Posted on Thursday 3 July 2014
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 , data from multiple large health plans [not for profit HMOs]. But there are other datasets involved in the analysis: PHARMetrics Patient Centric Database , BC Ministry of Health, and the Nationwide Inpatient Sample  – 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 , 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 , 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  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…
|Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs.
by Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ.
American Journal of Psychiatry. 2007 164:884-891.
[full text online]
|Persisting decline in depression treatment after FDA warnings.
Libby AM, Orton HD, Valuck RJ.
Archives of General Psychiatry. 2009 66:633-639.
[full text online]
|Data for this study come from the PHARMetrics Patient Centric Database, the largest national database of longitudinal integrated health care claims data commercially available from PHARMetrics, a Unit of IMS, Inc [llagerstown, Maryland], under unrestricted license. Data came from integrated medical, specialty, facility, and pharmacy-paid claims from more than 95 managed care plans nationally, representing more than 53 million covered patienls from January 1999 to December 2007. Patients were unidentified and anonymous; therefore, an ex- pedited review was obtained from the Colorado Multiple In- stitutional Review Board..|
|Identifying a cohort of new episodes of depression was the first step in building the analytic file. The definition of a new episode of depression was based on specifications of the National Committee for Quality Assurance Health plan and Hm- ployer Data and Information Set.’617 The resulting time hori- zon that accounted for episode creation, follow-up, and seasonality spanned from July 1999 to June 2007- The total cohort of 643 313 individual patients was separated into 3 depression cohorts comprising 792 807 episodes of diagnosis and possible treatment There were 91748 pediatric cases [aged 5-18 years at time of diagnosis], 70 311 young adult cases [aged 19-24 years at diagnosis], and 630 748 adult cases [aged 25-89 years at diagnosis]. Average ages for each cohort were 15 years for pediatric, 21 years for young adults, and 44 years for adults. Female patients accounted for roughly 60% of pediatric cases and 70% of adult cases; 4% of cases were receiving managed Medicaid benefits at the start of the episode.|
|Identification of hospitalizations for intentional self-harm when E-codes are incompletely recorded
by Amanda R. Patrick, Matthew Miller, Catherine W. Barber, Philip S. Wang, Claire F. Canning and Sebastian Schneeweiss
Pharmacoepidemiology and Drug Safety. 2010 19:1263–1275.
|Data were derived from two large population-based hospital discharge abstract databases. We chose to use two different databases in the interest of gaining some insight regarding the generalizability of our findings. These data were drawn from two countries with different suicide rates, different practice patterns, and different hospital payment schemes, which may translate into differences in coding practice. In addition, there is variation in the number of diagnosis and procedure codes recorded and the availability of patient-level linkable data on prior inpatient hospitalizations, physician visits, and prescription drug use.|
|Data from British Columbia [BC], Canada, were obtained from the BC Ministry of Health. The database includes records of hospitalizations for all patients in BC’s publicly funded healthcare system. Data elements include patient age and sex, up to 25 diagnosis codes including E-codes, up to five procedure codes, length of stay, and discharge disposition. An evaluation of this database found good specificity and completeness of diagnosis codes. We used data from 1999 through 2001, a period immediately prior to the transition from ICD-9-CM to ICD-10-CA diagnosis codes in BC.|
|Data from the United States came from the Nationwide Inpatient Sample [NIS], a publicly available dataset designed to approximate a 20% representative sample of all non-federal hospitals in the United States. The NIS is produced by the Agency for Healthcare Research and Quality [AHRQ] from hospital inpatient discharge records submitted by state health data organizations. The 2003 NIS included data from 37 states. Data elements include hospital location [state], patient age, sex, and race, up to 15 diagnosis codes, up to 15 procedure codes, up to 4 E-codes, length of stay, primary payer, and discharge disposition.|
| Letter to the Editor
How complete are E-codes in commercial plan claims databases?
by Christine Y. Lu, Christine Stewart, Ameena T. Ahmed, Brian K. Ahmedani, Karen Coleman, Laurel A. Copeland. Enid M. Hunkeler, Matthew D. Lakoma, Jeanne M. Madden, Robert B. Penfold, Donna Rusinak, Fang Zhang, and Stephen B. Soumerai
[full text in a madness to our method – a new introduction… ]
|Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study
by Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai
British Medical Journal. 2014 348:g3596.
[full text online]
|This study included 11 geographically distributed US healthcare organizations that provide care to a diverse population of 10 million people in 12 states. All organizations are members of the Mental Health Research Network. a division of the larger HMO Research Network, an established consortium of 19 research centers affiliated with large not for profit integrated healthcare systems. Members are enrolled through employer sponsored insurance, individual insurance plans, and capitated Medicare and Medicaid programs. Members served by these systems are generally representative of each system’s geographic service area [see supplementary table A]…|
|To examine changes in suicide attempts after the warnings, we used the same denominator population as defined previously. While encounters for suicide attempts can be identified in administrative databases using external cause of injury codes [E-codes]], they are known to be incompletely captured in commercial plan databases. Our preliminary analysis found that E-code completeness varied across study sites, treatment settings, and years. Therefore, instead of deliberate self harm E-codes, we used poisoning by psychotropic agents [international classification of diseases, ninth revision, clinical modification 969], a more reliable proxy for population level suicide attempts. Poisoning by drugs or toxic substances is the most common method of suicide attempt leading to hospital admission and emergency room treatments. 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.|
Posted on Thursday 3 July 2014
Pharmagossipby Jack FridayJuly 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]
Digital China Timesby Josh RudolphMay 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.
Posted on Wednesday 2 July 2014
Pharmalot WSJBy Ed SilvermanJuly 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 commentsBMJ: Rapid Responseby Carl Heneghan, Tom Jefferson, and Peter Doshi6 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].
Peter M EnglishPublic 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.
Patrick J SaundersProfessor of Public HealthJohn MiddletonUniversity 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.
Posted on Wednesday 2 July 2014
Comparison of Low and Moderate Dosages of Extended- Release Quetiapine in Borderline Personality Disorder: A Randomized, Double-Blind, Placebo-Controlled Trialby 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.
by Stoffers J, Völlm BA, Rücker G, Timmer A, Huband N, and Lieb K.Cochrane Database Systematic Review 2010 Jun 16;: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].
A Dose Comparison of Olanzapine for the Treatment of Borderline Personality Disorder: A 12-Week Randomized, Double-Blind, Placebo-Controlled Studyby 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, MDJournal of Clinical Psychiatry. 2011 72:1353–1362.
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.
Posted on Monday 30 June 2014
Daily MailBy Hugo Gye29 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’.
Posted on Monday 30 June 2014
In recent weeks, the Commission has received numerous emails, addressed to Ms Testori Coggi, in which citizens voiced their concern regarding the draft policy of the European Medicines Agency (EMA) on the publication of clinical data. We appreciate the interest that this topic triggered. The Commission values transparency as an important tool to increase the understanding of and trust in all decisions and assessments around the authorisation of medicinal products.
The new policy of EMA aims at fostering transparency by pro-actively publishing clinical data on which EMA’s scientific opinions are based. This includes clinical study reports that have been submitted to and were assessed by the Agency in the framework of a marketing authorisation procedure for human medicinal products. While the Agency is not required under its founding Regulation to publish such data, it is believed that a proactive release of clinical data will contribute to strengthening confidence in the system of authorising medicines in line with a global trend towards more transparency. Additionally, it may enable the independent secondary analysis of the evidence reviewed by the Agency and is expected to lead to public health benefits. Up to now, the clinical data concerned is only available through individual access to document requests under Regulation (EC) No 1049/2001.
In 2013 EMA launched a general consultation to which it received more than 1000 comments with sometimes competing views. In December 2013, the Agency proposed some basic principles of the future policy that were agreed by the EMA Management Board, which has to endorse the new policy. On the basis of those principles, the initial draft was reviewed and subsequently made subject to a targeted consultation in May 2014.
While there was large support for more transparency, you will certainly understand that such approach requires certain safeguards to ensure that any published data is used for legitimate purposes only. Those legitimate purposes include academic research, but exclude unfair commercial use by competitors.
The EMA policy can be seen as a preparatory step in view of the application of the new Clinical Trials Regulation (Regulation (EU) No 536/2014) and the publication requirements established thereunder, which will start to apply at the earliest from mid-2016. This Regulation requires that clinical study report covered by its scope be uploaded on an EU database, once the authorisation is granted, refused or the application withdrawn. The data and information contained in the database, including clinical study reports, will in principle be publicly accessible, except for personal data and commercially confidential information.
At the meeting of the Management board of EMA on 12 June 2014 the draft policy was further discussed, including some additional modifications. According to this latest revision, it will be possible to download, save and print the trial data for academic and non-commercial research purposes. The suggestion indeed corresponds to requests notably from research networks who feared that a view-on-screen-only access would be detrimental to any (re-)analysis of the data for non-commercial research purposes. The Management Board agreed in principle to this policy and on the basis of the discussion and comments received, the policy is intended to be adopted by the Management Board through a written procedure in July 2014.
DG Health and Consumers
Unit D5 / Medicinal products – Authorisations, EMA
Posted on Saturday 28 June 2014
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:
Posted on Friday 27 June 2014
PsychiatricNewsby Paul Summergrad, M.D.June 27, 2014
I recently covered on our inpatient psychiatry service at Tufts Medical Center. It is always valuable to see patients at the bedside and to spend time with wonderful psychiatric residents. As usual, the level of both medical psychiatric comorbidity and clinical complexity was challenging, as were the efforts to find the right clinical care and navigate a mental health system that is often fragmented and difficult at best. It was nevertheless greatly rewarding to see patients, to learn something about their life stories, and try to select care that was based on the best available science, and, when none was available, upon clinical experience and judgment…
By this I meant that we must always remember, first and foremost, that we are physicians. It is thus incumbent upon us to be aware of the best scientific evidence available when we make clinical decisions, doing so in the context of the total needs — medical and otherwise — of our patients. It means to speak on their behalf even when it may bring us into conflict with others whose primary focus may be financial, legal, or ideological. It requires us to be deeply knowledgeable not only about the scientific literature and best practices, but also to have more than a passing familiarity with the limitations of that literature and to be prepared to speak when we must despite those limitations. And to do so on our patients’ behalf, not our own…
Even more importantly, we must always be mindful that as physicians we have a special responsibility to speak from our rich clinical experience, and most importantly, from the best science available, wherever that may take us and regardless of opposition. These values and clinical and scientific expertise must be the primary touchstones of our policies and public statements about psychiatry. People may not always like what we have to say, and they may often disagree with it. But if we speak as physicians from our best understanding of what the science of our field is, and our honest view of the best interests of our patients, then they do listen. Ultimately, they will often trust, respect, and rely on our opinion…
Posted on Tuesday 24 June 2014
- a madness to our method…
- are you listening?…
- another campaign?…
- a madness to our method – a new introduction…
Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental studyby Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B SoumeraiBritish Medical Journal. 2014 348:g3596.
Objective To investigate if the widely publicized warnings in 2003 from the US Food and Drug Administration about a possible increased risk of suicidality with antidepressant use in young people were associated with changes in antidepressant use, suicide attempts, and completed suicides among young people.Design Quasi-experimental study assessing changes in outcomes after the warnings, controlling for pre-existing trends.Setting Automated healthcare claims data [2000-2010] derived from the virtual data warehouse of 11 health plans in the US Mental Health Research Network.Participants Study cohorts included adolescents [around 1.1 million], young adults [around 1.4 million], and adults [around 5 million].Main outcome measures Rates of antidepressant dispensings, psychotropic drug poisonings [a validated proxy for suicide attempts], and completed suicides.Results Trends in antidepressant use and poisonings changed abruptly after the warnings. In the second year after the warnings, relative changes in antidepressant use were −31.0% [95% confidence interval −33.0% to −29.0%] among adolescents, −24.3% [−25.4% to −23.2%] among young adults, and −14.5% [−16.0% to −12.9%] among adults. These reflected absolute reductions of 696, 1216, and 1621 dispensings per 100 000 people among adolescents, young adults, and adults, respectively. Simultaneously, there were significant, relative increases in psychotropic drug poisonings in adolescents [21.7%, 95% confidence interval 4.9% to 38.5%] and young adults [33.7%, 26.9% to 40.4%] but not among adults [5.2%, −6.5% to 16.9%]. These reflected absolute increases of 2 and 4 poisonings per 100 000 people among adolescents and young adults, respectively [approximately 77 additional poisonings in our cohort of 2.5 million young people]. Completed suicides did not change for any age group.Conclusions Safety warnings about antidepressants and widespread media coverage decreased antidepressant use, and there were simultaneous increases in suicide attempts among young people. It is essential to monitor and reduce possible unintended consequences of FDA warnings and media reporting.
Study cohorts and outcome measures…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.
…To examine changes in suicide attempts after the warnings, we used the same denominator population as defined previously. While encounters for suicide attempts can be identified in administrative databases using external cause of injury codes [E-codes], they are known to be incompletely captured in commercial plan databases. Our preliminary analysis found that E-code completeness varied across study sites, treatment settings, and years. Therefore, instead of deliberate self harm E-codes, we used poisoning by psychotropic agents [international classification of diseases, ninth revision, clinical modification [ICD-9] code 969], a more reliable proxy for population level suicide attempts. Poisoning by drugs or toxic substances is the most common method of suicide attempt leading to hospital admission and emergency room treatments. 35 36 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..
Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs.
by Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ.
American Journal of Psychiatry. 2007 164:884-891.
[full text online]
Persisting decline in depression treatment after FDA warnings.
Libby AM, Orton HD, Valuck RJ.
Archives of General Psychiatry. 2009 66:633-639.
[full text online]
At face value, the whole premise for the study is flawed. The SSRIs have only been shown to be effective in pediatric depression in Lilly’s earliest studies of Prozac, and in spite of their creative publications, the remainder have been ineffective. So, the idea that the SSRIs are even treatment for adolescent depression is in question, much less much a suicide attempt preventative. There is no direct linkage between the decrease in prescribing and their outcome parameter to validate the association implied. And the thing they actually measured is in itself a proxy for another proxy, based on the evidence from the most compromised of sources. My own takeaway from this article is that, once again, this was an attempt to answer a question using a huge dataset from a commercial administrative data, and it wasn’t up to the task. Having access to that much data is certainly tempting, but the absence of reliable E-coding doomed the study before it ever got off the ground. The errors intrinsic in any proxy, much less a second generation proxy, will probably never make them useful in answering subtle scientific questions.
There is a much larger question in this story, a question that has been present from the start – case studies versus population data. If you’ve seen Akathisia and suicidality in cases of adolescents put on SSRIs, and if you know of several completed suicides that you’re convinced were medication induced, how are you to look at a study like this even if you believe it? This line of thinking presumes that the only thing one can do for a depressed teen is give them SSRIs, which has never been true. A blog is no place to launch into all the things one might do besides give a questionable symptomatic medication, how to actually approach a depressed teen. But even common sense tells us that there are a wide range of answers to that question that don’t only rely on medication. And if, after careful consideration, you decide to try an antidepressant, knowing that this kind of reaction can occur in some cases would certainly heavily inform how you would closely follow such a case.
… it is disturbing that after the health advisories, warnings, and media reports about the relation between antidepressant use and suicidality in young people, we found substantial reductions in antidepressant treatment and simultaneous, small but meaningful increases in suicide attempts. It is essential to monitor and reduce possible unintended effects of FDA warnings and media reporting.