EMA wrangles restrain trial data progress

ChemistryWorld

by Andy Extance

3 July 2014

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

The chief concern was a ban on saving, downloading or printing clinical study reports [CSRs], making these huge documents available only on-screen. The Institute for Quality and Efficiency in Health Care [IQWiG], Germany’s national commission for assessing medical procedures, was especially outraged. It took to Twitter with a long series of photos underlining how hard this would make its job. The same groups also warned that the new ‘terms of use’ contract could let trial sponsors sue researchers, creating a legal chill that would deter scrutiny.

The EMA’s new redaction policy on what information could be hidden drew fire too. It arose because of comments in the initial consultation that patient privacy, trust in the system, and commercial confidentiality could be put at risk. Richard Bergstrom, director general of the European Federation of Pharmaceutical Industries and Associations [EFPIA], expressed worry over ‘putting transparency – at whatever cost – ahead of public health interests’.

The proposed EMA policy allows drugmakers to propose redactions for text they feel is commercially or otherwise sensitive, although the regulator will retain the final say on what is hidden. Campaigners say this measure and vague policy wording will mean too much is concealed. EMA spokesman Martin Harvey-Allchurch stresses that ‘third parties’ can petition or sue if they think that’s happening, and that the extent of redaction will always be visible.

Working too closely?

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

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

Following the pressure over its proposals on 12 June, the EMA’s management board agreed an amended policy. That allows downloading, saving and printing trial data for academic and non-commercial research purposes, although the other controversial areas remain unchanged. Nevertheless Harvey-Allchurch plays down the outcry surrounding the new policy. ‘The whole purpose of these targeted consultation exercises was to listen,’ he says. ‘We heard the feedback, we listened to it, and proposed an alternative to the board.’ But with Harvey-Allchurch underlining that this policy initiative is a bridge to the new EU regulations that will come in some time after May 2016, the final policy wording will be highly significant.

Industry delivers

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

IQWiG spokesperson Susanne Breuer highlights that a fragmented landscape of company data repositories would be less desirable than the single repository the EMA hosts. ‘The control of data completeness would be much more complicated, and analysing data it would take a lot longer,’ she says. ‘We would appreciate centralised access for scientists.’ Parts of the industry are making progress here, with Eli Lilly and Bayer Healthcare agreeing to make trial data available via Clinicalstudydatarequest.com. They bring the number of companies using the portal, created by GlaxoSmithKline last year, to eight.

Insel Looks to Transformation of Diagnostics, Therapeutics

"From Psychiatry to Clinical Neuroscience"

PsychiatricNews

by Mark Moran

June 17, 2014

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

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

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

Finally, he described the NIMH Research Domain Criteria (RDoC) project, which he said will work in tandem with DSM. “DSM/ICD will continue to be the basis of clinical care,” he said. “RDoC is a framework for research in which NIMH will support researchers to deconstruct current diagnostic categories or identify dimensions that extend across categories. RDoC will develop through an information commons that integrates data from many sources, transforming the way we diagnose mental disorders in the future.”

National Institute of Mental Health Clinical Trials

New Opportunities, New Expectations

by Thomas R. Insel,MD and Nitin Gogtay,MD

JAMA Psychiatry. 2014 71[7]:745-746.

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

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

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

These changes are the result of the changing ecosystem of treatment development, the advent of new tools to look at mechanisms of change, and the advice of experts both within and outside of our field. They are also a response to many patient advocates who remind us that “time matters.” The current timetable for a clinical trial, which spans nearly a decade from proposal to publication, is not acceptable to families with a child with autism or an adolescent with psychosis. However, in addition to fixing the delay, these families need to know that we are doing everything possible to deliver treatments that are better than what is available today. New treatments will require a deeper understanding of the disorders and a new approach based on experimental therapeutics for pharmacological, psychosocial, and neuromodulatory interventions.

I first became aware that PHARMA was giving up on CNS drug development three years ago when Dr. Stahl let loose with a rant of cosmic proportions [myopia – uncorrected…]. Within a month, the DSM-5 Task Force admitted their planned "biological" DSM-5 wasn’t going to fly, the RDoC from the NIMH was brought to the fore, and Dr. Insel began to talk about brain wiring [class action in the air…] initiating any number of schemes to jump·start CNS drug discovery – all the while whining endlessly about the inadequacy of our current drugs. The timetable for his Clinical Neuroscience seems to have been abandoned around then, though the term is never far from his lips.

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

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

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

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

The Black Box Warning added to antidepressant labeling in 2004 by the FDA created something of a cottage industry attempting to either discredit it or  reverse it. Those efforts are well documented throughout this and many other blogs. And there have been multiple attempts to say that the net effect has been an increase in suicidality resulting from the fall in prescribing attributed to untreated depression in children and adolescents. This claim has been based on data from large databases from several sources.

This most recent article in the British Medical Journal [Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study] relies primarily on the Mental Health Research Network [3], data from multiple large health plans [not for profit HMOs]. But there are other datasets involved in the analysis: PHARMetrics Patient Centric Database [1], BC Ministry of Health, and the Nationwide Inpatient Sample [2] – the latter two chosen because they include complete ICD-9 E-Codes [codes for external injury]. PHARMetrics is a commercial enterprise used for marketing intelligence [I’ve extracted the descriptions of these datasets from the referenced papers at the end of this post with links to their abstracts and full texts when available. I also added some charts from the reported ages.].

While I’m still grumbling about the Lu et al papers [3], my main agenda in this post is something else – the use of these large databases in research papers. The story begins with a problem – the commercial databases don’t have usable E-Codes, the ICD-9CM codes that directly address suicide attempts. In their Letter to the Editor [3], Lu et al prove that the database they are using doesn’t have these E-Codes with any consistency across sites. So they bring up Patrick et al [2] who did a study trying to deal with the missing E-Codes by locating other parameters that could be used as a proxy for suicide attempts. They tried a number of combinations and came up with an algorithm involving psychiatric diagnosis and injury to the lower arm or asphyxiation or overdose with psychotropic medications using two government databases that had required E-Codes as their gold standard.

"Patrick et al. developed and tested algorithms for identifying hospitalizations for deliberate self-harm in a population aged 10 years and over. This study used the US National Inpatient Sample data and data from British Columbia; both data sources had E-code completeness rates above 85 %. The gold standard for deliberate self-harm was defined as hospitalizations with a diagnosis of E950-958. Patrick et al. found that an algorithm combining diagnoses for psychiatric disorders [including depression] and injury/poisoning can produce a positive predictive value as high as 87.8% for identifying hospitalizations for deliberate self-harm [with specificity of 99.4% and sensitivity of 57.3%]. In the context of our longitudinal study on the impact of Food and Drug Administration warnings on antidepressant use and subsequent suicidality in youth, using Patrick’s algorithm may introduce ascertainment bias because rates of depression diagnosis declined subsequent substantially after the warnings."

Because previous studies showed that rates of depression diagnosis changed after the warnings and that outpatient claims are often incomplete for mental health conditions such as depression, to avoid introducing selection bias, we did not limit our cohorts to those with a coded diagnosis of depression.

Non-fatal poisoning by psychotropic drugs [predominantly tranquilizers] has a positive predictive value of 79.7% for suicide attempts [sensitivity was 38.3% and specificity was 99.3%], outperforming other types of injuries or poisonings.

Even though the intervals vary, just looking at the age ranges [at the end of this post], it’s apparent that these are different datasets. Further, they were created for different reasons, from different sources, and their ontogeny can’t be vetted, at least by me. All those things heighten the need to reproduce the findings of others in their own database, something not very hard to do [and obvious]. I would suggest that this study is uninterpretable, and shouldn’t have been published in a mainstream journal as is, but rather sent back suggesting resubmission when they’d done their necessary homework. My broader point is that population studies are hard enough to interpret when done thoroughly. Making the assumption that the results from any given dataset can be applied to any other dataset freely is untenable [also obvious]. A simple rule for such studies:

all databases are not created equal…

Investigators Face Trial Amid GSK Sex Tape Revelations

Pharmagossip

by Jack Friday

July 2, 2014

South China Morning Post’s Toh Han Shih reports that British/Chinese-American corporate investigator couple Peter Humphrey and Yu Yingzheng, who were arrested last summer during a bribery investigation into their clients GlaxoSmithKline, will stand trial in Shanghai on July 29th.

Chinese prosecutors originally wanted to charge Humphrey and Yu with several offences, including some relating to illegal business operations. But they decided to drop all of them except for one of illegally buying information, a source close to the family said. Although each faced only one charge, they risked being jailed if found guilty, the source added. Prosecutors had made Humphrey and Yu’s lawyers sign a non-disclosure agreement preventing them from revealing certain information to the couple, the source said. [Source]

News of the trial follows reports about a covert sex tape of GSK’s top China executive, which the pair had been hired to investigate. From Laurie Burkitt at The Wall Street Journal:

The British drug maker regarded the video — apparently shot without the executive’s knowledge — as a breach of security, the person said. The executive in the video, Mark Reilly, directed the company to hire a Shanghai-based private investigation firm run by a British national and his Chinese-born wife to investigate the breach, the person said. …Until this weekend’s disclosure about the video, it wasn’t clear whether ChinaWhys had been working for Glaxo when its owners were seized by authorities. The details of the video were reported by Britain’s Sunday Times newspaper. …Chinese law enforcement in May accused Mr. Reilly of ordering subordinates to commit bribery that generated billions of yuan in revenue for Glaxo’s China operations. Authorities alleged that Mr. Reilly, a Briton, ordered his sales team and other employees to bribe hospital doctors, health-care organizations and other parties on “a large scale” to boost drug sales in China. [Source]

China Charges British Former GSK Boss With Bribery

Digital China Times

by Josh Rudolph

May 14, 2014

Ten months after opening a corruption investigation into the mainland practices of British pharmaceutical giant GlaxoSmithKline (GSK) for “serious economic crimes,” British national and former head of GSK’s Chinese operations William Mark Reilly has been handed multiple bribery charges. Xinhua reports:

After ten months of investigation, police found that William Mark Reilly, a British national and executive of GSK China, had ordered his subordinates to commit bribery, said the police of Changsha, capital of central China’s Hunan Province, in a statement. Reilly allegedly pressed his sales teams to bribe hospitals, doctors and health institutions through various means and gained an illegal revenue worth of billions. He and two other executives, Zhang Guowei and Zhao Hongyan, were also suspected of bribing officials with the industry and commerce departments of Beijing and Shanghai. [Source]

GSK has not yet been charged, but is carrying out internal investigations for corruption allegations in other countries, including Iraq, Jordan and Lebanon. In 2012, GSK plead guilty to criminal charges in the U.S. and paid a $3 billion fraud settlement.

The South China Morning Post has background on the Chinese GSK probe and the case against Reilly:

The Ministry of Public Security alleged that Reilly, GSK vice-president Zhang Guowei and GSK legal affairs supervisor Zhao Hongyan formed an emergency group in 2012 to bribe law enforcement and other officials in Beijing, Shanghai and elsewhere to block a government investigation of GSK. “Reilly and other senior GSK executives proactively covered up the bribery activities and strongly maintained the financing channels through which the bribes were funnelled,” the ministry alleged. Since 2010, GSK’s Chinese subsidiary GlaxoSmithKline (China) Investment (GSKCI) had spent tens of millions of yuan bribing hospitals to use GSK’s liver drugs instead of Chinese-produced drugs, the Ministry of Public Security claimed. GSKCI spent 13 million yuan buying gifts like cars, television sets and video cameras, which were given as bribes to clients in health-care organisations, it said. […] The prosecution of foreign nationals by the Chinese authorities is likely to prompt or accelerate similar investigations by the regulators of other countries, said Keith Williamson, head of forensic and dispute services for Asia at Alvarez & Marsal, an international professional services firm. [Source]

This becomes the highest-profile corruption scandal involving a foreign company in China since 2009, when four executives of British-Australian mining company Rio Tinto were arrested for bribery and espionage. The four—one of whom was an Australian citizen—were sentenced to between 7 and 14 years in prison. Under China’s Criminal Law, “serious” cases of bribery can carry a maximum sentence of life imprisonment, and a minimum 5-year prison sentence. Coverage from Reuters notes surprise at the bribery charge among the foreign business community, and GSK’s place in China’s lucrative and rapidly growing pharmaceutical market:

Kenneth Jarrett, president of the American Chamber of Commerce Shanghai, said he was surprised at the “strong response” from the police. “I would agree that it’s not what I would have expected because it seemed like GSK were cooperating very closely with the authorities,” he told Reuters. […] China is a key growth market for large drugmakers, which are counting on its swelling middle class to offset declining sales in Western countries. China is set to be the second-biggest pharmaceuticals market behind the United States within three years, according to consultants IMS Health. […] “Later they could bring an action against the company and seek penalties against the company and I wouldn’t be surprised if they did that actually, because the claim is so egregious that the company could be charged and fined,” said Steven Dickinson, Qingdao-based partner with law firm Harris Moure. “But the thing is you can’t put a company in jail and they want someone in jail. They want Mr. Reilly in jail for about 10 years. That’s what they’re looking to do,” he added. [Source]

As the initial probe was spreading to the wider pharmaceutical industry last year, commentators noted that foreign firms operating in China are sometimes compelled towards questionable business practice to keep up in an industry overrun by corruption.

Roche Strikes Back at Study That Criticized Tamiflu Stockpiling

Pharmalot WSJ

By Ed Silverman

July 1, 2014

Three months after a study concluded the widely used Tamiflu® treatment was not proven to reduce the spread of the flu or its complications, Roche has struck back by calling the analysis “seriously flawed” and warns the conclusions could lead to public health risks by confusing patients and physicians. In a letter to the British Medical Journal, which published the study, the drug maker claims the authors made “basic errors” in assessing effectiveness data, “over-interpreted” the “limited” safety data that was evaluated and “wholly ignored” other types of data in reaching their conclusion.

The study authors “have drawn many conclusions that would not be supported by a methodologically robust and comprehensive analysis of all relevant [Tamiflu®] data,” Roche scientists wrote. “Equally important, they have not exhibited the diligence necessary when working with large clinical trial datasets and extensive regulatory documents.”

The missive was made in response to a study by the Cochrane Collaboration, a non-profit, global network of health care academics. They concluded that Tamiflu® was no more effective than aspirin, and one of its authors said governments that stockpiled the drug had thrown money “down the drain.” The study, however, did not question the ability of Tamiflu® to treat flu symptoms.

One of the Cochrane researchers wrote us that the authors stand by their conclusions. “Their response was disappointing window dressing designed for those who do not know the story,” Tom Jefferson, a study co-author, wrote us. He adds that a complete rebuttal will soon be provided in BMJ.

Tamiflu® was approved by the FDA in 1999 and became a big seller several years ago as governments moved to stockpile the treatment in the wake of the H1N1 swine flu pandemic. This prompted the Cochrane researchers to assess the effectiveness. They analyzed results from 46 of 107 trials pertaining to both Tamiflu® and Relenza®, a less widely used flu drug sold by GlaxoSmithKline.

But their study was released only after they battled, sometimes publicly, with Roche over access to Tamiflu data, because most of the trial information was unpublished. The episode, which played out in the pages of BMJ as the researchers often chronicled their efforts to convince Roche to release data, became a linchpin in the wider debate over access to clinical trial data harbored by drug makers.

As a result, the European Parliament recently passed a law requiring drug makers to publish all clinical trials related to a drug, but only those approved since January 2014. Both Roche and Glaxo now say they are committed to publishing all clinical study reports on all their drugs, although some Cochrane researchers have also squabbled with Glaxo about data for its Paxil antidepressant.

• The battle over Tamiflu
• What the Tamiflu saga tells us about drug trials and big pharma
• Complications: tracking down the data on oseltamivir

Re: Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

BMJ: Rapid Response

by Carl Heneghan, Tom Jefferson, and Peter Doshi

6 April 2014

With the publication of our systematic reviews on oseltamivir and zanamivir for influenza in adults and children, we are making all 107 full clinical study reports publicly available. Despite the worldwide stockpiling of antivirals, these reports have never been reviewed by the World Health Organization, the US Centers for Disease Control and Prevention [CDC] and its European counterpart, the ECDC.

It took us four years to obtain the full set of reports. The story relating to the acquisition has been documented at the BMJ’s open data campaign [http://www.bmj.com/tamiflu]. If you disagree with our findings, or if you want to carry out your own analysis or just want to see what around 150,000 pages of data look like, they are one click away [http://dx.doi.org/10.5061/dryad.77471].

20 April 2014

Peter M English

Public Health Physician

The comments colleagues and I made previously still stand: http://www.bmj.com/content/339/bmj.b2728

Early in the "containment phase" of the pandemic the health secretary promised that everybody with flu-like symptoms would be given antivirals. The effect of this was that we were obliged to honour this promise. There were not the resources to do this in a timely fashion: most people, while I was involved, were delivered the antivirals a week after the onset of symptoms. We were unable to prioritise high-risk patients.

The government has claimed that the "containment phase" was effective; that the reduction in viral shedding that may plausibly have been a consequence of antiviral treatment slowed the spread of the pandemic. There is no reason to believe that antivirals given more than 48 hours after the onset of symptoms had any other benefit; although respiratory physicians tell me they believe it may have had some benefit in the most seriously ill patients.

16 April 2014

Patrick J Saunders

Professor of Public Health

John Middleton

University of Staffordshire

… We remain concerned however, that the insights of service providers on the ground during the pandemic have not been given the same level of public consideration. It is well documented that even drugs which may be effective in clinical trials can be inefficient, or fail to deliver the patient benefit predicted by trial results, when subject to limitations of general service use. The lessons from service insights in the pandemic are: the wanton abandonment of first principles such as isolation, basic control of infection measures and clinical assessment in favour of the stubborn insistence on managing ‘England as a single epidemiological unit’; and the irrational maintenance of the ‘containment’ phase which led directly to perverse and damaging interventions and over-reliance on antivirals in mass prophylaxis exercises particularly in schools. Anti-viral collection centres became loci for the spread of infection as thousands of symptomatic and sub-clinical cases [there is good evidence that flu can be spread by asymptomatic patients] and unaffected contacts convened for a wonder drug with serious potential side effects, and which would now appear to be no more effective in pandemic management than paracetamol [US name: acetaminophen or Tylenol].

It would be irresponsible for these lessons not to underpin current planning for pandemics and any subsequent responses. We believe there is no place for antiviral distribution in a pandemic based on the current evidence of the effectiveness of the drugs, their ineffectiveness for mass prophylaxis and the likely spread of infection brought about by bringing people to a centre for the drugs.

Comparison of Low and Moderate Dosages of Extended- Release Quetiapine in Borderline Personality Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

by Donald W. Black, M.D. Mary C. Zanarini, Ed.D. Ann Romine, R.N. Martha Shaw, B.A. Jeff Allen, Ph.D. S. and Charles Schulz, M.D.

American Journal of Psychiatry. 2014 Jun 27. [Epub ahead of print]

Objective: The authors compared the efficacy and tolerability of low and moderate dosages of extended-release quetiapine in adults with borderline personality disorder.

Method: Ninety-five participants with DSM-IV borderline personality disorder were randomly assigned to receive 150 mg/day of quetiapine [the low-dosage group; N=33], 300mg/day of quetiapine [the moderate-dosage group; N=33], or placebo [N=29]. Total score over time on the clinician-rated Zanarini Rating Scale for Borderline Personality Disorder [“Zanarini scale”] was analyzed in a mixed-effects model accounting for informative dropout.

Results: Participants in the low-dosage quetiapine group had significant improvement on the Zanarini scale compared with those in the placebo group. Time to response [defined as a reduction of 50% or more on the Zanarini scale total score] was significantly shorter for both the low-dosage quetiapine group [hazard ratio=2.54, p=0.007] and the moderate-dosage quetiapine group [hazard ratio=2.37, p=0.011] than for the placebo group. Among participants who completed the study, 82% in the low- dosage quetiapine group were rated as “responders,” compared with 74% in the moderate-dosage group and 48% in the placebo group. Treatment-emergent ad-verse events included sedation, change in appetite, and dry mouth. The overall completion rate for the 8-week double-blind treatment phase was 67% [67% for the low-dosage quetiapine group, 58% for the moderate-dosage quetiapine group, and 79% for the placebo group]. Participants who experienced sedation were more likely to drop out.

Conclusions: Participants treated with 150 mg/day of quetiapine had a significant reduction in the severity of borderline personality disorder symptoms compared with those who received placebo. Adverse events were more likely in participants taking 300 mg/day of quetiapine.

Pharmacological interventions for borderline personality disorder.

by Stoffers J, Völlm BA, Rücker G, Timmer A, Huband N, and Lieb K.

Cochrane Database Systematic Review 2010 Jun 16;[6]:CD005653.

…

AUTHORS’ CONCLUSIONS: The available evidence indicates some beneficial effects with second-generation antipsychotics, mood stabilisers, and dietary supplementation by omega-3 fatty acids. However, these are mostly based on single study effect estimates. Antidepressants are not widely supported for BPD treatment, but may be helpful in the presence of comorbid conditions. Total BPD severity was not significantly influenced by any drug. No promising results are available for the core BPD symptoms of chronic feelings of emptiness, identity disturbance and abandonment. Conclusions have to be drawn carefully in the light of several limitations of the RCT evidence that constrain applicability to everyday clinical settings [among others, patients’ characteristics and duration of interventions and observation periods].

And the Seroquel XR® study is no different, having no significant effect on core symptoms [speaking of significance, the higher dose Seroquel XR® was not statistically significant]. This study is a classic "experimercial" aiming towards fostering the off-label use of Seroquel XR® in this condition. This whole enterprise of doing Clinical Trials in Borderline Personality Disorder is not science based, more a shotgun approach to see what sticks. Here’s another one from four years ago, funded by Eli Lilly aiming to study Zyprexa in this group of patients, also by Dr. Schulz. Similar results:

A Dose Comparison of Olanzapine for the Treatment of Borderline Personality Disorder: A 12-Week Randomized, Double-Blind, Placebo-Controlled Study

by Mary C. Zanarini, EdD; S. Charles Schulz, MD; Holland C. Detke, PhD; Yoko Tanaka, PhD; Fangyi Zhao, PhD; Daniel Lin, PhD; Walter Deberdt, MD; Ludmila Kryzhanovskaya, MD; and Sara Corya, MD

Journal of Clinical Psychiatry. 2011 72[10]:1353–1362.

Objective: To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder.

Method: In this 12-week randomized double-blind placebo-controlled trial, 451 outpatients aged 18–65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d [n = 150], olanzapine 5–10 mg/d [n = 148], or placebo [n = 153]. The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries [United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela]. The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder [ZAN-BPD] total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale.

Results: An overall mean baseline ZAN-BPD total score of 17.2 [SD = 4.9] indicated moderate symptom severity. Only treatment with olanzapine 5–10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo [−8.5 vs −6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06–0.52]. Response rates [response indicated by ≥ 50% decrease from baseline in ZAN-BPD total score] were significantly higher for olanzapine 5–10 mg/d [73.6%] versus olanzapine 2.5 mg/d [60.1%; P = .018] and versus placebo [57.8%; P = .006]. Time to response was also significantly shorter for patients taking olanzapine 5–10 mg/d than for placebo-treated patients [P = .028]. Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase [all P values < .05]. Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo-treated patients [olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5–10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001]. The overall completion rate for the 12-week double-blind treatment period was 65.2% [ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5–10 mg/d, and 61.4% for placebo].

Conclusions: Olanzapine 5–10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events [particularly weight gain], which were consistent with the known safety profile of olanzapine.

a·nach·ro·nism  [-nkr-nzm]
   n.
   a thing or person that belongs to another, especially an earlier, time.

It’s time for our journals to realize that they’re not roadside billboards and put an end to publishing articles whose primary purpose is advertising expensive drugs, off-label, particularly the major journals like the American Journal of Psychiatry. That’s just not what they’re for. That’s never been what they are for…

How a secret sex tape plunged British drugs giant Glaxo into a £90million bribery probe

Daily Mail

By Hugo Gye

29 June 2014

A covert sex tape involving a senior executive and his Chinese lover was the trigger for a major investigation into corruption at British drugs giant GlaxoSmith-Kline, it was revealed yesterday. The video of married Mark Reilly and his girlfriend was filmed by secret camera and emailed anonymously to board members of the pharmaceutical firm. It led to an investigation that has rocked the £76billion company – which stands accused of bribing doctors and other health officials in China with £320million of gifts, including sexual favours from prostitutes, to persuade them to prescribe its drugs.

Mr Reilly, who ran the company’s Chinese business, was charged six weeks ago with running a ‘massive bribery network’ involving £90million of illegal sales and banned from leaving the country. It was the culmination of a year-long corruption investigation into the FTSE 100 firm. But yesterday, it was revealed the scandal first erupted after the sex tape was emailed by ‘GSK whistleblower’ to board members, including chief executive Andrew Witty, in March 2013, in what was believed to be a threat or blackmail attempt. The footage showed father-of-two Mr Reilly, who is separated from his wife, having sex with his Chinese girlfriend.

He was given permission to hire investigator Peter Humphrey, 58, to find out who had hidden the camera in his Shanghai flat and who had sent two separate emails making serious fraud allegations. The £20,000 probe, codenamed Project Scorpion, focused on disgruntled former employee Vivien Shi, 49, a prominent businesswoman whose family is part of Shanghai’s communist elite. But a few months after starting to investigate Miss Shi, Mr Humphrey was arrested along with his wife Yu Yingzeng, a US citizen and daughter of one of China’s most eminent atomic weapons scientists. According to the Sunday Times, Mr Humphrey’s arrest and detention in July was at around the same time that China began a police probe into GSK’s alleged bribery.

Mr Reilly, 52, of Sawbridgeworth, Hertfordshire, stepped down from his post as China manager soon after Mr Humphrey’s arrest but remains a GSK employee. He returned to Britain around the same time but voluntarily went back to China within days to assist police with their inquiries. He was charged in May this year and accused by police of presiding over a web of corruption and pressing his sales teams to bribe health officials to meet targets…

hat tip to pharmagossip…  

If found guilty, Mr Reilly, who has a PhD in pharmacology and neurosciences from University College London, could face life in prison. Mr Reilly joined GSK in 1989 and has worked in Singapore, Hong Kong and China. He is separated from Jill, 49, with whom he has two teenage daughters, and has moved out of their £1.2million home. It is understood he met Mrs Reilly at university, where she was studying psychology. Like her husband, she took up a post at GSK, working as a director of capital planning…

In with no echo…, I was hypothesizing that by settling out of civil and criminal suits, the pharmaceutical companies avoid any verdict, and invariably quickly say "we admit to no wrongdoing" implying that they settled for who-knows-what reason [like admitting to the least ignoble of the charges]. In doing that, they dampen the incriminating story which then fades quickly – the anechoic effect [see echo echo echo echo echo echo…]. The most obscene version was GSK settling a $3B suit and signing this agreement – then writing a response in a letter to the Chronicle of Higher Education that denies admission of guilt [see the only enduring contract…]. The way this China-gate story is going, it doesn’t at this point look like that’s going to be an option. This is just plain old crime, and one that has the Chinese up in arms [as it should].

Last month, Britain’s Serious Fraud Office announced it is to investigate the company’s ‘commercial practices’.

Earlier, I mentioned "Vanessa’s Law" currently proposed in Canada [doing the right thing… and missing link…]. This is a Canadian Religious Program, "Context," where the author of that proposed legislation is interviewed: