to get us started…

Posted on Tuesday 30 September 2014

Background: "European Union lawmakers reached agreement in December over a new Clinical Trials Regulation, which replaces a 2001 directive. Under the agreement, pharmaceutical companies and academic researchers will be obliged to upload the results of all their European clinical trials to a publicly accessible database. A publicly accessible EU database will be set up and run by the European Medicines Agency (EMA) which will contain a register of all trials carried out in the EU, a summary of results for all trials, uploaded one year after the end of the trial at the latest. Enhancing the competitiveness of clinical research was a primary aim of the directive’s revision amid claims that Europe would become an unattractive place to conduct large-scale trials on potentially lucrative new medicines. The regulation also speeds up how researchers get ethical approval for medical trials and seeks to improve standards in how new medicines are tested and manufactured."
eurActiv
Date: 30/09/2014

Medical researchers in Europe are facing new challenges over access to clinical trials data, according to the European Ombudsman Emily O’Reilly. The Ombudsman warning came just month after the EU adopted a new clinical trials regulation, which obliges pharmaceutical companies to share scientific data on new medications submitted for approval to the European Medicines Agency (EMA). O’Reilly said scientific data on clinical trials should be made more transparent, for the benefit of patients, doctors and researchers who need "maximum information about the medicines they take, prescribe and analyse".

The EU Ombudsman, who took office a year ago, held a debate in the European Parliament on Monday (29 September) on the matter with representatives of the pharmaceutical sector, MEPs, health campaigners and the European Medicines Agency (EMA). In May, she sent an open letter to the EMA’s executive director Guido Rasi, expressing concern about a significant change to the agency’s draft transparency policy on clinical trials. The EMA is responsible for evaluation of the safety of medicines before they enter the market, and for monitoring the drugs that are already on the market. The EMA has proposed that future access to clinical trials results should be available "on screen only" for researchers. This version would exclude the possibility of researchers being able to print, distribute, or transfer the information, making scientific analysis of clinical study data "highly problematic" according to critics.

EMA will hold a management board meeting on Thursday (2 October) to adopt its new pro-active transparency policy.

« Read: EU Ombudsman worried over lack of transparency at medicines agency»

Speaking at the Parliament event, the EU Ombudsman stated that she has over the past five months opened three transparency investigations concerning the agency and public access to data.  "I will continue to examine closely whether the EMA continues to be committed to transparency and I’m looking forward to hear the evaluation by Rasi on the challenges he is facing in the area," O’Reilly said. Rasi answered that while the EMA believes that clinical trials data should be transparent, there were some cases where commercial confidentiality applies. US pharma company Abbvie took the EMA to court in 2013 over its disclosure policy but later withdrew the complaint after reaching a settlement with the London-based EU agency, leading to changes in the agency’s transparency policy. Consumer groups and transparency activists branded the change as a U-turn on the agency’s earlier commitments.

« Read: Growing concerns over medicines agency’s proposed rules for transparency »

"Therefore our new policy will spell out clearly what will be the principles to gain access. The decisions, however, will always be taken by the EMA. Next Thursday, our management board will approve this new version of the policy. That should give us, from the start of 2015, the possibility to start to actively make data available. By 2016, we should have the first clinical trials data available," Rasi said.

« Read: Health experts critical of industry’s new transparency rules »

Ben Goldacre, a British physician and author of the best-selling book Bad Pharma, said no one can make informed choices on treatments as long as results of clinical trials are being withheld from doctors, researchers and patients. "This is not about being anti-industry. Academics are just as bad about withholding bad results. The key difference is that it’s only the industry which is actively lobbying against change," Goldacre said, adding that he wants all trials, including retrospectively, registered, that summary results are made available and that the clinical study report is made available to highlight changes in methods.

« Read: Pharma industry tries to mobilise patient groups in clinical trials battle »

Richard Bergström, director general of EFPIA, which represents the pharmaceutical industry in Europe, said the industry has faced up to the calls from society on being more transparent. "We have agreed with our global partners on a global set of principles. Our companies will give data and study reports to researchers. We have committed to do this since the beginning of this year. It’s already up and working," Bergström said. "We are not there yet. These are the early days, but we are really moving," he continued. Margrethe Auken, a Danish MEP from the Greens, who was shadow rapporteur of the clinical trials regulation, said that clinical trials should benefit patients first and foremost. A clinical trial belongs first of all to the patient and to humanity and not the industry, she continued. Auken added that apart from more transparency in clinical trials, she also wishes to see more transparency regarding declarations of interests among policymakers.

I haven’t been able to write about much recently with the EMA decision just a couple of days up ahead. Nothing else seems to rise to the level of importance of this decision. It may be overblown in my mind, but the way I see it, it’s much bigger that simply a decision about commerce – it’s a decision about the fundamental medical ethic:
    ethos \ë-thäs\
    noun
          : the guiding beliefs of a person, group, or organization

We know that our literature and our academic institutions have become a palette for a variety of industries to paint their own skewed versions over the works of our old masters. But just knowing that there are counterfeiters about isn’t enough. We are at a point where we need the means to validate that worth of what we’re told – and Data Transparency is, by consensus, what we need to get us started. There are plenty of other things to give us pause, like payola – basically turning doctors into paid vendors [What We’re Learning About Drug Company Payments to Doctors]:
But without valid information, even physicians who resist becoming paid agents of the pharmaceutical industry will have nothing to go on except a contaminated literature. If the European Medicines Agency fails to uphold the initial promise to promptly release the raw data from drug studies submitted to them, it will be a testimonial to the power of industry and the weakness of the governments that are supposed to regulate them [along with the complicity of the medical establishment]. So what else could there possibly be to write about this week?
Mickey @ 12:29 PM
Filed under: OPINION
private coziness…

Posted on Thursday 25 September 2014

Pharmalot: WSJ
By Ed Silverman
September 24, 2014

In a boost to Pfizer, the FDA has updated labeling on its Chantix smoking-cessation pill to indicate the drug may not carry the risks of suicidal behavior, a controversial issue that prompted the agency to include a serious warning in the labeling in 2009. The changes are being made to reflect the results of various studies. One study involved a so-called meta-analysis of five studies involving nearly 2,000 patients that Pfizer says did not show an increase in suicide thoughts or actions among people who took Chantix compared with a placebo.

The drug maker also pointed to four observational studies of between 10,000 and 30,000 people that did not find differences in risk between Chantix and other nicotine treatments, although these had several limitations [most of the label changes appear on page 3]. The labeling change is welcome news for Pfizer, which hoped Chantix would become a blockbuster but has instead encountered a marketing challenge. Shortly after Chantix was approved in 2006, the drug was increasingly linked in news reports of acts of violence or suicide. The FDA issued successive alerts, the Federal Aviation Administration banned usage by pilots and air traffic controllers, and the Departments of Defense and Transportation restricted use in sensitive occupations. Meanwhile, Chantix sales slid to $648 million last year from $846 million in 2008. And Pfizer settled hundreds of lawsuits last year by people who claim Chantix caused them harm.

The labeling change, by the way, was made on September 19, but Pfizer had not publicly discussed the changes until today, when a watchdog group called the Institute for Safe Medicine Practices planned to release an analysis placing Chantix in an unflattering light and calling for the Black Box warning to be strengthened. The timing of the disclosure of the labeling change suggests that Pfizer sought to mitigate any negative publicity that may have ensued…

Pfizer would like the serious warning, which is known as a Black Box in regulatory parlance, removed, the Associated Press writes. A Pfizer spokesman writes us that the labeling change and upcoming meeting “both serve as a step forward in the process of accurately communicating the clinical and observational data” in relation to serious side effects referenced in the warnings section of the labeling.

Even though the Black Box remains unchanged, Pfizer may benefit to some degree, anyway. How so? The updated labeling now includes new information about the studies in the Warnings & Precaution section. As a practical matter, the Black Box is still front and center, but new language may soften the blow, at least if enough physicians interpret the new information as Pfizer would like. We asked the FDA if the Black Box may be removed and will update you with any reply.
    [UPDATE: Thomas Moore, a senior scientist at ISMP, contends the labeling may not help Pfizer very much. "The new studies added to the label provide little new insight into the psychiatric side effects of Chantix. The meta-analysis of suicidal behaviors included only a few of the many clinical studies, was much too small to detect these rare but catastrophic events, and was not published or peer reviewed.  The observational studies had even more limitations. Neither the observational studies nor the meta analysis included the full range of psychiatric side effects reported."]

    Meanwhile, ISMP reviewed side effect reports filed with FDA and found that Chantix accounted for more cases of suicide, self-injury or homicidal thoughts than any other therapeutic drug between 2007 and the third quarter of 2013. Moreover, Chantix ranked first in both suicidal and self-injurious thoughts as well as homicidal thoughts, and these reports outnumbered those for any other drug by more than three times. Moore says there is still more evidence that Chantix causes psychiatric side effects. And so the watchdog group plans to ask the FDA to further strengthen the Black Box warning and widen the restrictions on Chantix use to still other occupations. He declined to name those occupations…

    There were limitations on some Pfizer findings, as well. The observational studies were conducted after widespread publicity about Chantix and suicidal or hostile behavior, which means patients with a history of psychiatric illness may have been prescribed an alternative treatment. And only reports that resulted in hospitalizations were included, suggesting other incidents were not noted. 

    [UPDATE: ISMP's Moore writes us that "the study of psychiatric hospitalizations omitted 85% of the known psychiatric side effects and depended on diagnostic codes that had not been studied or validated."]

    [EDITOR'S NOTE: An earlier version of this story indicated all the observational studies were conducted by Pfizer].
I declare ongoing resentments against Pfizer on any number of grounds: the way Zoloft® was approved by the FDA was insider trading [see [zoloft: the approval III…]; their shameful clinical trial of Zoloft® in adolescents [Wagner et al][see tuning the quartet…]; financing Robert Gibbons’ recurrent attacks on the various Black Box Warnings [see very monotonous…]; promoting Gabapentin [Neurontin®] as a pain medication [E-mails suggest Pfizer tried to suppress study on drug]; but mostly for their ads that put the phrase "chemical imbalance" into the public register.

Pfizer has run into black box warnings with all three drugs [Zoloft®, Neurontin®, and Chantix®] and spent a mint trying to counter them [very monotonous…way past time…]. They seem to feel picked on to have 3/3 drugs under warning. Another more reasonable interpretation is that they aren’t very good at looking at their data or are given to sleight of hand in reporting. All of the studies are industry funded and are based on population studies. But the part that has me writing is that they seem to have a habit of operating privately with the FDA. They sure did that getting approval for Zoloft® in the first place [zoloft: the approval III…]. Now, here they go again with Chantix®:
The labeling change, by the way, was made on September 19, but Pfizer had not publicly discussed the changes until today, when a watchdog group called the Institute for Safe Medicine Practices planned to release an analysis placing Chantix in an unflattering light and calling for the Black Box warning to be strengthened. The timing of the disclosure of the labeling change suggests that Pfizer sought to mitigate any negative publicity that may have ensued…
Private coziness with the FDA just isn’t going to do, even if they do bring in $50 B/year. And for what it’s worth, my anecdotal experience with Chantix® has been negative – no successes and complaints about agitation in most cases. I decided to stop prescribing it fairly early. 
Mickey @ 1:10 PM
Filed under: OPINION
a lot riding on…

Posted on Wednesday 24 September 2014

The meeting when the EMA will deliver their formal policy for Data Transparency is just a week away. Earlier, I’ve mentioned my apprehension about what they might say [the other shoe] and given an outline of the kind of data that might be involved [it matters…]. Several of years ago, I was pointed to some of the original trials of Imipramine from before they were required by the FDA [remembrance of things past…, remembrance of things past redux]. Their outcome variable was much closer to the one familiar to all clinicians – they interviewed the patients. They had a placebo control group and the study was double-blinded as in modern trials. They saw the subjects weekly and classified their responses based on the clinical interview:

The results of treatment were assessed as symptom free, greatly improved, somewhat improved, no change, or worse. For the purpose of assessing the value of the drug as a significant therapeutic agent, the first two of these categories have been combined as a good or worth-while result and the other three as a poor result. Patients showing a good result were able to return to their normal activities without undue effort…
Note that they didn’t even settle for "somewhat improved." They did do a statistical analysis, but they didn’t need to. All you had to do was look at the results to see the effect of the drug. The formal output was the size of the effect expressed as the NNT [Number Needed to Treat], and those are robust responses [2.08, 2.56].

They concluded:

A controlled trial was carried out to evaluate the effects of imipramine on endogenous and reactive depression. In endogenous depression 74% of cases showed a good response to the drug, while 22% responded to the placebo [P<0.01]. In reactive depression 59% responded satisfactorily on imipramine, as compared with 20% on the placebo [P<0.02]. On comparing these results with those of a previous trial of iproniazid the impression was obtained that imipramine was the more effective agent in treating endogenous depression.
It’s a different world now – 50 years later. The trials are conducted by technicians trained specifically to do drug trials. They follow formal protocols and administer formal tests – rating scales that are used for diagnosis and to catalog responses. They ask about adverse experience and transcribe what they’re told. The patients are recruited from clinics and through advertisements rather than just being people who are seeking treatment. The results are tabulated and analyzed on computers by statisticians. The trials are primarily financed by the drug’s manufacturer and analyzed by their own scientists. Many of the published articles have been written by medical writers hired by the trial sponsor. The involvement of the actual clinician authors whose names are on the published papers varies from none to some, but they’re rarely authors of the sort who did that early Imipramine study. Like I said, "It’s a different world now."

It would be the naive person, indeed, that was unaware of the increasingly blurred boundary between commerce and medical practice. Yesterday at a charity clinic in a very rural community, over 10% of the patients I saw asked if Cymbalta® was right for them. Being asked that repeatedly is bad enough. But what’s worse – I  don’t  can’t even know the answer. It feels like a pincer move – living between a contaminated literature and a successful Direct-To-Consumer ad campaign. Throw in ineffective and complicit professional organizations, an academic community that is often asleep, the restrictions from third party payers, and the accusations of activists, and sometimes you just want to throw up your hands and surrender. And sadly, many physicians [and patients] have done just that.

It would be equally naive to think that having the kind of Data Transparency originally promised by the European Medicines Agency will fix all of those things. The dyke has too many holes in it for that. But it would be one fine place to start. The threat of having their work checked would have a major impact on the invasion of the medical literature by commercial interests. And while it wouldn’t necessarily tell me if Cymbalta® is right for you, it would make it at least possible for me to approximate the answer if I or others were actually able to study the studies [and we did it]. So from my perspective, there’s a lot riding on next week’s report on the EMA’s definitive policy…
Mickey @ 2:00 PM
Filed under: OPINION
monotonous and trivial…

Posted on Monday 22 September 2014

Medscape Psychiatry
by Robert L. Findling, MD
July 31, 2014

"Hello. I’m Dr. Robert Findling, Director of the Division of Child and Adolescent Psychiatry at Johns Hopkins University and a vice president at the Kennedy Krieger Institute in Baltimore. The US Food and Drug Administration [FDA] issued a warning in 2004 that treatment with antidepressants could lead to an increased risk for suicidality in young people. Today I will talk about a new study that examined the impact of this FDA warning. This article was published in BMJ, and the first author is Christine Lu."

"Suicide in teens is not only tragic but is a leading cause of death in youngsters. A major risk factor for suicide is depression, so safe and effective treatments for depression are needed. Among high school students, 8% say that they have attempted suicide, and 30% of those youngsters have made a suicide attempt that required medical attention. Suicidality in teenagers is all too common. Moreover, it is associated with a reasonably high rate of morbidity and a real risk for mortality. For that reason, it’s important to consider events that could alter the rates of suicidality. The impact of the FDA warnings has already been examined. This paper asks more and different questions…"

 

"What did the study find? First, there was a 31% reduction in the rate of antidepressant prescriptions. Second, there was an increase of 21% in the rate of psychotropic drug poisonings in adolescents. Finally, the study did not find an increased rate of completed suicides. An accompanying editorial commented that the net effect was that the FDA warning led to more harm. The data from this study suggest that adverse events not only can occur from medicines but also as a result of warnings. This leads to the unanswered question: How do we communicate treatment-related outcomes and treatment-related concerns effectively and openly to ensure improved patient outcomes without unwanted consequences? I’m Dr. Robert Findling. Thank you for watching."
At times, I fantacize that there’s some Fu Manchu, Keyser Söze, Professor Moriarty, Karl Rove, some evil puppet-master in the background that orchestrates articles like this one, diabolically undermining the wisdom of the FDA’s Black Box warning about akathisia and suicidality as a potential adverse experience from the antidepressants, particularly in adolescence. For the decade since the warning was issued, articles debunking it come at regular intervals from many directions – the most recent being the one by Lu mentioned here.

They’re all similar, the studies purporting  to either refute the warning or to say that it has caused harm. They seem to all rely on some large population study with a proprietary database showing that suicidality hasn’t fallen or has actually risen in the aftermath of the warning. They all document that the prescription of antidepressants to adolescents has fallen since it was issued [or at least not continued to rise]. The authors are an odd lot: adult psychiatrists, statisticians, bio-mathematicians, a conservative think-tank, etc. They imply that the Black Box warning resulted in withholding needed treatment from depressed kids. Like the Medscape presentation above, they leave out the fact that any literature that suggests that these drugs are effective in adolescents show minimal effects [if any] and are notorious examples of the experimercials of the era [eg Paxil Study 329]. They have resulted in multiple settlements against pharmaceutical companies for damages and false advertising.

So is there some evil genius in the background pulling the strings trying to dampen the impact of the warning? or maybe have it removed? Some of it has been PHARMA driven, at least early on, but it’s still coming even after all the antidepressant patents have expired. Dr. Findling may or may not be PHARMA friendly, but there’s no point any more. PHARMA may have started this mess, but they’re long gone now. So my hypothetical evil manipulator isn’t likely in that camp anymore. How about some other source – maybe among the ranks of Managed Care? They certainly stand to gain if people give antidepressants to kids rather than something else that costs the insurers more money [particularly now that the generic antidepressants are widely available and cost very little]. They’re a good candidate and the studies often use their databases. Actually, that’s who the author of the study discussed by Dr. Findling above [Dr. Lu] works for studying cost containment.

But there’s another factor, one suggested by a lot of activists and critics of psychiatry – that psychiatrists just like to give out pills.  Yet another possibility – maybe they really think that antidepressants help depressed kids. I personally think there’s a simpler explanation that doesn’t postulate an arch-fiend in the background or even demonize or dumbify child psychiatrists. They don’t know anything else to do. Seeing the kid frequently and getting to the bottom of the problem isn’t in vogue, nor is it reimbursed. There’s no hospital for the really sick, at risk kids. In the modern world that focuses on diagnostic groups [as in the unitary domain - Adolescents with MDD], evidence-based medicine has no place for the kind of single-case model that asks "What’s wrong in the world of this unique adolescent who is floundering at a time in life when floundering is more rule than exception?" Most of the kids survive, but the consequences can and do play out in problems that persist for a lifetime in the enduring identity formed in the teen years. Dramatic? That’s intentional.

I expect that many prescribers have benevolent and therapeutic intent, but ignore the relative ineffectiveness of the drugs and the rare adverse side effects that can be fatal because they don’t know anything else to do; because they can feel that something needs doing that they either don’t know how to do or isn’t "allowed"; and they hide from those uncomfortable twinges behind the kind of rationalizing and uncritical thought we hear in this monotonous and trivial Medscape presentation that parrots a widely discredited article [read from a teleprompter]…
Mickey @ 11:17 AM
Filed under: OPINION
a buddy system…

Posted on Sunday 21 September 2014

"So what we wanted to do is to find a diagnostic test that can be done in any clinical laboratory whereby a patient can go to the doctor and the doctor can send blood to the clinical laboratory that can help the physician to decide if the patient is clinically depressed or not. It will help them to live better lives, but it also would help to eliminate the stigma, because if there is an objective measure, a blood test, that can tell whether you are depressed or not, that it’s not likely that anyone can tell you ‘Oh, just get over it.’ In addition to eliminating the stigma, and of course to help the physician make a correct diagnosis, we are also helping society altogether, as depression is going to be the number one burden in the world by 2030."

When I looked at Blood transcriptomic biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy on Friday [see don’t ask, don’t tell…], I read the write up in TIME Magazine, and linked the one in the  Chicago Tribune, but I hadn’t gone to the site. It was a videotaped interview with Eva Redei, PhD, the senior author. I transcribed it [above] thinking I wanted to write about it. It’s the kind of exaggerating I just hate. But once I heard it, I went back and looked at the article itself. In don’t ask, don’t tell… , I had been sarcastic: my blog title, their small sample size, the pay for publication online journal, I made fun of needing a test to know if you’re depressed [or better]. Maybe I looked back at it because I felt guilty about being so sort of nasty. I know I planned to pan that interview, which I thought was a sham, particularly the  plague-of-depression ending. So I read it through again, looked at the tables, and instead of softening, I went from sarcastic to bombastic.

Your don’t need to hear another rant, so I thought I’d just stick to the sleight of hand that set me off. These two tables below are from the article with a few additions of my own – the red highlighting, and the columns and headers in shades of salmon: The upper table has the BASELINE data for control and MDD subjects and the lower one is both groups at 18 weeks:

 

I couldn’t figure out why there were two control groups, and why they were different. They were just an age/sex/race matched group used to assay the distribution of the various RNAs they looked at. So I did some Student T-Tests like they prescribed but got very different results. Then I reread the methods. They did paired T-Tests! What that means is that every MDD case had a unique age/sex/race matched control subject:
    Paired t-tests are a form of blocking, and have greater power than unpaired tests when the paired units are similar with respect to "noise factors" that are independent of membership in the two groups being compared…

    A paired samples t-test based on a "matched-pairs sample" results from an unpaired sample that is subsequently used to form a paired sample, by using additional variables that were measured along with the variable of interest. The matching is carried out by identifying pairs of values consisting of one observation from each of the two samples, where the pair is similar in terms of other measured variables. This approach is sometimes used in observational studies to reduce or eliminate the effects of confounding factors.

That greatly increased their power to find a significant difference, but it plays havoc with Dr. Redei’s comment above, "…the doctor can send blood to the clinical laboratory that can help the physician to decide if the patient is clinically depressed or not." This is more like it:
    If you go to the doctor for this test, be sure that you take an age/sex/race matched friend who’s not depressed to act as your matched control – it’s sort of a "buddy system"
which is, of course, ridiculous [actually, even that wouldn't be enough]. They had also calculated Cohen’s D [see about my connectomes]. So I redid those Effect Sizes too and they were also very different! I couldn’t figure out why from the methods, but I suspected it was some matched pair method similar to the T-Tests. Who knows? I couldn’t check their figures as the individual values weren’t included. Just more smoke and mirrors . this time it’s not from PHARMA – but likely some plan to market this test.

If someone actually really found a blood test that accurately correlated with depression, including being able to discriminate active depression from the trait of being a depressive, the American Journal of Psychiatry, the British Journal of Psychiatry, and JAMA Psychiatry would be fighting over the chance to publish it. It wouldn’t be tucked away in a pay-for-play online journal. It would already be in the PsychiatricNews and the author would be being bombarded with speaking engagement requests. That’s certainly not what we have here…

…but if you read those media reports and watch the video, this is the very giant leap forward she’s talking about…
Mickey @ 9:06 PM
Filed under: OPINION
the other shoe

Posted on Saturday 20 September 2014

Reuters
By Ben Hirschler
July 15, 2012

Europe’s medicines regulator, criticised in the past for excessive secrecy, is opening its data vaults to systematic scrutiny in a move that will let independent researchers trawl through millions of pages of clinical trial information.The change is a landmark in transparency that puts Europe ahead of the United States, according to critics of the $1 trillion-a-year global drugs industry, who have long argued for full access to trial data. Such information is a treasure trove for scientists wanting to test drug company claims and potentially expose product deficiencies. As part of a process of opening up, the European Medicines Agency (EMA) plans to hold a conference in November to consider ways of making large data sets available rapidly and routinely to outside investigators…
It was some of the best news ever, this announcement that the EMA was going to make Clinical Trial Data available. And they did it, at least until the suits from AbbVie and InterMune got it stopped with a court order. But that seemed to be resolving, and we all waited for the EMA’s formal policy due out this summer. The buzz among the growing Data Transparency movement was hopeful, and joined by several encouraging governmental moves in the UK and the EU supporting Data Transparency. Positive change was in the air. There was little doubt about it.

But then in May the EMA released a draft of their proposed policy, and a pale fell over the land. It wasn’t the promised open data access. Besides a restrictive application process and the specter of redactions, it required using a screen-only interface. By then, our RIAT group had been using such a system or months and I can attest to the difficulties, likening it to going to sea to see the world in a submarine using a periscope. Peter Doshi and Tom Jefferson [the Tamiflu group at Cochrane] coined the term "U-Turn" to describe this change of heart and there was a universal outcry. Looking back,  I could write about little else [posts catalogued below in case you care to review what happened]. At the time, the general suspicion was that the EMA had made concessions in settling with AbbVie and InterMune. The European Ombudsman got involved and initiated an investigation:

the U-Turn… 19 May 2014
the end game… 23 May 2014
to be continued… 24 May 2014
a decision to reconsider… 25 May 2014
a crushing setback… 31 May 2014
something terribly wrong… 01 June 2014
oh how we’ve missed our Pharmalot!… 04 June 2014
except where necessary to protect the public… 11 June 2014
tomorrow… 11 June 2014
awaiting further information… 12 June 2014
some further information… 12 June 2014
in the shadows… 13 June 2014
out of the shadows… 14 June 2014
just in… 30 June 2014

In response to the general alarm, the EMA reconsidered and pledged to drop the restrictions. But when the day came to announce their final policy, they postponed things until October, saying:

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…

… so there was little to do but wait:

fine summary… 05 July 2014
a long hot summer… 09 July 2014

For the last several months, the climate has been less filled with optimism – more an uneasy waiting with the vague concern that "the other shoe was about to drop." This week, there was a development that didn’t inspire any confidence. The new administration of the European Union is moving the EMA with the responsibility for drug and device approval from the Health Ministry to the Ministry of Enterprise and Industry [I should say, back to the Ministry of Enterprise and Industry where it had been before]. I don’t understand the workings of the EU well enough to know the ins and outs of exactly what that means, but it certainly feels like that "other shoe" dropping to me. I don’t have any idea if that has an ominous portend for the Data Transparency policy due in just two weeks, but it sure raises the question. And it makes one worry that the earlier postponement was about more than "wording and practical arrangements":

abuzz over there… 17 September 2014
a coup d’état… 17 September 2014

Niccolò di Bernardo dei Machiavelli [1469 – 1527]I’m aware that I tell this story as if it is a Masterpiece Mystery or a Machiavellian court drama, but I come by that quaisi-paranoia honestly. The pharmaceutical industry may have moved on from the psychiatric drug arena, but they’ve left a legacy of disreputable wheelings and dealings that is inescapable. PHARMA doesn’t want Data Transparency, and I would expect them to use every bit of their considerable power and financial resource to undermine it wherever possible. Without the cloak of secrecy surrounding Clinical Trial results, none of the CNS blockbusters of the last few decades would’ve ever left the gate. And that’s likely true as well industry-wide with other drugs.

So I suggest that the fine print in whatever policy the EMA ends up with deserves our closest scrutiny, and that we keep our ears cocked listening for that "other shoe"…
Mickey @ 8:30 AM
Filed under: OPINION
weep no more for Witty…

Posted on Friday 19 September 2014

Pharmalot: WSJ
by Ed Silverman
September 19, 2014

After months of anticipation, a Chinese court found the GlaxoSmithKline subsidiary in China guilty of bribing doctors, hospital officials and other non-government personnel, and fined the drug maker more than $490 million, The Wall Street Journal reports. This becomes the largest such penalty levied on a company in China. At the same time, Mark Reilly, the former head of the Glaxo unit in China, pleaded guilty to bribery-related charges and was given a three-year suspended sentence. There are varying reports, however, whether he will be deported or required to remain during that time. Four other senior Glaxo managers in China also received suspended sentences of between two and four years…

The court decisions cap a tumultuous episode for Glaxo, which was already struggling to restore its image and revamp business practices in the wake of a $3 billion settlement with U.S. authorities two years ago. The drug maker had been accused of failing to disclose clinical trial data for certain medicines and improperly marketing drugs, among other things.

Andrew Witty, the Glaxo chief executive, issued a brief statement: “Reaching a conclusion in the investigation of our Chinese business is important, but this has been a deeply disappointing matter for GSK. We have and will continue to learn from this. GSK has been in China for close to a hundred years and we remain fully committed to the country and its people.” [here is the official apology, too]

Glaxo previously acknowledged investigating claims employees bribed doctors in Poland, Iraq, Syria, Jordan and Lebanon. Meanwhile, the FBI and the U.S. Securities and Exchange Commission are probing its activities in China. As part of a probe into the pharmaceutical industry, U.S. authorities have been eyeing its overseas dealings since 2010 for possible violations of the Foreign Corrupt Practices Act. And the U.K.’s Serious Fraud Office is also conducting an investigation…

Lest you are feeling sorry for Sir Andrew Witty and GlaxoSmithKline, you might want to check out this bio from Forbes with his 2012 Financials:

Sir Andrew Witty, 31 January 2008 and as Chief Executive Officer on 21 May 2008. Sir Andrew joined GSK in 1985. He has worked in the UK, South Africa, the USA and Singapore in various senior roles. In 2003, he was appointed President of GSK Europe and joined GSK’s Corporate Executive Team. In 2003 he was awarded the Public Service Medal by the Government of Singapore and in August 2012 was also awarded the Public Service Star. In the 2012 New Year Honours list, he was awarded a Knighthood for services to the economy and to the UK pharmaceutical industry. He served as the Lead Non-Executive Board member for the Department of Business, Innovation and Skills to December 2013. He was also President of the European Federation of Pharmaceutical Industries and Associations until July 2013.

Salary $1,033,000
Bonus $905,000
All other compensation $49,000
Non-equity incentive plan compensation $1,905,000
Total Compensation $3,892,000

And if you’re a stickler for dates, you might notice that his Presidency of the EFPIA [European Federation of Pharmaceutical Industries and Associations] ended in July 2013 which happens to be right after the damning leaked memo [a closing argument…, in the shadows…] outlining their plan to undermine the EMA [European Medicines Agency] Data Transparency efforts [which may have succeeded] [see abuzz over there…, a coup d’état…].

Ed goes on to tally up Sir Andrew’s assets column:
It is worth noting that Witty has now spent half of his six-year tenure trying to overhaul business practices, and has still more fines and investigations to show for his efforts. Granted, cultural differences require varying approaches to success around the world, and Glaxo is not the only drug maker facing this challenge. But Glaxo is now something of a poster child for scandal.

Witty has made headway in other areas. In particular, he has won kudos for his push to make clinical trial data more readily accessible to researchers, a move that has helped Glaxo deflect much of the criticism leveled at the pharmaceutical industry otherwise. In trying to resolve this highly contentious issue, he placed himself and Glaxo in a leadership position. And Witty is cutting ties between compensation for sales reps and the number of prescriptions that doctors write for Glaxo drugs

Whether he emerges unscathed by the latest developments in China – and unfolding events elsewhere – remains to be seen, of course. But Witty may need to have Glaxo executives practice some of the self-criticism that Chinese Communist Party leaders preach as a path toward rehabilitation.
I am in a less forgiving mood. It’s impossible for me to imagine that he wasn’t involved in that EFPIA plan to undermine Data Transparency, even if publicly, "he has won kudos for his push to make clinical trial data more readily accessible to researchers, a move that has helped Glaxo deflect much of the criticism leveled at the pharmaceutical industry otherwise." Enough already with his double dealing!
Mickey @ 5:05 PM
Filed under: OPINION
don’t ask, don’t tell…

Posted on Friday 19 September 2014

It looks as if the Windy City of Chicago is taking the lead in figuring out if people are depressed without even asking them. Dr. Robert Gibbons of the University of Chicago is planning an an iPhone App that lets the cloud figure it out [insider trading…], and now Dr. Eva Redei of Northwestern’s Feinberg School of Medicine adds a blood test to the mix, launched in the pages of Time Magazine, no less, …
TIME Magazine
Health Mental Health/Psychology
by Alice Park
Sept. 16, 2014

As with any disease, detecting depression early is critical for reducing suffering and for finding an effective course of treatment. Now, in a study released Tuesday, scientists led by Eva Redei at Northwestern Medicine say it may be possible to test for depression in the blood—and figure out which patients will benefit most from behavior-based therapy as a treatment.
First blood test to diagnose depression in adults
Date: September 17, 2014
Source: Northwestern University
Summary: The first blood test to diagnose major depression in adults has been developed, providing the first objective, scientific diagnosis for depression. The test also predicts who will benefit from cognitive behavioral therapy, offering the opportunity for more effective, individualized therapy. The test also showed the biological effects of the therapy, the first measurable, blood-based evidence of the therapy’s success and showed who is vulnerable to recurring episodes of depression…
But that’s not all. If you’ve been treated with Cognitive Behavior Therapy, either face-to-face or on the telephone, and you don’t know if it helped, their blood test will answer the question for you [or at least it panned out in the 64 subjects where they tried it]:
by E E Redei, B M Andrus, M J Kwasny, J Seok, X Cai, J Ho and D C Mohr
Translational Psychiatry. 2014 4:e442.
Published online 16 September 2014

An objective, laboratory-based diagnostic tool could increase the diagnostic accuracy of major depressive disorders [MDDs], identify factors that characterize patients and promote individualized therapy. The goal of this study was to assess a blood-based biomarker panel, which showed promise in adolescents with MDD, in adult primary care patients with MDD and age-, gender- and race-matched nondepressed [ND] controls. Patients with MDD received cognitive behavioral therapy [CBT] and clinical assessment using self-reported depression with the Patient Health Questionnaire–9 [PHQ-9]. The measures, including blood RNA collection, were obtained before and after 18 weeks of CBT. Blood transcript levels of nine markers of ADCY3, DGKA, FAM46A, IGSF4A/CADM1, KIAA1539, MARCKS, PSME1, RAPH1 and TLR7, differed significantly between participants with MDD [N=32] and ND controls [N=32] at baseline [q< 0.05]. Abundance of the DGKA, KIAA1539 and RAPH1 transcripts remained significantly different between subjects with MDD and ND controls even after post-CBT remission [defined as PHQ-9 <5]. The ROC area under the curve for these transcripts demonstrated high discriminative ability between MDD and ND participants, regardless of their current clinical status. Before CBT, significant co-expression network of specific transcripts existed in MDD subjects who subsequently remitted in response to CBT, but not in those who remained depressed. Thus, blood levels of different transcript panels may identify the depressed from the nondepressed among primary care patients, during a depressive episode or in remission, or follow and predict response to CBT in depressed individuals.
You can read the full paper in Translational Psychiatry, a peer reviewed, on-line only journal where the authors paid the price of admission:
Translational Psychiatry levies the following Article-Processing Charges [APC] [plus local taxes where applicable] per article accepted for publication. As the Creative Commons Attribution 3.0 Unported License grants greater end user rights including commercial reuse, papers published under this license will be charged at a premium APC. For more information on this license please see the press release.
FEE SCHEDULE
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Mickey @ 2:23 PM
Filed under: OPINION
still…

Posted on Friday 19 September 2014

 

Mickey @ 12:22 AM
Filed under: politics
a coup d’état…

Posted on Wednesday 17 September 2014

One of the great lessons of psychotherapy is the importance of formulating good questions along the way, even though the answers are often not available for a while. If the question is already on the table, when the answer happens to come along, you don’t miss it. It’s like finding that last piece of a vacation picture puzzle that fell on the patterned rug. One of those questions just sort of floating around in the background for me has been why the European Medicines Agency has been so sensible about Data Transparency. Nobody else has. They decided to release the data on approved drugs in 2010, and did just that until they were stopped by the courts [the AbbVie/InterMune suits]. Were they just good guys? I knew nothing of that story until this morning when I happened onto the bruhaha discussed in the last post [abuzz over there…]. Another question, what was the story behind Tamiflu? How did that epic get to be the the definitive battlefield for the issue of Data Transparency? I was a late comer to this party, and didn’t know any of that history.

Reading along this morning, I found that the efficacy of the drugs being stockpiled for a potential epidemic was an older question than I knew. Back then, the European Medicines Agency was under the Directorate-General for Enterprise and Industry! No wonder the approval of medications was weighted towards Industry! So when the last new administration took over in the European Union in 2009 [on a five year cycle], moving the EMA to the Health Commissioner was a reform move of some note:
    Health technology and pharmaceutical policy was transferred to the Health Commissioner in 2009 to, among other reasons, facilitate emergency preparedness [in response to the emergence of H1N1 and the alleged inability of DG Enterprise to provide the necessary leadership and coordination of vaccines] and to harmonise pharmaceutical governance along the lines of Europe’s Member States, all of whom manage pharmaceutical policy under their Ministries of Health.
    EPHA press release, September 14, 2014

Looking back five years:
    José Manuel Barroso, President of the European Commission, has announced the portfolio responsibilities for the next Commission. The new Health and Consumer Policy portfolio will now include responsibility for pharmaceutical products and medical devices. These changes will be reflected at the level of the directorate generals, with the Pharmaceutical Products and Cosmetics and Medical Devices Units F.2 and F.3, and consequently the European Medicines Agency, moved from DG Enterprise and Industry [ENTR] to DG Health and Consumers [SANCO].

    "We are certain that this governance change puts public interests and the health of Europeans at the centre of vital decisions affecting our health. With the responsibility for pharmaceutical and medical devices policies and for the European Medicines Agency too, the Health and Consumer Policy Commissioner is now better equiped to lead a consistent and coherent approach to public health policy and more specifically to ensure protection of patients and safety of medicines throughout the European Union.", said Monika Kosinska, Secretary General of the European Public Health Alliance. Moreover, "This bold decision by President Barroso demonstrated the power of political leadership and enables the European Commission to fulfill its Treaty responsibility as the guardian of public health.", she added.

    EPHA press release, November 27, 2009

And the EMA Data Transparency policy followed that change and was a response to the whole question of the stockpiled flu medications. Was it really effective? was on the front burner. They were good guys after all, but it was in response to something – suspected interference in the process of drug approval by industry and an industry friendly governmental agency. Here, Fiona Godlee, BMJ editor picks up the story:
    In 2010, the EMA announced a proactive policy on transparency and public access to the data on which the Agency bases recommendations that directly affect the health of European citizens. This policy was in line with an inexorable international trend towards greater transparency and with what MEPs and the European Council wanted to achieve as part of the new regulations governing clinical trials.

Their good-guy-ness was an end to a story, not the beginning. And the recent waffling on Data Transparency [fine summary…, a long hot summer…] came as something of a shock to people who knew the story:
    To the astonishment of observers and of activists who had been deeply involved in this positive development, the EMA made a spectacular retreat in recent months, coinciding with the arrival of the new head of its legal service [whose background was in the pharmaceutical industry]. The EMA explained its change of heart by saying that it had to take into account the Commission’s position in ongoing negotiations on transatlantic trade.

But now it has a more ominous look and feel. It appears to be a part of another story that we didn’t know was coming – putting the European Medicines Agency back in the hands of the industrial arm of the EU. That’s the kind of background story that has probably been being worked on since 2009 by whatever forces the EFPIA and the pharmaceutical industry could muster [which I expect were impressive]. Campaign contributions? Who knows? Godlee continues:
    An incomprehensible step backwards. Your decision to transfer responsibility for drugs policy and the EMA back to the Directorate-General for Enterprise and Industry is a great disappointment, which none of the groups concerned about public health in Europe can understand. What are the reasons for this step backwards? What will it mean for the future direction of the EMA and for European patients?
    Fiona Godlee’s letter, September 16, 2014

Googling this issue as the sun came up this morning came up empty. But tonight, there’s plenty to read. It all essentially says "WTF?!" and it all seems to reach the same conclusion I’ve reached – that this is a behind the scenes reclaiming of dominion over the drug approval process by the pharmaceutical industry, long in the making – a coup d’état
Mickey @ 11:00 PM
Filed under: OPINION