1 Boring Old Man

All systems have a weak spot: the weakest link in the chain; an Achilles’ heel; an O-Ring that’s sensitive to the cold. Where are the vulnerabilities in the elaborate scheme [see in the details…] that has evolved for conducting Clinical Trials of medications?

It’s the blinded piece of the study that has the most rigid standardization. The protocol  can be flawed, for example: choosing either a too low or too high dose for a comparator compound that results in a weak efficacy result or an inflated adverse event profile, but that should be apparent on careful reading. Assuming the trial is truly blind, there’s not much one can do to jury-rig the outcome during this phase. In the case if the Individual Participant Data [IPD], the numeric and categorical values are cut and dried, but there are places where subjective information is coded or translated into scales and that can either be done badly or inaccurately, so the unabstracted Case Report Forms [CFRs] are the most accurate source for adverse events. But again, if the blind is true, such manipulations should affect all groups. Thus, the heavily regulated blinded portion of a Clinical Trial has a few vulnerabilities, but is not the Achilles’ heel [unless you consider the biggest vulnerability of all – not publishing the study if you don’t like how it comes out].

The actual Achilles’ heel comes after the blind is broken in the analysis, the creation of the Clinical Study Report [CSR], and the subsequently published journal article. With eyes wide open, there are infinite paths to misuse and misrepresention of study results – most avenues well traveled. And recall that the long narrative CSR is as vulnerable to spin as the published paper. For example, in 2004 as part of the settlement in New York, Attorney General Elliot Spitzer stipulated that GSK make their Paxil Study 329 data public on the internet. But until August 2012, it looked like the listing on the left below [see here via the Wayback Machine]:

Finally, with urging, they added the IPDs as appendices like on the right [see here]. The CSR is only a prequel to the published paper, vulnerable to the same sleight of hand. There were tables galore in the CSR as originally offered, but they were summaries, not the raw IPDs that could be checked. Those appendices in the later version are the data itself.

Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications

by Emma Maund, Britta Tendal, Asbjørn Hróbjartsson, Karsten Juhl Jørgensen, Andreas Lundh, Jeppe Schroll, and Peter C Gøtzsche.

British Medical Journal. 2014 348:g3510.

[full text on-line]

Objective To determine, using research on duloxetine for major depressive disorder as an example, if there are inconsistencies between protocols, clinical study reports, and main publicly available sources [journal articles and trial registries], and within clinical study reports themselves, with respect to benefits and major harms.

Design Data on primary efficacy analysis and major harms extracted from each data source and compared.

Setting Nine randomised placebo controlled trials of duloxetine [total 2878 patients] submitted to the European Medicines Agency [EMA] for marketing approval for major depressive disorder.

Data sources Clinical study reports, including protocols as appendices [total 13 729 pages], were obtained from the EMA in May 2011. Journal articles were identified through relevant literature databases and contacting the manufacturer, Eli Lilly. Clinicaltrials.gov and the manufacturer’s online clinical trial registry were searched for trial results.

Results Clinical study reports fully described the primary efficacy analysis and major harms [deaths [including suicides], suicide attempts, serious adverse events, and discontinuations because of adverse events]. There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial. Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias. In each trial, a median of 406 [range 177-645] and 166 [100-241] treatment emergent adverse events [adverse events that emerged or worsened after study drug was started] in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively. We also found publication bias in relation to beneficial effects.

Conclusion Clinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports. There were inconsistencies between protocols and clinical study reports and within clinical study reports. Clinical study reports should be used as the data source for systematic reviews of drugs, but they should first be checked against protocols and within themselves for accuracy and consistency.

• the original protocol with any legitimate amendments
• the IPDs
• if the question is about Adverse Events, the CRFs

With all of this talk of Data Transparency in Clinical Trials, people in-the-know tend to talk in shorthand jargon, and it’s easy to get lost. And since what they’re talking about actually matters, this is a mini tutorial on what the acronyms mean:

The Protocol is the nuclear document in a Clinical Trial, an a priori description that lays out everything about how the study is to be conducted and evaluated in detail. One part of those specs is to define the primary and secondary outcome variables, the methods used to analyze them, and the criteria for reaching conclusions. The Institutional Review Board is tasked with insuring that the study justifies doing a trial in humans, meets all the standards for human research, and is designed with sufficient power to answer the research question – pro or con.

These days, the Clinical Trial itself is often spread among multiple sites, coordinated by a contracted CRO [Clinical Research Organization]. The subjects are randomized and double blinded so neither the study staff nor the subjects know what medication any subject is taking. Each of the tests and observations throughout the duration of the trial are recorded on a variety of individual Case Report Forms [CRFs] – the true Raw Data from a Clinical Trial. When the last subject enrolled completes the study, the stacks of CRFs are abstracted – turned into analysis ready tables called the Individual Participant Data [IPD], usually in an electronic format. This whole process takes place while the study is still fully blinded. The IPDs that tabulate the numeric or categorical scores from tests likely mirror the CRF data [but those cataloging Adverse Effects  and other notations can lose something in translation].

When the blind is broken, the IPD datasets are ready for Analysis. That’s when the investigators, sponsors, and statisticians get their first look at the data sorted by treatment, and can apply all the tricks of their trade that tell us all if the study drug separates from placebo, the magnitude of the effect, and whether there are significant adverse effects from use. At this point, the whole process is turned into something called a Clinical Study Report [CSR], a long narrative document that tells the story from start to finish including the results. One thing to note, usually the relevant IPD tables are appended to the CSR, but that’s not always true. So it’s important when CSRs are being offered to find out if they have the unanalyzed data attached or not.

One might think with a set of such rigidly structured procedures like this, everything ought to come off like clockwork – and yet we all know that it hasn’t. In psychiatry in particular, but to a lesser extent in the rest of medicine, Clinical Trials have become a major vehicle for misinformation, published in our top peer reviewed journals. Subtle manipulations in data analysis, presentation, and interpretation appear regularly in journal articles; many negative studies go unpublished, sins of omission and commission abound. So there has been a mounting consensus that making the raw data from Clinical Trials routinely available instead of the [hidden] property of the sponsors of the studies will allow independent vetting of the results. I’d like to take a look at these various proposals for Data Transparency, but it’s hard to figure exactly what’s being suggested. It gets lost in the acronyms. Thus my mini-tutorial to at least get the terminology straight.

^{hat tip to Peter Doshi…}

Europe Does a U-Turn on Trial Data Policy, Says Ombudsman

WSJ: Pharmalot

by Ed Silverman

June 4, 2014

Late last month, the European Medicines Agency circulated a long-awaited draft policy on disclosure of clinical trial data by drug makers. Transparency has been a contentious topic following scandals over safety or effectiveness data that was not publicly shared. Initially, the EMA committed to ensuring data is accessible in ways that are easily analyzed and indicated data would not be considered confidential commercial information, which drug makers cite as a key reason for limiting access.

Now, though, the EMA is being accused of backtracking. The proposed policy, which will be voted on June 12, would not allow anyone to do more than view clinical study reports, which collect and summarize trial data, on computer screens. And some information, including details of trial designs and study results, can be redacted if a drug maker believes the information is commercially confidential.

The apparent switch comes shortly after the EMA settled a legal action with one drug maker, AbbVieABBV -0.02%, which attempted to prevent the EMA from releasing trial data about one of its medicines. In response, European Union Ombudsman Emily O’Reilly wrote the EMA to object to what she calls a “significant” policy change and plans to contact the European Commission for an opinion. We spoke with her about the implications. This is an excerpt.

Pharmalot: You wrote the EMA that you’re concerned about significant changes. What concerns you most?
O’Reilly: Let me start by saying that the European Union Ombudsman has actually been working on this issue for a number of years, regarding a number of drugs where there were concerns about transparency. And we were critical of [EMA] decisions. The result was that EMA eventually decided to completely revamp its transparency policy toward clinical trial data. They decided, in the future, they would have trials publicly accessible in a way they described in 2009 as ‘targeted understandable accessible information.’ They also noted that only in rare circumstances could data be described as commercially confidential information. All that was important. But that now seems to have changed.

Pharmalot: What happened, do you think, to cause this?
O’Reilly:  I’m not sure. But we asked if we could be part of the AbbVie case [that involved another drug maker, Intermune, which also sought to block the EMA from releasing trial data]. At the time, we were waiting for EMA to produce its final transparency policy. The court case had some relevance, of course, to the issue. But then a couple of months ago, it was announced that AbbVie had withdrawn the case and that it was settled. But as part of settlement, there was further redaction of the records.

Pharmalot: You mean the records pertaining to AbbVie and its drug?
O’Reilly: Yes. And we asked EMA to see the redacted records and they declined, at which point we used our powers to inspect the documents. We have a right to see any documents we need to see in the courts, anything that will help our investigation. We wanted to see if the redactions were appropriate.

Pharmalot: It would appear you’re suggesting the settlement with AbbVie had something to do with the policy changes.
O’Reilly: That’s what we’re trying to find out. I can’t speculate, but we’ve gone from a position of great openness and transparency that recognized, except in rare circumstances, trial data could not be considered commercial sensitivity. Now we have a larger number of barriers to researchers and general public. My role is to ask for an explanation. I do know that a couple of weeks ago, we were invited to a stakeholder meeting by EMA to see a draft of the new transparency plan. When the policy was sent, we saw it appeared to be quite a reversal to what they committed to doing a few years ago. They put lots of terms and conditions on what they said they would do. Rather than a proactive policy, the companies now have a great deal of say about how researchers and members of public have access. It’s a ‘look, but don’t touch’ policy. In our view, the draft represents a major step back. The interest of public health outweighs considerations of commercially sensitive information.

Pharmalot: Can you be more specific?
O’Reilly: You can read things on screen, but can’t use them. You are not allowed to download or save or edit the information. But you have to sign on to terms and conditions that would appear to put a lot of restrictions [on individuals who seek access]. They also have to disclose how they want to use the information and sign something that recognizes the information could be commercially sensitive. And so if they distributed the information in an unauthorized way, they could be liable to litigation. The draft policy also doesn’t say how the EMA will deal with trial information that is sought through freedom of information requests.

Pharmalot: In your view, what’s at stake?
O’Reilly: These clinical study reports don’t give the recipe for a drug – they just tell us what happened afterward. There’s nothing in the reports that could point to how a drug is made or manufactured, which are commercial secrets and certain of which could be useful to competitors. But these only show what happens when the drug is taken. A lot of researchers are concerned and alarmed. We’ve been inundated from various research bodies around the world. We need to be reassured, as individuals who decide which medicines to take or give to our families, that we have all the information we need to be assured the drugs are safe, and any information that points to a potential harm is publicly available. We also need to be assured there is independent verification of these trials. Part of that verification is from EMA and other agencies around the globe, but also by independent researchers who are looking at these trials and provide assurance that they are what the companies say they are and the drugs are what the tests have shown.

hat tip to jamzo…

So, I’m glad to hear that Emily O’Reilly [the European Ombudsman] validates how obstructive this change of plans really seems to her, because as someone who has actually worked in this environment, it feels huge. It’s also nice to hear that she’s "been inundated from various research bodies around the world." My name has been on some of those complaints, but It’s confirming that many that look at this new plan are equally outraged. I, too, think they are way overdoing the restrictions claiming safety and protection issues they’re really using those claims to make any real transparency next to impossible. What’s worse, the EMA is going along with it [or doing it for them]. And EMA Executive Director Guido Rasi’s upbeat letter is anything but reassuring to any of us [to be continued…].

Pharmalot: You mean the records pertaining to AbbVie and its drug?
O’Reilly: Yes. And we asked EMA to see the redacted records and they declined, at which point we used our powers to inspect the documents. We have a right to see any documents we need to see in the courts, anything that will help our investigation. We wanted to see if the redactions were appropriate.
Pharmalot: It would appear you’re suggesting the settlement with AbbVie had something to do with the policy changes.
O’Reilly: That’s what we’re trying to find out. I can’t speculate, but we’ve gone from a position of great openness and transparency that recognized, except in rare circumstances, trial data could not be considered commercial sensitivity. Now we have a larger number of barriers to researchers and general public.

Fool Me Twice? – Boehringer Ingelheim, Medtronic Settle Lawsuits Alleging Deceptive Marketing

Healthcare Renewal

by Roy Poses

June 3, 2014

… Per the New York Times, Boehringer Ingelheim executives continued to maintain:

 …that it stood behind the safety and efficacy of Pradaxa and continued to believe that the lawsuits lacked merit, but that settling the case allowed the company to move on. ‘Time and again, the benefits and safety of Pradaxa have been confirmed,’ said Desiree Ralls-Morrison, senior vice president and general counsel of Boehringer Ingelheim USA.

This is typical of most legal settlements involving large health care organizations, whether they end lawsuits brought by private parties or by the US government.  The settlements often allow the parties to continue to disagree, do not establish guilt or innocence, but leave one to wonder why executives would pay so much of admittedly other peoples’ money just to "move on" without upholding their or their companies’ honor, especially when documents revealed and legal findings made in cases prior to settlement remain unchallenged…

… Once again, the settlement did not resolve the allegations.

Medtronic said it did not admit that any of its activities were improper or illegal and that the settlement would bring to a close a long-running review of events dating from 2001 to 2009.

Also,

Asked to comment specifically on the strip club allegations and the accusation that it financially facilitated unnecessary implantations, Medtronic reiterated that its $9.9 million payment was not an admission that it had done anything illegal or improper.

See my comments above.  Why would executives with even the slightest ability to feel shame not contest such allegations if they were untrue?

Summary

These sorts of cases provide evidence that large health care corporations, including not just pharmaceutical companies, but biotechnology and medical device companies, commonly use deceptive and unethical practices to market their products.  Such marketing lets them charge high, even outrageous prices and sometimes results in patients getting expensive treatments that do them no good, or worse, that do more harm than good.  Some of the executives of these companies doubtless got large bonuses, and may have gotten millions in compensation partially because of the sales generated by these practices.  However, they get to walk away from such lawsuits without any personal accountability, just by paying out a few millions, or billions, of the company’s, that is, other peoples’ money.  They get do pay that money without any other explanation that it eliminates distractions and allows them to move on [with whatever they have already made]. The more this goes on, the more health care dysfunction continues, and the more the health care oligarchy prospers.  As we have written many times,

He talks frequently about something called "the anechoic effect." It just means that when something gets exposed, it doesn’t echo – the story gets lost, forgotten, and loses the power it really ought to have [often as a result of the interventions of the exposed]. I guess it’s the opposite of that saying journalists use about a story "having legs" for one that grows bigger by the hour… So Dr. Poses uses Health Care Renewal to keep us focused on stories that didn’t get enough echos to grow any legs…

How does settling a suit create the anechoic effect?
In a settlement, there is no real verdict. No matter what the settlement agreement says, the company always says that they admit to no wrong-doing as above. They never bring it up again themselves. If someone else brings it up, they reiterate the no wrong-doing line and say that they settled to move on [which is, ironically, the truth]. The net result is that they undermine the echo [the verdict].

So, why does the prosecution settle and let the companies walk?
Lots of reasons. A lot of these are whistle blower suits and the whistle blowers want their money [there’s no appeal to a settlement]. The same holds for the lawyers who take such cases on contingency. Whether it’s civil or criminal, settling avoids the lengthy appeal process and gets the case off the books. They all go out and celebrate, ignoring the fact that they’ve played into the hands of the companies.

What can we do about it?
Don’t ask us aging bloggers to tell you how to do your jobs. We’ve defined the problem for you. Put some young hot-shot government lawyers on the case and figure it out. Insanity is doing the same thing over and over again expecting different results. Make a new law! It takes two to settle – so Stop settling! Do something different!!

As a child, I frequently visited my grandparents in a small Georgia town. They lived in an old Victorian house that was filled with wonderful cousins and "show people" – friends from their earlier days as wandering Vaudevillians who passed through town. It was a magical place etched forever in my mind. One of my favorite things was visiting the old couple in the cottage next door. The husband had Diabetes in a time when that was difficult to manage, so he was rarely seen. But the wife, an elderly lady with multiple deformities from Rheumatoid Arthritis was always on the porch, glad to see me, giving out various treats and telling magical stories of her own. She called me her "pal." She had been a traveling Vaudevillian herself until she was stricken with a storm of arthritis that left her barely able to get to her front porch, much less sing and dance. So her stories were of her pre-RA adventures going from town to town and doing shows on the Mississippi River boats – the vacation cruise liners of the day. She loved telling those stories and I loved hearing them. In medical training, it never occurred to me that my choice of specialties, Immunology and Rheumatology, had anything to do with my childhood "pal," but there’s little question in my mind now that she was perhaps the deciding factor [in that place that runs in the background of things].

In case you’re wondering where I’m headed with these reflections, it’s my response to a lively and interesting discussion in the comments to my post fire in the belly…. But I’m not quite ready just yet to connect the dots…

Now I’m nearly ready…

I’ve finally arrived at my comment on those comments to fire in the belly…

In the comments, the discussion turned to the writing of Joanna Moncrieff [eg How do psychiatric drugs work?][see also not with a Hamilton Rating Scale…]. She contrasts a disease centered model [the medication treats the disease itself] and a drug centered model [the medication creates an altered state, and the therapeutic effects are secondary to the altered state]. In the comments, there was an argument about the utility of her point. I avoid taking sides when people I respect argue with each other and try to just listen to learn, seeing argument and debate as our greatest legacy from the scholars of old. But I thought I’d add in my own thoughts about Dr. Moncrieff’s point.

When I first read Dr. Moncrieff’s writings, I didn’t get it. I already thought what she said. I had never had a single moment in my life thinking antipsychotics were disease-specific. For that matter, I only thought antidepressants were disease-specific for a short time after a particularly eloquent lecture in my Internist years of yore [I got over it quickly]. And one would have to be blind not to notice that both groups of drugs could and did create altered states. I had a similar reaction on reading Robert Whitaker’s books when he talked about the dangers of medications and particularly their their continual use. I agreed with him, but I always had. I knew that many recommended keeping people on antipsychotics all the time to prevent relapses, but I also knew that patients often didn’t like taking them and stopped. I had seen enough obtunded states and Tardive Dyskinesia to know that I wanted no part of causing either. And I’m also old enough to have seen the patients like those rescued by Dr. Brooks, crippled by years of unmodifed psychotic illness – crippled in a different way from my childhood "pal," but crippled nevertheless.

And I’ve heard activists talk about psychiatrists drugging patients for my whole career – like it’s something we want to do or don’t understand the consequences of or enjoy. And I listened to Dr. Szasz’s point about the myth of mental illness – even read some of his books. And I’ve heard the recommendations and read the guidelines for "staying on meds" ad infinitum. And when I was a chief resident and later a training director, the residents and medical students quickly learned not to present a case to me with "stopped taking her meds" as an explanation for a relapse, knowing they were in for one of my diatribes that started with, "I wonder why she stopped taking her meds? Let’s go ask her," as I marched them en masse to the ward to see the patient.

I understand why people who work in some places, particularly mental health centers or academic jobs, gravitate towards the "stay on meds" end of the spectrum. Patients going off meds do frequently relapse. It’s not very good for them [and it’s exhausting]. And I understand why people who see the long term consequences of these medications come to oppose their existence. I decided that I had to make my own peace with all of those things and I had trouble getting there when I thought about "all patients." I am by training and preference an n=1 doctor and what usually happens when I try to think about "all" anythings is that I end up with a headache. I also see physicians as advisers and so the involuntary stuff isn’t my cup of tea. I’m actually pretty good at it, but I just don’t like it [which is probably why I was good at it]. So public mental health wasn’t going to be my choice, even though by temperment and history, I’m afflicted with a "do gooder" gene.

What I decided was that my job was to learn everything I could learn about these medicines and the illnesses they were used to treat, and then deal with one patient at a time – the ones that saw me as their doctor and I saw as my patients. That’s the way I learned to be a doctor and it was, in my opinion, the right way to do things. I followed a reasonable number of patients with psychotic illnesses over the years. I always aimed for them to be medication free, but only occasionally achieved that goal. We had to settle for either intermittently medication free, or medications minimal. I learned that if I was more liberal with antianxiety drugs than usual, I could minimize the antipsychotics more easily because the patients tended to use them for their anxiety. To be honest, the Rheumatologists who had taught me to carefully manage their even more toxic medications were more helpful than the psychiatrists or their guidelines in my own work.

I personally believe that these patients are really helped by long contact with professionals and others who know their illnesses, vulnerabilities, and pitfalls. I believe judicious use of neuroleptics is an important, and sometimes essential, part of the picture. And I agree that the best way to work is collaboratively as an adviser rather than as an authority figure. As for Dr. Moncrieff, I came to see why she says what she says by listening to the KOLs and reading their guidelines. They need to hear it. But I see that point everywhere in interventional Medicine. As an old man, I guess I see most "meds" as poisons or potential poisons. The skill is maximizing the useful effects, minimizing the noxious effects, and living with the constant terror of doing long term harm always sitting on your shoulder. I now think that’s what Joanna Moncrieff is saying and if I’m right, I agree with her. I wish she’d aim it a bit more towards the people who most need to hear it, and not at those of us who have always known it.

The Paradox of Parity

Director’s Blog – NIMH

By Thomas Insel

May 30, 2014

… The paradox of parity is that even with the new laws, in the absence of such a framework, some treatments might not be covered even to the extent that they were covered in the past. To address this concern, NIMH and other stakeholders have asked the Institute of Medicine [IOM] to develop a framework by which standards for psychotherapeutics can be established to help guide both payers and providers. The IOM has set up an expert panel to review the issues and recommend a way forward. At a meeting last week, the IOM panel heard how other providers like surgeons have established guidelines for rigor and quality that ensured parity for their interventions, many of which have less evidence than what we have for cognitive behavioral therapy.

In the world of parity, psychosocial treatments may need to be accompanied by measures of quality and fidelity [e.g., evidence of homework if the treatment is cognitive behavior therapy], measures of dose and duration [e.g., a predetermined length of intervention], and measures of outcome [e.g., improvements on a standardized rating scale]. And electronic records may become as essential to psychotherapy as the rest of medicine for ensuring that treatments meet established standards and are reimbursed.

Of course, many providers may look for reimbursement outside of the insurance or Medicaid systems. A recent report from Bishop et al found that only 43 percent of psychiatrists accepted Medicaid and only 55 percent accepted private non-capitated insurance. These figures are much lower than rates for other medical specialties [73 percent for Medicaid and 89 percent for private insurance]. And the rates for psychiatrists accepting private insurance are going down, decreasing 17 percent from 2005–2006 to 2009-2010 when these data were collected.

It would be a sad irony if in the era of parity only those who could afford to pay out of pocket could get access to effective psychosocial treatments. The IOM study can help by providing some guidelines, but true parity may require that the mental health community take steps to demonstrate that they provide the most evidence-based treatments with measures of both rigor and fidelity. We will need standardized reporting systems. And we will need a detailed definition for each evidence-based intervention, including not only dose and duration but indication…

I don’t even know where to start. And since I didn’t want to rant, I took a break and made coffee [it seemed to have helped]. They created a reimbursement system that essentially directed psychiatrists to do pharmacotherapy, and backed it up with an academy obsessed with Clinical Neuroscience, a disease-model Diagnostic System, psychopharmacology, and a not-so-subterranean alliance with the pharmaceutical industry. Insel mentions CBT [Cognitive Behavior Therapy] as his example of an evidence-based psychosocial intervention because it and its variants are essentially the only ones that have earned the EBM moniker. I was certainly influenced by the principles of CBT, incorporating them into my everyday approach to people, but I’ve never personally been or worked with a psychiatrist who does formal time-limited CBT with homework for very long beyond training – though it’s listed on most résumés. And if there were or will be such psychiatrists, they will need either lots of free time or an expensive support staff to manage the system described in the highlighted paragraph above [to handle the paperwork/electronic records involved]. Being independently wealthy would also be an adjunct.

I see nothing in this vision of mental health parity that will change the practice of psychiatry represented even by the insurance-accepting psychiatrists in those graphs, or do anything to halt their dwindling numbers. I see nothing in this vision of mental health parity that reflects anything but Dr. Insel’s disconnect with the specialty of psychiatry and its practice. He and his colleagues in academic psychiatry and the American Psychiatric Association created a vision of the future that lead us to where we are now based on an as-yet-undiscovered neuroscience with a reliance on some not-so-very-effective drugs based on a not-so-very-helpful diagnostic system and a not-so-very-enduring-or-healthy relationship with industry. Their hope for a breakthrough neuroscience pharmacologic future has now tanked, and they’re scrambling to find some new directions with things like collaborative care and whatever-you-call-the-thinking in this post. Were I to allow my suppressed rant unrestricted access, I would speak heatedly about the role the non-practicing psychiatrists like Dr. Insel and his cronies in academia and organized psychiatry had in creating this un-holy-hell-of-a-mess, and their unwillingness to accept responsibility for the impact of their short-sightedness-and-monocular-ideology on the fate of both psychiatrists and our patients.

The Latin phrase deus ex machina [from deus, meaning "a god", ex, meaning "from", and machina, meaning "a device, a scaffolding, an artifice"] was referred to by Horace in his Ars Poetica, where he instructs poets that they should never resort to a "god from the machine" to resolve their plots "unless a difficulty worthy a god’s unraveling should happen"… Aristotle criticized the device in his Poetics, where he argued that the resolution of a plot must arise internally, following from previous action of the play.

The ancient advice to poets to make the resolution of their tales follow from the plot as presented to the audience remains a critical principle in literature. We want Poirot to find the murderer[s] among passenger[s] on the Orient Express, not some new outside character. We don’t like our stories ended with divine intervention or the unexpected landing of aliens. If our settlers are saved by the arrival of the cavalry, we at least want to have known they were on the way. And, by the way, that’s our beef with Clinical Trials of medications. We’d like for the reports on their efficacy and side effects to flow logically from the results of the trial itself. And that hasn’t been the case in many of the Clinical Trial reports in recent years.

History: But we didn’t know it, at least I didn’t. The Clinical Trials in question weren’t complete lies. They were subtly manipulated by the initial design, by the choice of analytic methods, by omission of data, by non-publication of negative results – a compendium of techniques that mirrored Johnny Mercer’s old lyrics:

You’ve got to accentuate the positive
Eliminate the negative
And latch on to the affirmative
Don’t mess with Mister In-Between

Flash forward: As the corruption of the Clinical Trial literature became more widely known, opposition arose from a variety of foci. The Clinical Trials themselves weren’t the central Achilles heel in the system, it was in the handling of the raw data – the space between unblinding the study and the publication [or burying] of the results. That was the vulnerable spot, because the pharmaceutical companies had control of access to the raw data as intellectual property [the why of that and how it came to be is beyond me]. So the consensus was that the solution to the problem was to insist that the raw data from all Clinical Trials be made available for independent analysis. Thus began the many campaigns…

An Aside: As the corruption in Clinical Trials became more widely known, the pharmaceutical companies began to take a small beating in the courts, settling more and more suits, civil [blue] and criminal [red]. But the charges were things like false advertising or off-label promotion rather than directly for deceitful data analysis. And they went out of their way to avoid retracting the targeted articles or admitting their data manipulations. They went to extremes to deny such wrong-doings, in one case even when they had essentially admitted to it in a $3 B settlement agreement [the only enduring contract…].

Until Last Week: As the various campaigns for Data Transparency and grown, the call has reached into governments and regulatory agencies. The pharmaceutical industry has had to make concessions, fighting the whole time to maintain their hold on the ownership of Clinical Trial raw data. They’ve argued that the reasons are patient confidentiality, protecting trade secrets, spawning innovation, and they speak as if this is some kind of fundamental right – a copyright or a property. A major breakthrough came when the European Medicines Agency [equivalent to our FDA] announced that they were going to begin releasing the Clinical Trial data once a drug was approved, and actually began doing it. It was slowed down by the suits from AbbVie and Intermune, but they were overturned and withdrawn. The European Parliment supported Clinical Trial registration in April and things were again on track for the EMA transparency initiative to move forward.

Now: Then last week, the EMA released an altogether different and very restrictive policy claiming it was little changed [to be continued…]. But that’s simply not true. It was radically changed [the U-Turn…, the end game…, a decision to reconsider…, a crushing setback…]. Did the EMA make this compromise with AbbVie to get their suit dropped? Does it have something to do with AllTrials sidling up to GSK? Did PHARMA threaten the EMA with more suits? Was this in the cards all along? Conspiracy theories abound. None of us know the answers to any of those questions. But independent analysis of Clinical Trial data sure got a lot harder in this last week – perhaps too hard. But this time, we know some things for certain. The Deus Ex Machina in this story is the pharmaceutical industry. They’re going to fight to the finish to protect their right to distort the results of Clinical Trials. And however the U Turn went down, they did it behind closed doors. It’s being presented so far by the EMA as a fait accompli, and it may well be – something of an 11th hour coup.

There’s something terribly wrong with this story. There’s a large cadre of people – doctors, scientists, healthcare advocates, and patients who are only united by an outrage at the disreputable behavior of the pharmaceutical industry in regularly distorting the scientific information from the Clinical Trials of their drugs. We want to see the raw results and are willing to put in the time – mostly unfunded – to check their analyses for accuracy. Their misbehavior has been blatant enough and damaging enough to require that kind of vigilance. And yet the European Medicines Agency is rolling out a program that makes doing that extremely difficult, has caveats that allow these companies ways to continue to hide and distort data, and have a listing of potential penalties we might endure and oaths we have to swear that are sure to discourage any but the most hearty.

EMA’s Proposed Data Release Policy Promoting Transparency or Expanding Pharma Control over Data?

PLoS Blogs

By Trudo Lemmens

May 30, 2014

[full text on-line]

Things were looking good recently in Europe for data transparency, a necessary, albeit not sufficient, tool to promote integrity of pharmaceutical data. The European Court’s Vice-President overturned in November 2013 two lower court interim suspensions of EMA’s data access decision in relation to Abbvie’s drug Humira and Intermune’s Esbriet, which had stalled EMA’s data release approach. Shortly after, Abbvie withdrew the Humira lawsuit. Then in April 2014, the European Parliament approved the new Clinical Trials Regulation that introduced a requirement to register all clinical trials and make all clinical study reports in relation to EMA approved drugs publicly available. These developments put EMA again in the driver’s seat for the further implementation of its promised prospective data release policy.

Yet, when EMA recently distributed the draft policy to participants of its Clinical Trials Data Policy advisory groups, scientists and patient advocacy groups were dismayed, and the European Ombudsman sent a letter to inquire about EMA’s apparent shift: the proposed “Terms of Use” [TOU] and “Redaction Principles” impose various technical restrictions on data access, which would make it practically impossible to conduct decent research. If it were only technicalities, further discussions with the scientific community could fix the problems. But in the fracas around the technicalities, the legal booby-traps hidden in the [admittedly still draft] TOU received little attention. I therefore sent a letter to EMA’s executive director Guido Rasi outlining several legal concerns. Combining these with the technical restrictions suggests a problematic legal hijacking by industry of the transparency agenda.

What are the legal traps? First, by signing the TOU, data users would “acknowledge […] that the Information is protected by copyright and proprietary rights … and can be considered commercially valuable”. Brand name pharmaceutical companies increasingly insist that clinical trials data are protected by copyright and proprietary rights, and considered commercial confidential information. In the European Court cases, companies even made the spurious claim that companies have a fundamental human right to privacy over the data. But the idea that data are protected by copyright is highly doubtful, and it is little wonder that companies like to use the vague notion of ‘proprietary rights’ and refrain from using more concrete terms. Simply put, whether they have any such rights in data remains hotly contested, and is not firmly established in law. Many have convincingly argued the opposite, that these data are public goods, and that case law supports access to data on the basis of health related human rights. Remarkably, EMA is now asking scientists to recognize these rights while it is still involved in one case before the European General Court?the Intermune case? where a company is invoking such rights to block EMA’s decision to grant access to data. In light of this case and possible future court challenges, EMA has an interest in arguing for the most narrow interpretation of companies’ rights over data.

Second, the documents also strengthen industry’s attempt to qualify some data as commercial confidential information, which would offer industry the most far-reaching data protection. The TOU only mentions that data ‘can be considered commercially valuable’, which is indeed different than ‘confidential’. But the draft Redaction Principles, which set out how information will be made public, state that “novel statistical or other analytical methods and exploratory endpoint results about potential new uses of a medicine that are not the subject of the marketing authorization application” can qualify as “commercial confidential information.”  Here again EMA embraces a questionable legal position that favours industry. Statistical methods are part of the scientific commons. It’s hard to see how they can be ‘unique’ enough to qualify as commercially confidential information while still providing reliable evidence according to widely accepted scientific methods. The ‘endpoint results of potential new uses’ appears to include clinical trials data related to off-label prescribed drugs. Some of the most troubling controversies that underlie the widely supported calls for data transparency involve pharmaceutical companies’ misrepresentation of data related to off-label prescribed drugs. These practices have impacted on the health, life and wellbeing of thousands of patients. Even if these ‘endpoint results of potential new uses’ are obtained at an exploratory stage with new statistical methods, accessing these data is of public health importance.

The “Redaction Principles” further grant industry much leeway in deciding what will be made public: companies would submit two different clinical study reports to EMA: a full report that EMA will keep hidden; and a redacted one that will be publicly available. What kind of information was hidden, and why, will likely be very difficult to know.

Third, EMA is also asking researchers to contractually agree that they can be sued under UK law “in accordance with the provisions of the Contracts [Rights of Third Parties] Act 1999.” As a result, pharmaceutical companies will be able to challenge researchers directly in court for violation of EMA’s TOU. This puts companies in a comfortable legal position, particularly when this is connected with the recognition of proprietary rights, copyrights, the commercial confidential nature of some information and the severe technical restrictions on data use, which make good faith violations of the TOU much more likely. This could have a significant chilling effect. The mere risk or threats of litigation could seriously hamper open scientific debate. Researchers may think twice about publicly challenging a company’s interpretation and representation of data or about correcting the published literature on the basis of EMA held data, as called for by the recent RIAT proposal.

In short, EMA’s approach is strengthening industry’s legal control over data, making it more difficult and legally risky for independent scientists to use them. These are in essence regulatory data, created for public interest use. For the EMA, a key public institution, to now support the privatizing of pharmaceutical knowledge through contractual affirmations of companies’ rights over these data is truly astounding. Dr. Rasi’s recent response to the Ombudsman, that EMA’s new policy is a ‘reasonable compromise’, and does not prevent researchers from asking for access to specific data sets on the basis of the existing access to information policy, does not reassure. His response does not recognize the legal concerns raised by the draft TOU and Redaction Principles, let alone justify the approach taken. And Abbvie’s withdrawal of the legal challenge of the Humira data release notwithstanding, EMA appears back in the business of imposing more extensive limits on what it gives access to in response to specific access requests.

This troubling development is not entirely surprising. Even if the transparency movement had some major victories, including the adoption of transparency requirements in the recent European Clinical Trials Regulation, opposition has been mounting. Industry may now employ other regulatory initiatives to fight transparency. The European commission recently released a draft directive aimed at streamlining and strengthening Trade Secret protection in Europe. The European Federation of Pharmaceutical Industries and Associations [EFPIA] jumped already enthusiastically on the occasion, emphasizing the need to protect the “proprietary know-how” of drug development, including in the “clinical trials phase”. In the context of ongoing and largely secret transatlantic trade negotiations between Europe and the United States and Canada, the pharmaceutical industry has also been lobbying hard to strengthen data and IP protection and to include better data protection in the package. EMA now appears to be lending a helping hand.

• Ombudsman concerned about change of policy at Medicines Agency as regards clinical trial data transparency
• EMA’s data sharing policy – towards peeping tom based medicine?
• Is the EMA poised to make a major U-turn on its transparency initiative?
• Just look, don’t touch
• European drug agency backtracks on plan to give researchers access to clinical trial reports
• Letter from Jefferson and Doshi to the European Ombudsman regarding access to EMA held data

The patients, as a group, were very slow, concentrated poorly, seemed confused and frequently had some impairment or distortion of recent or remote memory. They were touchy, suspicious, temperamental, unpredictable, and over-dependent on others to make minor day-to-day decisions for them. They had many peculiarities of appearance, speech, behavior, and a very constricted sense of time, space, and other people so that their social judgment was inadequate. Very often they seemed to be goal-less or, if they had goals, they were quite unrealistic They seemed to lack initiative or concern about anything beyond their immediate surroundings. Because of their very low socio-economic level and prolonged illness, they suffered from profound poverty, inadequate educational opportunities, and a very limited experience in the world.

In the early 1950s, one of us began to study the efficacy of the then-new drug chlorpromazine. The back-ward "hopeless cases" were chosen as subjects. Some patients responded well and were eventually released. Other patients did not respond as well, but the effect of the releases was to give fresh hope to both the staff and the patients. In 1955 a multidisciplinary clinical team, sponsored by the Vermont State Hospital and the Vocational Rehabilitation Division of the Vermont State Department of Education, initiated a program of comprehensive rehabilitation and community placement for those backward patients who had not improved sufficiently with chlorpromazine.

From January 1955 to December 1960, 269 patients who were considered among the most severely disabled and chronically mentally ill in the hospital were referred to the program. After the re-education of the staff, a program was constructed in collaboration with the patients that consisted of drug treatment, open-ward care in homelike conditions, group therapy, graded privileges, activity therapy, industrial therapy, vocational counseling, and self-help groups.

In the community treatment component, the same clinical team went into the community and established halfway houses and outpatient clinics, found job openings, made job placements, and linked patients to natural support networks. In that era of custodial care, before the advent of community mental health centers and the later deinstitutionalization movement, this comprehensive program was considered unusual and innovative.

 

I find it fascinating to know that the innovative rehab program introduced by George Brooks at Vermont State Hospital in the 1950′s, which was the basis of Courtenay Harding’s ground breaking long term study in the 80′s [2/3′s living full lives in the community, 50% on no medications, another 25% using them intermittently], was predicated on a non-hierarchical approach. Brooks brought in the patients and asked them what THEY needed in order to be able to be well enough to leave the hospital.

Obviously, the patients who were unable to live in the general community even with the wonder drug of the day, chronically psychotic, institutionalized, and without resources are a different population from the First Psychotic Episode cases addressed by the RAISE ETP program and targeted by its Individual Resiliency Training [IRT]. In reacting to the approach of RAISE, Dr. Steingard mentions the Open Dialog program in Finland as a program that includes the patient and family in the treatment process from the very beginning – a program that directly addresses the first episode patients. As I’ve read about Open Dialog, I’ve also been impressed and expect I’ll be reviewing it here shortly as well, but first I want to say something else that is one of the reasons I took the time to go back and review the Vermont story from the early days.

Dr. Brooks was an innovator who rallied his staff and patients around an approach that achieved something impressive. He put his most refractory cases on the new treatment [Thorazine] that helped 40% leave the back ward of the hospital. Buoyed by that success, he re-educated his staff and developed a program that was value added to the medication and helped many of the remaining non-responders move on to a much better life. It was a remarkable and enduring achievement. In fact, the Rhetoric associated with his program was exactly what I was taught as a psychiatric resident in 1974 when I started my training – the Rhetoric of the Community Mental Health Movement. I later even taught those very principles myself when I was on the faculty. But the Reality I saw was something very different. I saw chronic mental patients living under bridges and moving through what we called "revolving door" hospitalizations. Over the years, I saw "transinstutionalization" – the jails and prisons filling up with mental patients rather that the heroic successes of the Vermont experiment. I saw my friends in Public Mental Health "burning out" more quickly as centers and hospitals evaporated. And I saw anything that worked drowning under the weight of decreasing funds and an increasing case load. The Rhetoric/Reality gap has been consistent for the forty years I’ve been around.

When I look back at the Vermont studies, I question why some version of their program hasn’t been widely implemented for the last fifty years. The only part that really consistently stayed with us was the Thorazine [or some equivalent]. That’s what I saw in the 1970s and that’s what I see now. I would attribute that to several things. First, the Vermont program was initiated by Dr. Brooks and a staff that had fire in their bellies – they were on a mission. That’s a major factor in their success. And it was more or less time limited [outrunning burnout]. Second, Vermont is a homogeneous place – mostly rural or village/town based. Such a program is made for that kind of world. The Open Dialog program is in a similar location in Finland. Those communities tolerate chronically mentally ill people in a different way than urban environments. I live in such a place now, and can see that in my daily life away from the metropolis of Atlanta.

So when I look at the RAISE program and the push to implement it on a large scale, I think several things. I see nothing in the psychopharmacology manual that says what I want it to say – use antipsychotic medications only when you need to and the idea of using medications for life has long outlived any rational justification. The notion of using a computerized decision support system to medicate patients is unjustified by any science I know and antithetical to the principles of clinical medicine. The Individual Resiliency Training [IRT] Manual is paternalistic and not based on any understanding of the patients it’s designed to treat or the paths to the outcome being aimed for. Put it on the Internet along with the materials for any number of other approaches and let the individual programs figure out how they can best serve the clients they’re trying to help. Include what Dr. Brooks said, what’s happening with Open Dialog in Finland, etc. Develop another module to train the staff called "on being psychotic" developed by recovered patients and people who have spent their lives working among these patients – something designed to give new staff an acquaintance with the experience and difficulties involved in living with what has happened to their clients. And think about an ongoing staff project/meeting where people present their cases or things they’ve read about helping them. But most of all, do any and everything possible to help the staff develop the kind of "fire in the belly" that makes such programs actually work. Finally, adapt the program to the social and cultural environment where it’s being implemented. There will never be a one size fits all program.

One of the nicest things about being retired is that I can think about what I want to think about. And it’s obvious that my response to the Individual Resiliency Training [IRT] component of the RAISE project has hit one of those things that I’ve wanted to muse about for a long time. I realize I’m off on a personal tangent of my own here, but a blog is thinking out loud, and it’s what I’m thinking about right now.

So in a further comment…, I was chasing down the experiment of George Brooks in the 1950s in getting chronic mental patients out of Vermont’s State Mental Institution and into the community, and the follow-up studies that went on for decades. Just a note of historical interest. The way the Vermont study got started was with a study of Thorazine® [Chlorpromazine], the first antipsychotic. They had given the new drug to everyone in their "back ward," and 178 responded enough to be discharged from the hospital. The "back ward" in those days meant something akin to "hopeless," so this response seemed even bigger than a minor miracle then. Thorazine® was the blockbuster of the day, and this was before the FDA was tasked to approve either efficacy or indication, attested by the ads of the day – one step this side of the patent medicines:

But that study left behind 269 patients who weren’t helped enough by the Thorazine® to be released. So Dr. Brooks took another approach [again, this was also a time before the Community Mental Health Movement].

The Vermont longitudinal study of persons with severe mental illness, I: Methodology, study sample, and overall status 32 years later.

by Harding CM, Brooks GW, Ashikaga T, Strauss JS, Breier A.

American Journal of Psychiatry. 1987 144[6]:718-26.

[full text online]

The authors report the latest findings from a 32-year longitudinal study of 269 back-ward patients from Vermont State Hospital. This intact cohort participated in a comprehensive rehabilitation program and was released to the community in a planned deinstitutionalization effort during the mid-1950s. At their 10-year follow-up mark, 70% of these patients remained out of the hospital but many were socially isolated and many were recidivists. Twenty to 25 years after their index release, 262 of these subjects were blindly assessed with structured and reliable protocols. One-half to two-thirds of them had achieved considerable improvement or recovery, which corroborates recent findings from Europe and elsewhere.

The Vermont longitudinal study of persons with severe mental illness, II: Long-term outcome of subjects who retrospectively met DSM-III criteria for schizophrenia.

by Harding CM, Brooks GW, Ashikaga T, Strauss JS, Breier A..

American Journal of Psychiatry. 1987 144[6]:727-735.

[full text online]

The authors present the findings from a long-term follow-up study of 118 patients from Vermont State Hospital who, when rediagnosed retrospectively, met DSM-III criteria for schizophrenia at their index hospitalization in the mid-1950s. The patients were studied with structured, reliable, multivariate instrument batteries by raters who were blind to information in their records. The rediagnostic process is described, and results of the follow-up are presented. Outcome varied widely, but one-half to two-thirds of the sample had achieved considerable improvement or recovered, in contrast to statements in DSM-III that predict a poor outcome for schizophrenic patients.

The Maine and Vermont three-decade studies of serious mental illness. I. Matched comparison of cross-sectional outcome.

by DeSisto MJ, Harding CM, McCormick RV, Ashikaga T, Brooks GW..

British Journal of Psychiatry. 1995 167[3]:331-338.

[full text online]

BACKGROUND: This study compared long-term outcome of serious mental illness in two states using a matched design to assess psychiatric rehabilitation programmes; Vermont subjects participated in a model psychiatric rehabilitation programme, while the Maine group received more traditional care.

METHOD: Maine and Vermont subjects [n = 269] were matched by age, sex, diagnosis, and chronicity. Demographic, illness, and life history information were abstracted from hospital records by clinicians blind to outcome. DSM-III criteria were applied retrospectively. Outcome was assessed by clinicians blind to history.

RESULTS: Vermont subjects alive at follow-up [n = 180] were more productive [P < 0.0009], had fewer symptoms [P < 0.002], better community adjustment [P < 0.001] and global functioning [P < 0.001] than Maine subjects [n = 119].

CONCLUSIONS: Outcome differences may be due to Vermont’s model programme and a policy of allowing an earlier opportunity for community life.

The Maine and Vermont three-decade studies of serious mental illness. II. Longitudinal course comparisons.

by DeSisto M, Harding CM, McCormick RV, Ashikaga T, Brooks GW..

British Journal of Psychiatry. 1995 167[3]:338-42.

[full text online]

BACKGROUND: This paper supplements the cross-sectional outcome comparisons of the companion paper by providing a brief account of the longitudinal courses of the Maine and Vermont samples across several outcome domains.

METHOD: A Life Chart method was used to document changes in individual lives over the domains of residence, work, income source, and use of community resources over a 20-year period. Reliability studies between states were conducted.

RESULTS: Throughout much of the period, more Vermont subjects lived independently, were working, and were less likely to use community resources compared to Maine subjects.

CONCLUSIONS: Differences in both policies and programmes contributed to course differences between the groups. System characteristics that may lead to better outcomes are discussed.

Dr. Brooks initial use of Thorazine® [shortly after it became available] allowed him to release 40% of his back ward patients from the hospital. But he was dealing with a number of problems – the conditions that had brought the patients to the hospital in the first place; the condition they had developed by having been there for a long time that came to be called institutionalization; and the impossibility of separating these things with any precision.

I think my remarks in another IRT prequel… apply here as well. I was saying that we use Resiliency as a noun, as if it represents an entity. I claimed that it’s really more an adverb, a tautology. We’ve elevated observations of behaviors to the level of an existent. We could say the exact same thing about Schizophrenia and Institutionalization. Both are based on observations of what certain people do [or don’t do], but are talked about as things. It’s the point made repeatedly by Thomas Szasz and his followers – The Myth of Mental Illness. The other side of the coin is in our very words – Dis-ease, Ill-ness, Sick-ness – words that define the domain of medicine in terms of how people feel, not something they have. One can only think about that conundrum for so long. I think 40 years must be the limit because that’s how long it has been for me, and I repeatedly glaze over now with ‘Is Schizophrenia one disease? or many diseases? or even a disease at all?‘. Fortunately for the inhabitants of the Vermont Mental Institution up there in that picture and to his credit, Dr. Brooks didn’t get lost in such musings, which was Dr. Steingard’s original point in mentioning these papers: "Brooks brought in the patients and asked them what THEY needed in order to be able to be well enough to leave the hospital."