickey @ 11:56 AM
Filed under: politics
part two: the dogma…

Posted on Monday 7 July 2014

Even though we know the long term consequences of using antipsychotics, most psychiatrists think that antipsychotics are helpful in controlling challenging/disruptive/oppositional behavior in intellectually impaired or autistic kids. Tyrer et al call it "Dogma," and that seems right [part one: the bind…]. Why do we think that? For one thing, we’ve seen antipsychotics used in out of control patients – mania, psychosis, the mentally impaired, agitated people of all kinds. It works in those circumstances if you give enough. But we’ve also been told repeatedly that it works in these circumstances with kids. When the first Atypical Antipsychotic [after Clozaril], Risperdal®, was approved, Janssen quickly began a Clinical Trial of the drug in Mental Retardation done by their Risperidone Disruptive Behavior Study Group:
They went for FDA Approval and were turned down. The study was published in 2002:
Here’s the Janssen business plan for 2002 lest you think the didn’t get mileage from that study [trial 93: a very bad penny…]:
    The clinical development program for RISPERDAL has yielded important new efficacy and safety data in the child and adolescent area. These efforts have previously been focused in the area of Disruptive Behavior Disorders and Subaverage IQ. Several trials, RI5-U5A-93 and RI5-CAN- 19 (as well as the open label 48 week follow up trials, USA-97 and CAN-20), initially designed to support filing for an FDA indication, have been completed and have yielded an impressive volume of new efficacy and safety data. Unfortunately, the FDA determined that Disruptive Behavior Disorder lacks the diagnostic specificity necessary to receive an approved indication. Nevertheless, these studies have contributed significantly to the clinical knowledge of RISPERDAL in the child and adolescent population, and provide a basis for ongoing medical education activities… It is expected that the request will include the following requirements:
      • Pediatric PK trial;
      • Adolescent schizophrenia trial; and
      • Pediatric bipolar trial.
    … the child and adolescent market is not driven by diagnosis, but rather by treatment of symptoms such as aggression, agitation, self-injurious behavior, and explosive rage. This lack of consistent diagnosis stems from a reluctance to "label" children at an early age, as well as a fundamental lack of consensus regarding the actual underlying disease states causing this symptomatic behavior. As a result, multiple diagnoses and comorbidities are the rule, rather than the exception in this area. These issues have influenced the clinical development process and limited the ability to achieve an FDA approved indication for RISPERDAL in children…
As it turned out, this focus on symptoms became an industry-wide meme and formed the nidus for the message from the sales reps who visited individual physicians. In the TMAP trial. we heard example after example of the detailing of clinicians who saw a lot of foster children. focusing on symptoms, not diagnosis. But then along came Dr. Joseph Biederman and the Bipolar Child craze. His notion that "super angry/grouchy/cranky irritability" was a symptom of Bipolar Disorder in Children gave broad license to prescribing antipsychotics to a whole new cohort of kids. In a move that seems almost too bizarre for words, that same study mentioned above was repurposed by Excerpta Medica and published under Dr. Biederman’s name as a study about treating these supposed affective symptoms in the newly created unofficial category of the Bipolar Child with Risperdal®:
The point here is that the pharmaceutical industry and particularly Janssen were vigorously detailing the Atypical Antipsychotics as a treatment for disruptive children including the mentally retarded, autistic, Bipolar, and psychotic groups without making much of a diagnostic distinction [bipolar kids: biedermania and super angry/grouchy/cranky irritability…]. They were essentially pushing treating the symptom of being a difficult child with antipsychotics.

My point in this post is that while I’m sure that Tyrer et al’s comment that "Drug treatment has been a mainstay for managing a common syndrome subsumed under the label ‘aggressive challenging behaviour’ since chlorpromazine was first introduced for its treatment over 40 years ago" is true, it was also actively amplified and reinforced during the period of aggressive marketing of the Atypical Antipsychotics. That these antipsychotic drugs are for treating disruptive challenging kids was oozing from every pore of the pharmaceutical companies that manufactured them, and that surely had something to do with that usage becoming "Dogma" – even though it was mostly an off label campaign. And the problem Tyrer et al addresses in their editorial spills over into any disruptive behavior in children – not just in mental retardation.
Mickey @ 8:00 AM
Filed under: politics
part one: the bind…

Posted on Sunday 6 July 2014

by Peter Tyrer, Sally-Ann Cooper, and Angela Hassiotis
British Medical Journal. 2014 348:g4323.

Time to rethink?

Do we still need to be reminded that the drug treatment of people with intellectual disability is often prolonged and not without dangers? We probably do. Drug treatment has been a mainstay for managing a common syndrome subsumed under the label “aggressive challenging behaviour” since chlorpromazine was first introduced for its treatment over 40 years ago… Challenging behaviour is the most common disturbance requiring intervention in intellectual disability services, but it does not have proper diagnostic status in standard psychiatric classifications.

Yet this does not inhibit the wholesale import of adult psychopharmacology into its management. Psychotropic medication in its many forms mainly antipsychotics, sedatives and tranquillisers, antidepressants, and mood stabilisers — has seen extensive off-label prescribing for the past 50 years. Thus, a recent population based cohort study of 1023 adults with intellectual disabilities showed that 49.5% were taking some form of psychotropic drug, with 23.2% taking an antipsychotic despite only 4.4% having a psychotic disorder…

This prescribing would not be a concern if adverse effects were few and easily corrected, but neither of these is true. The high levels of obesity, metabolic syndrome, and diabetes in this population are largely due to these drugs and predispose to premature mortality. National audits such as those carried out by the Prescribing Observatory for Mental Health suggest that more people with intellectual disability are being regularly checked for known and established side effects of antipsychotic medication in secondary care. But there is a lack of primary care data on whether people with intellectual disability prescribed psychotropic drugs receive similar care and are targeted as a higher risk group. Once these drugs are prescribed they far too often become part of long term management, reinforced by the nervousness of care staff with limited knowledge of psychopharmacology and reluctance of practitioners and carers to alter a treatment when it may be wrongly perceived as effective. Attempts to stop these drugs after people have been taking them for many months or years have had only limited success.

What is the evidence for the benefits of these drugs in the treatment of challenging behaviour? Virtually none. Almost all the evidence in favour comes from small trials conducted by drug companies. Yet it would be perverse if doctors continued to prescribe these drugs, knowing about their adverse effects, if they were entirely without efficacy, and many claim that they cannot care adequately for their patients without the option of drug treatment. We therefore need clear indications for drug treatment, as well as to develop a range of more effective psychosocial treatments, for which there is now increasing evidence, but there is still ground to cover. In the interim, a key element is education of prescribers… Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population..

Drug treatment of challenging behaviour in people with intellectual disability should no longer be on the sidelines of evidence based medicine. If we are going to achieve parity of esteem for people with mental illness, we can no longer tolerate our ignorance on this subject. Quite apart from the deficiencies in evidence allowing dogma and opinion to rule, the cost of prescribing these drugs is enormous. If they truly are unnecessary, clinicians, pharmacists, service managers, and those who fund services for people with intellectual disability need to know, and soon.
The belief that one can control or at least dampen the disruptive [challenging, aggressive, etc] behavior in impaired children with antipsychotics really is in the range of Dogma as this editorial implies. I think I even believe it, though I wish I didn’t. So they’re absolutely correct in saying, "Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population." Absent that, the belief will persist along with Papal Infallibility and Transubstantiation throughout the ages – Dogma endlessly debated but unresolved. And even if it turns out to be true that these medications are somewhat effective, the problem remains in the form of adverse effects – metabolic syndrome, weight gain [often dramatic], diabetes, neurological symptoms, tardive dyskinesia – because the disruptive [challenging, aggressive, etc] behavior doesn’t just evaporate on its own. It comes with the package and leads to long term use once started, again as this editorial implies.

Which brings me to Hamlet and company, the tragic figures in Shakespeare’s immortal play. Thirty plus years ago, my kid sister [now a retired academic] wrote a paper about that play, Hamlet, "A Man to Double Business Bound", out of her usual genre [Milton]. She analyzed the play using Double Bind theory, and did a mighty fine job of it, if I do say so myself [ignoring my obvious COI]. I knew Double Bind theory, but her paper etched it on my brain, and I thank her for that. It was an invaluable tool in understanding the narratives of the patients I saw over the years, and it was no small factor in working out my own dilemmas – as the life of a physician is filled with Double Binds that never stop coming. A Double Bind, oddly enough, has four commands: Two injunctions that are diametric opposites [thus the synonym - an impossible situation] – one overtly stated and the other usually covert. Then there’s a third injunction – that you have to act, to do something [even though there's nothing right to do]. And the final rule caps the nightmare, you can’t address the obvious impossibility of this complex of commands. All you can think to do is pick one or the other side and surely fail; or give endless soliloquies about a paralysis of mind; or go crazy. Most psychotherapists can think of endless examples in a heartbeat. I sure can [see postscript…].

So you’re a doctor and a parent/caregiver brings a mentally retarded child to see you who is oppositional/challenging/disruptive in the waiting room and in your office. Then you look at the child’s parent/caregiver and you see a person hanging on by a thread, on the edge of tears, spent from dealing with this child. Maybe it’s a Foster Parent, one you already know to be a real trooper, about to give up return the child to DFCS. And you think hope that an antipsychotic might possibly help [or you can't think of anything else to do], knowing full well the long term side effect profile of the drugs. That’s when the prescriptions often get written, even by the most principled doctor in the clinic. If you do nothing, you’ve done nothing, reinforcing the hopelessness the parent/caregiver already feels. If it doesn’t work, you’re in trouble because you’ve implied that medication is the way to go and what’s next? If it does work, you’re committing to a road you might really not want to be on sooner than you think. That’s what a Double Bind feels like – absolutely nothing right to do, and a pressure to act [yesterday].

Tyrer et al have written an excellent editorial. They obviously don’t think these kids should be on antipsychotics or at least not like they are now, but they don’t preach, rant, or moralize like many ["those damn doctors think everybody needs to be on medications!"]. They simply present an all too common clinical problem, one that’s often handled by the gestalt of the moment with no clear evidence-based guidance. And their heading ["Time to rethink?"] is a confrontation of sorts, because they’re implying that this is a topic doctors don’t want to think about [I would add "don't want to think about because it doesn't have any apparent solution"]. And the definition of a confrontation is simple – telling someone something they don’t want to hear.

If you’re not on to my ways, you haven’t figured out that this is the first of several posts [hints: "part one" in the title; this is the last paragraph and I'm not close to an ending]. The take home point for this post is that this is not necessarily a moral problem having to do with the ethical commitment of the doctor. It’s a clinical problem that’s often handled as if it’s acute [as in my scenario], but is actually chronic and needs to be approached as such with the long haul in mind. We obviously need some real data to formulate rational interventions – not quick decisions made in the fog of the moment…
Mickey @ 8:00 PM
Filed under: politics
still watching…

Posted on Sunday 6 July 2014

It has been eight months since this apology was published in JAMA Psychiatry. After over a decade of Dr. Kupfer self-righteously swatting away accusations that his DSM-5 Task Force was riddled with members who had conflicts of interest, he was forced to acknowledge that he had a whopper of a conflict of his own – a company poised to capitalize on his wished-for "dimensional diagnoses" as a screening device:
by Robert D. Gibbons, PhD, David J.Weiss, PhD, Paul A. Pilkonis, PhD, Ellen Frank, PhD, and David J. Kupfer,MD.
JAMA Psychiatry. Published Online: November 20, 2013. doi:10.1001/jamapsychiatry.2013.3888

To the Editor: We apologize to the editors and readers of JAMA Psychiatry for our failure to fully disclose our financial interests in an article1 that reported a diagnostic tool, the Computerized Adaptive Test for Depression [CAT-DI]. Following acceptance of the paper, we disclosed that “The CAT-DI will ultimately be made available for routine administration, and its development as a commercial product is under consideration.” The company that owns the rights to CAT-DI and several related tests is Psychiatric Assessments, Inc [PAI], which uses the trade name of Adaptive Testing Technologies [ATT] on a website describing these tests. Lead author Robert D. Gibbons, PhD, is the president and founder of PAI,which was incorporated in Delaware in late 2011, then registered to do business in Illinois in January 2012. Dr Gibbons awarded “founder’s shares in PAI” to us, yet all 5 of us failed to report our financial interests in connection with our article and again in a Reply to Letters to the Editor regarding the article. Neither PAI nor ATT has released the CAT-DI test [or any other test] for commercial or professional use, but our ownership interests were relevant to the research article and Reply we submitted and should have been disclosed to the editors. Our submitted disclosure lacked transparency, and we regret our omission.
The APA investigated and said everything was fine. You may or may not have noticed that my letter to the APA and Timeline went unacknowledged [open letter to the APA…]. Since then, we’ve heard little to nothing from Dr. Kupfer, Dr. Gibbons, or their other partners in Adaptive Testing Technologies. This post is just a marker to remind them that we’re still watching…
Mickey @ 8:00 AM
Filed under: politics
no commercial interruptions…

Posted on Saturday 5 July 2014

Why have I reproduced this entire Perspective piece even though it’s available full text on-line? It’s because it’s in the New England Journal of Medicine – that’s why. I want to emphasize its existence in a top flight American Journal. As much as I’ve appreciated all the play Data Transparency has gotten in Europe, it’s time for some official noise like this on this side of the pond. It has been a long time coming. So here it is [with no commercial interruptions]:
by Kevin Outterson, J.D., LL.M.
New England Journal of Medicine. 2014 371:1-3.

This year promises to be an auspicious period for some long-running battles over the dissemination of biomedical research. Some companies seeking more freedom to promote their products have bristled at recent guidance documents from the Food and Drug Administration [FDA] regarding promotion of drugs and devices for off-label uses, claiming that they violate the First Amendment. Simultaneously, industry is divided over calls for increased transparency of clinical trial results. But as the FDA’s regulatory authority is weakened by First Amendment challenges, the need for clinical trial transparency becomes more urgent.

In the recent guidance documents, the FDA recommended that scientific articles used for off-label promotion be scientifically sound, come from peer-reviewed journals, and be distributed in unabridged form with the approved labeling and a comprehensive bibliography. Clinical practice guidelines used for marketing should be based on a systematic review of the evidence and "be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups." The FDA also recognized the growing importance of social media, describing the situations in which a company is responsible for comments on Facebook and patient advocacy websites focusing on specific diseases and treatments. In early June, the FDA expanded this guidance process to include communications about new risk data for existing drugs. The FDA is concerned that companies might use incomplete new information to weaken the impact of warnings on the approved drug label.

Some companies have complained that these rules overly constrain their marketing practices and impermissibly infringe on commercial speech. These claims find some support in recent cases that have undermined the FDA’s regulatory authority over drug marketing. The First Amendment has emerged as a potent deregulatory weapon for corporations. Governments increasingly face First Amendment challenges to rules related to the marketing of regulated products, not only from the drug industry but also from companies selling tobacco, alcohol, and processed foods. These industries claim that the government violates a core principle of liberty — freedom of speech — by regulating how food, drugs, alcohol, and tobacco are sold. The FDA issued the new guidance documents with these concerns in view.

In recent years, drug companies have paid billions of dollars in fines related to off-label promotion. Whether the First Amendment protects this activity remains an open question. The FDA’s position is nuanced. Under the law, a drug is viewed as "mislabeled" unless "its labeling bears adequate directions for use." The FDA does not require labels to discuss all possible uses, which would be burdensome to the companies, but only those actually intended by the company. One way to prove this intention is to examine company statements about the drug, including promotional activity. Companies can make any truthful and nonmisleading statement about their drugs, but when they choose to speak about any particular use, the label must bear adequate directions for that use. Speech is frequently used to prove elements of other crimes; examples include perjury, premeditated murder, and conspiracy.

Seen in this light, the recent draft guidance documents do not constrain First Amendment values. They provide safe harbors, listing circumstances in which the FDA will not consider actions to be evidence of intent to sell a drug for a particular use. And the guidance is quite lenient: a company can sponsor biomedical research for an off-label use, refuse to submit that research to the FDA for an expanded label, but nevertheless widely distribute reprints of relevant journal articles to physicians and chat about them on Facebook and other social media. The FDA is keeping a respectful distance from the First Amendment, while gentry reinforcing better practices, including peer review and disclosure of conflicts of interest.

If the Supreme Court’s interpretation of the First Amendment continues to constrain FDA influence over the dissemination of research, then even greater importance must be placed on improving research quality and providing the support independent research teams need to reanalyze clinical trial data. Studies have highlighted strategic weaknesses in the research enterprise, including failures in peer review, publication bias, bias introduced by sponsors or investigators, and extensive financial relationships.

Transparency is an important tool for addressing these issues, and many stakeholders are working to improve transparency in biomedical research. The International Committee of Medical Journal Editors has adopted standards to improve the quality of the peer-review process, require registration of clinical trials before patient enrollment, and improve disclosure of conflicts of interest The United States requires advance registration of many clinical trials; since 2007, summary results must also be published. Similar initiatives have been implemented in Europe and beyond, including a global clinical trial registry maintained by the World Health Organization. Advance registration and summary publication are important tools for reducing opportunities for publication bias and making it harder to hide negative studies.

Pressure is now building for two additional data-transparency goals: giving responsible independent researchers access to patient-level data to enable them to replicate studies and perform meta-analyses; and requiring public release of clinical study reports submitted to governments for marketing approval, which have substantial informational value.* Companies have traditionally protected these data as trade secrets,* but maior changes are under way. In the United States, the FDA requested comments in 2013 on a proposal supporting a limited level of transparency for product-masked patient data. Product masking protects the identity of both the drug and the patient, which limits the data’s clinical utility for research. Currently, this effort appears to be on ho!d, awaiting results from a review by the Institute of Medicine. Meanwhile, transparency initiatives by some companies and legislative action in Europe may have reached the tipping point, with momentum growing for transparency that goes well beyond product-masked data.

Limited patient-level data are now being made available to independent researchers. In May 2013, GlaxoSmithKline opened some of its patient-!evel data to responsible researchers, with an independent review pane! acting as the gatekeeper.4 Johnson & Johnson followed suit in January 2014, partnering with a group at Yale. These programs are welcome improvements and should expand across the industry.

I believe that transparency should also extend to the clinical study reports submitted to the FDA and other drug-regulatory authorities. On April 2, 2014, the European Parliament adopted reforms to its rules governing human clinical trials, including a key provision requiring delayed release of clinical study reports submitted to the European Medicines Agency. The next day, AbbVie dropped its lawsuit against the agency, which had sought the release of clinical study reports on two AbbVie drugs. Other litigation remains pending, and the European Union may yet weaken these rules, but these events suggest that disclosure of clinical study reports may soon be the norm in Europe.

In public comments on the European reforms, the drug industry raised objections to the release of clinical study reports. Although companies have no trade-secrecy right to hide safety data on medicines, they make a reasonable point regarding the danger of substantial competitive harm from full transparency. Governments offer non-patent-based incentives for special categories of drugs, such as orphan drugs and biologics. These incentives have frequently rested on data exclusivity, prohibiting other companies from using data for regulatory approval purposes. To the extent that transparency disrupts data-exclusivity incentives and the timing of generic entry, both domestically and internationally, the law will need to be adjusted in order to restore the competitive position of the companies. The alternative is to delay data releases until many years after a drug is approved, but neither the progress of science nor public safety should wait for full transparency. The companies will also retain the full force of patent law to block premature generic entry. If this issue is resolved, the onus will be on the industry to articulate why clinica! study reports should not be immediately released when a drug is approved.

After decades of criticism about bias in the clinical trial enterprise, new norms are being established that promote transparency. Additional transparency is particularly welcome in the United States, since the Supreme Court has increasingly constrained the FDA’s ability to regulate off-label marketing activities. In the deregulatory environment fostered by First Amendment challenges. clinical trial transparency is perhaps the best remaining option for informing physicians and protecting patients.
One Perspective piece in the New England Journal of Medicine doesn’t mean this issue is resolved, but it’s damn sure better than none…
Mickey @ 10:02 PM
Filed under: OPINION
fine summary…

Posted on Saturday 5 July 2014

Though ChemistryWorld is not one of my usual sites, I give them credit for one fine summary of the current state of the European Medicines Agency Data Transparency story:
ChemistryWorld
by Andy Extance
3 July 2014

Tempers are being tested as the pharmaceutical industry’s journey towards transparency on clinical trial data enters a critical phase. Even as drug companies announce more voluntary access schemes, campaign group AllTrials has accused the European Medical Agency [EMA] of a ‘backroom deal with pharma’ to weaken earlier commitments. The disputes have arisen following EMA consultations over its clinical trial data policy, which it hopes to finalise in mid-July, and bring into force in October. The pioneering plan would be the first of its kind to proactively publish clinical trial reports, giving people access for non-commercial use without needing to request it from companies. After receiving over 1100 comments covering a broad spectrum of opinions, the EMA conducted follow-up meetings in May to discuss the resulting proposals. Following the meetings researchers, AllTrials, and even the EU Ombudsman reacted critically.

The chief concern was a ban on saving, downloading or printing clinical study reports [CSRs], making these huge documents available only on-screen. The Institute for Quality and Efficiency in Health Care [IQWiG], Germany’s national commission for assessing medical procedures, was especially outraged. It took to Twitter with a long series of photos underlining how hard this would make its job. The same groups also warned that the new ‘terms of use’ contract could let trial sponsors sue researchers, creating a legal chill that would deter scrutiny.
I’m particularly glad there was such widespread outrage about their "screen only" proposed interface. Having used such a system for the last months, I was afraid that people wouldn’t realize what a hinderance that really is. Our analogy of going to sea to see the world in a submarine looking through a periscope was no exaggeration.
The EMA’s new redaction policy on what information could be hidden drew fire too. It arose because of comments in the initial consultation that patient privacy, trust in the system, and commercial confidentiality could be put at risk. Richard Bergstrom, director general of the European Federation of Pharmaceutical Industries and Associations [EFPIA], expressed worry over ‘putting transparency – at whatever cost – ahead of public health interests’.

The proposed EMA policy allows drugmakers to propose redactions for text they feel is commercially or otherwise sensitive, although the regulator will retain the final say on what is hidden. Campaigners say this measure and vague policy wording will mean too much is concealed. EMA spokesman Martin Harvey-Allchurch stresses that ‘third parties’ can petition or sue if they think that’s happening, and that the extent of redaction will always be visible.
I hadn’t read that red part elsewhere, but that’s a reasonable request if the process of petitioning is clear. That last part ["the extent of redaction will always be visible"] is reassuring. I’d prefer that there be no redaction clause at all. What business is Commercially Sensitive Information of the European Medical Agency anyway? But one can’t expect to win every battle.
Working too closely?

Yet the new policy still seemed to many a significant departure from the EMA’s previous hard line on data disclosure. Its 2010 ‘access to documents’ policy considers that most CSRs are not commercially confidential information, and promised to disclose CSRs for every drug it had reviewed. The confidentiality point has drawn fire from some drugmakers, with AbbVie and InterMune disputing it in court. But in April, AbbVie dropped its case, the day after the EU passed regulations that will make clinical trial registration and data sharing a legal requirement. Then, at the end of May, InterMune dropped some of its cases against the EMA.

AllTrials subsequently suggested that the price for dropping the cases had been a more industry-favourable transparency policy, something Harvey-Allchurch ‘absolutely refutes’. ‘AbbVie realised that we’re going to stick with our definition of commercial confidentiality – they knew they were not going to win that one,’ he says. ‘They went away, and came back with proposals for what they wanted redacted. In the end, what they proposed was in line with our redaction principles. The main InterMune case is still running.’

Following the pressure over its proposals on 12 June, the EMA’s management board agreed an amended policy. That allows downloading, saving and printing trial data for academic and non-commercial research purposes, although the other controversial areas remain unchanged. Nevertheless Harvey-Allchurch plays down the outcry surrounding the new policy. ‘The whole purpose of these targeted consultation exercises was to listen,’ he says. ‘We heard the feedback, we listened to it, and proposed an alternative to the board.’ But with Harvey-Allchurch underlining that this policy initiative is a bridge to the new EU regulations that will come in some time after May 2016, the final policy wording will be highly significant.
I don’t believe what PHARMA says anymore. That was actually a conscious decision on my part. I made it the day I read GSK’s response in the Chronicle of Higher Education denying an agreement they’d just signed [see the only enduring contract…]. Life has been easier not having to obsess about what to trust. I’d suggest it to all as a general strategy. To stick to my penchant for old sayings: "The best predictor of future behavior is past behavior."
Industry delivers

Meanwhile, pharma companies continue to progress their own schemes to make data available, with Bristol-Myers-Squibb [BMS] becoming the latest to open up its trial results. The Duke Clinical Research Institute at Duke University in Durham, North Carolina will act as the gatekeeper for BMS’ data. It will review study proposals and check final manuscripts ‘for scientific integrity and consistency with the original proposed work’ like Yale is doing for Johnson & Johnson. Boehringer-Ingelheim has also said that it will publish documents for all approved products going back to 1998. That move goes beyond the ‘Principles for responsible clinical trial data sharing’ introduced by the EFPIA and the Pharmaceutical Research and Manufacturers of America [PhRMA] last July.

IQWiG spokesperson Susanne Breuer highlights that a fragmented landscape of company data repositories would be less desirable than the single repository the EMA hosts. ‘The control of data completeness would be much more complicated, and analysing data it would take a lot longer,’ she says. ‘We would appreciate centralised access for scientists.’ Parts of the industry are making progress here, with Eli Lilly and Bayer Healthcare agreeing to make trial data available via Clinicalstudydatarequest.com. They bring the number of companies using the portal, created by GlaxoSmithKline last year, to eight.
I’m on a team looking at the data from a questionable study, and except for the maddening "screen only" interface, I feel comfortable with the access we have to the information we wanted to see. I hasten to add that there was a good deal of negotiating involved in getting it. I think I would be more accepting of these recent examples of industry delivering if they had given in much earlier. I’m suspicious of foxhole conversions and that’s what this is. And there’s really no need for PHARMA to maintain that kind of control. In the end, we really should be privy to everything that goes to the regulatory agencies. That’s also true for all Clinical Trials, but that’s another part of the fight…
Mickey @ 1:38 PM
Filed under: politics
time for a sabbatical…

Posted on Saturday 5 July 2014

Insanity: doing the same thing over and over again and expecting different results.
not Albert Einstein 1
"From Psychiatry to Clinical Neuroscience"
PsychiatricNews
by Mark Moran
June 17, 2014

NIMH Director Thomas Insel, M.D., says that more people are getting more treatment, but outcomes are not getting better, so many of today’s treatments may not be sufficient to “bend the curve.” The field of psychiatry and neuroscience is haunted by four “inconvenient truths” about the diagnosis and treatment of mental illness, said National Institute of Mental Health (NIMH) Director Thomas Insel, M.D., in a lecture titled “From Psychiatry to Clinical Neuroscience” at APA’s 2014 annual meeting in New York in May. These are his four inconvenient truths: the field has failed to “bend the curve” in the prevalence and cost of mental illness; more people are getting more treatment, but outcomes are not getting better; the current knowledge base is insufficient to ensure prevention, recovery, or cure for too many people with serious mental illness; and a transformation of diagnostics and therapeutics is necessary to make significant progress in treating mental illness.

Insel contrasted the remarkable progress of the last several decades in reducing morbidity and mortality associated with major medical conditions such as stroke, heart disease, pediatric cancers, and AIDS with the stubbornly high rates for mental illness. He noted, as an example, that the suicide rate in the United States is as high as it has ever been. “I can’t tell you a success story as I can for pediatric cancer or AIDS when we talk about suicide,” he said. “It’s rather remarkable that over the last two decades the suicide rate hasn’t budged at all. With about 38,000 suicides a year, we are as high in absolute numbers as we have ever been.”

Knowledge of the brain, despite enormous advances in recent years, is still in its infancy, Insel pointed out. “The brain is a world consisting of a number of unexplored continents and great stretches of unknown territory,” he said.But he also described a promising future in which mental illness is reenvisioned as a disorder of brain circuitry that will be greatly advanced by President Obama’s BRAIN Initiative, announced in April 2013. Research is revealing how chemical imbalances can lead to circuit dysfunction, and in turn to behavioral symptoms, and Insel said the connections that are emerging can be used in the development of diagnostic tests for brain disorders that are today diagnosed late through observation of symptoms. “We can now study the mind with the tools of neuroscience,” he said. For instance, he presented evidence that is revealing attention-deficit/hyperactivity disorder to be a disorder of delayed cortical maturation. He also presented evidence of schizophrenia as a neurodevelopmental disorder with distinct risk and prodromal stages that allow for early intervention.

Finally, he described the NIMH Research Domain Criteria (RDoC) project, which he said will work in tandem with DSM. “DSM/ICD will continue to be the basis of clinical care,” he said. “RDoC is a framework for research in which NIMH will support researchers to deconstruct current diagnostic categories or identify dimensions that extend across categories. RDoC will develop through an information commons that integrates data from many sources, transforming the way we diagnose mental disorders in the future.”
New Opportunities, New Expectations
by Thomas R. Insel,MD and Nitin Gogtay,MD
JAMA Psychiatry. 2014 71[7]:745-746.

There can be little question that we need better treatments for mental disorders. The recent Global Burden of Disease Study demonstrates how neuropsychiatric disorders are a leading source of medical disability in the United States, increasing since 1990 despite a concomitant increase in pharmacologic treatments. Although there have been many commercially successful medications for anxiety, depression, and psychosis, few compounds have shown truly new mechanisms of action, and even fewer represent true breakthroughs in efficacy. For many of our most serious clinical challenges, such as anorexia nervosa, posttraumatic stress disorder, the core symptoms of autism, and the cognitive deficits of schizophrenia, to name a few, we lack effective medications altogether.

With this background, in 2010, the NIMH asked its advisory council for guidance on the best way to address the urgent need for new treatments. The National Advisory Mental Health Council’s report, “From Discovery to Cure,” recommended several changes to the NIMH clinical trials portfolio. Among those recommendations was a call to accelerate the development process, moving quickly into humans for proof-of-concept studies, and a request for trials that identify and validate new targets. From these recommendations, the NIMH has developed a focus on experimental therapeutics, in which interventions are used as probes of disease mechanisms, as well as tests of efficacy.

In February of this year, the NIMH released 4 new funding announcements to transform its investments in clinical trials. These new announcements can be summarized as calling for changes in “what” and “how” trials are conducted. What are we looking for in these new announcements? Each of the 4 covers a different phase or area of clinical investigation, but they all share a focus on learning more about the disorders, as well as the mechanisms of intervention. Each requires a demonstration of target engagement, in addition to assessing changes in symptoms. And each seeks to identify a critical dose and duration of intervention that would engage or modulate the target in addition to assessing symptom change, with a goal of informing further research or treatment strategies.

These changes are the result of the changing ecosystem of treatment development, the advent of new tools to look at mechanisms of change, and the advice of experts both within and outside of our field. They are also a response to many patient advocates who remind us that “time matters.” The current timetable for a clinical trial, which spans nearly a decade from proposal to publication, is not acceptable to families with a child with autism or an adolescent with psychosis. However, in addition to fixing the delay, these families need to know that we are doing everything possible to deliver treatments that are better than what is available today. New treatments will require a deeper understanding of the disorders and a new approach based on experimental therapeutics for pharmacological, psychosocial, and neuromodulatory interventions.
I first became aware that PHARMA was giving up on CNS drug development three years ago when Dr. Stahl let loose with a rant of cosmic proportions [myopia – uncorrected…]. Within a month, the DSM-5 Task Force admitted their planned "biological" DSM-5 wasn’t going to fly, the RDoC from the NIMH was brought to the fore, and Dr. Insel began to talk about brain wiring [class action in the air…] initiating any number of schemes to jump·start CNS drug discovery – all the while whining endlessly about the inadequacy of our current drugs. The timetable for his Clinical Neuroscience seems to have been abandoned around then, though the term is never far from his lips.

I’m so regularly moved to criticize everything he writes that I’m even tired of readng myself. So I thought that, for a change, I would take a moment and consider why I’m so negative whenever I read something from him. The first thing that was immediately apparent – he doesn’t stop and think himself. He doesn’t sit under a tree and consider the fact that the NIMH has been in a constant state of flux, mostly at his beckoning, and has essentially gone nowhere for years [his years]. He’s always coming up with new plans, programs, initiatives and they just flow from one to the other with little to show for the effort. My overused heroic graphic is borrowed from an old Russian Red Army poster, but when I first made it, I was looking for something else I couldn’t find – a picture I remember of Jeb Stuart from our Civil War. At least in popular lore, Stuart and his Cavalry were out racing pell-mell through the country-side with adrenaline flowing and the wind blowing in their hair, forgetting their assigned mission [intelligence], contributing to Lee’s loss at Gettysburg. That’s how I see Dr. Insel – bouncing from experimental medicine to translational science to personalized medicine to connectomes  to whatever-the-RDoC-is to experimental therapeutics without taking a long enough breath to take stock of the state of play.

I suppose another thing is that he seems to think he knows where we’re going and is frustrated that he can’t make us get there with his incentives [like in this JAMA Psychiatry opinion piece]. It’s easy to say all kinds of negative things about the pharmaceutical companies and their disreputable marketing ways, but they also happen to represent a massive, well financed, scientific consortium. They haven’t been able to find what they [and Dr. Insel] are looking for in decades – and they were looking plenty hard. CNS-anythings were selling like hot-cakes and they would have been as pleased as punch to find new targets and new animal models instead of watching those tired rodents floating in beakers eking out me-too antidepressants. PHARMA gave it their all and came up mostly empty handed. What makes Tom Insel think that he can beat their record by taking over their failed quest with his pea-shooter budget?

Were Dr. Insel able to transcend his fixation on Clinical Neuroscience and the as-yet-unfound-novel-breakthroughs-around-the-corner he’s chasing, and could sit quietly under the Bodhi tree beside the river, what faint music might he hear building in the stillness as he mused on his koans? "Why are the people who so embraced the DSM-III so turned off by its current incarnation? or his RDoC proxy?" "Why is there so much negativity about the drugs that were cheered as they flowed from the pipeline not so very long ago?" "Why have so many gurus of the past faded into obscurity, or retirement [or exile in Miami]?"

That music might just say to him that these are the signs and symptoms of Thomas Kuhn’s phase of paradigm exhaustion, a time when something once new and filled with such hope and explanatory power has all its warts showing in bas relief, a time when it’s hard to even recall the former glitter or even that there was such a golden time. All that shows are the exceptions and failings of the now tired paradigm. And the aging former messiahs seem like old men clinging to a dream past its time. What’s supposed to happen is that the passing era gets reconstructed through a more realistic set of lens than the the rose colored glasses that came with the passion of new discovery. But what’s supposed to happen rarely does happen. The proponents try to keep the dream alive, and in the process add a dark patina that increases and prolongs the depth of the period of disillusionment.

We don’t need a new program. We need a new programmer…
Mickey @ 12:08 AM
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