How difficult it is to get the truth about questionable drugs
The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.
Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative.
Jon Jueridini and colleagues have reanalysed SmithKline Beecham’ infamous Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression.
The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.
Their analysis finds that neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs.
Study 329 reanalysis illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base
2015 (2nd) Study Abstract
The RIAT re-analysis marks a new chapter in the story of Study 329, showing the remarkable power of open data. But it also shows how much our current systems are failing patients and the public. It should not have taken 14 years to get to this point. It shows that we need regulation, and perhaps legislation, to ensure that the results of all clinical trials are made publicly available and that individual patient data are available for legitimate independent third party scrutiny.
Objectives To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.
Setting 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998.
Participants 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality.
Interventions Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo.
Main outcome measures The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified.
Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.
Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.
Woman, whose daughter died at 14 months, sues GSK over drug she took while pregnant
Nov 27, 2015 – CALGARY – The makers of an anti-nausea drug prescribed to pregnant women for morning sickness are being sued for $11-million by an Alberta woman whose daughter died 10 years ago.
In 2012, the US Department of Justice announced that GlaxoSmithKline, maker of Zofran, would pay more than $1 billion to settle claims that it illegally marketed Zofran and other medications for off-label, unapproved uses. Specifically, GlaxoSmithKline allegedly “promoted certain forms of Zofran, approved only for post-operative nausea, for the treatment of morning sickness in pregnant women.” Although doctors are free to prescribe Zofran for off-label use, it is illegal for a drug company to market its medications for unapproved uses.
Sources and more information
Woman, whose daughter died at 14 months, sues GSK over drug she took while pregnant, cnews, Nov 27, 2015.
It has always been legal for U.S. doctors to prescribe drugs for off-label uses but marketing of off-label uses has been illegal. In August, U.S. District Judge Paul A. Engelmayer ruled that the First Amendment allows a drug company to “engage in truthful and non-misleading speech promoting the off-label use” of drugs and that the FDA cannot bar such “speech.” The ruling, pertaining to the drug Amarin, which targets high triglyceride levels, is likely to be appealed and only applies to the 2nd U.S. Circuit Court of Appeals, which includes New York, Connecticut and Vermont. But patients had better beware.
Off-label marketing is irresistible to Big Pharma because it saves years and millions spent on clinical trials which may not assure FDA approval anyway. It allows drug companies to circumvent the pesky and slow FDA altogether and get on with the business of making money– bringing their sales pitch to doctors and patients directly. Almost all major drug companies—GSK, Eli Lilly, Abbott, AstraZeneca, Pfizer, Johnson & Johnson, Amgen, Allergen, Bristol-Myers Squibb, Cephalon, Novartis and Purdue (which makes Oxycontin)––have agreed to huge settlements which include charges of off-label marketing.
In court-released confidential memos, Pfizer (then Parke-Davis) admits why it chose to off-label market Neurontin (only approved for postherpetic neuralgia and adjunctive seizure therapy) for the unapproved indication of bipolar disorder. “The U.S. market for Bipolar Disorders is an attractive commercial opportunity that warrants clinical development of Neurontin. Based on the current patent situation, an investment in full clinical development is not recommended at this time since completion of two pivotal trials and regulatory filing and approval would occur close to patent expiration,” says the memo. Translation: It would take too long to get legal approval—our patent would expire. Instead, says the memo, “it is recommended to implement only an exploratory study in outpatients with bipolar disorders with the results highlighted through a peer reviewed publication.” Translation: Let’s not do the studies and plant some info in medical journals that looks like we did.
Pfizer paid a $430 million fine and signed a corporate integrity agreement for off-label marketing of Neurontin which was linked to wrongful deaths and suicides. But that did not stop Pfizer from off-label marketing Lyrica, sometimes called “son of Neurontin,” soon afterward. Who can say incorrigible?
Nor did Eli Lilly’s guilty plea in 2009 to the off-label promotion of the antipsychotic Zyprexa deter it from requesting permission from the FDA to market Zyprexa to childrenthree months later. The FDA said—yes! At the same time, Pfizer and AstraZeneca also requested permission to market their antipsychotics, Geodon and Seroquel respectively, to kids though both agreed to off-label marketing those exact drugs months later.
Another off-label marketing scheme centered around the selective estrogen receptor modulator Evista. Eli Lilly, its manufacturer, had noted fewer incidences of breast cancer in an Evista trial and wanted to market it not just for its approved treatment of prevention of osteoporosis but for prevention of breast cancer. A group of doctors told Lilly the anticancer marketing claims were “an egregious stretch” and that Evista’s high risk of stroke canceled out any anticancer benefits.
Undaunted, Lilly armed 1000 of its drug reps with an off-label Evista sales plan to sell the unapproved use of breast cancer prevention. Drug reps were told to hide a disclosure page that said, “The effectiveness of [Evista] in reducing the risk of breast cancer has not yet been established,” and “All of the authors were either employees or paid consultants of Eli Lilly at the time this article was written,” according to the Department of Justice.
Lilly was charged with a violation of the Food, Drug, and Cosmetic Act and ordered to pay a $36 million settlement for the off-label marketing. But Evista did receive approval to reduce the “risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.” The problem was the drug, marketed so freely for off-label uses, was far from safe. Prescribing information warned “Serious and life-threatening side effects can occur while taking EVISTA” and ads warned about “death due to stroke.” Its effectiveness was also not impressive. Patients were warned that Evista doesn’t “completely prevent breast cancer,” and “Breast examinations and mammograms should be done before starting Evista and regularly thereafter.”
Clearly, forgiveness is cheaper than permission for drug makers who consider such settlements the cost of doing business. But are drug sales pitches really “speech?” Can a “truthful and not misleading” determination really be made by the for-profit company selling the product? If drug companies’ product claims are protected under the First Amendment and they can sell directly to doctors and patients why even have an FDA?
Over 50 years ago, Big Pharma was also annoyed with the slow-paced FDA whose efforts to ensure drugs were safe cut into profits. One company even complained to an FDA official’s bosses that she was a petty bureaucrat. The company made thalidomide.
With the NHS drug bill topping £10 billion in 2013, this BBC investigation examines the tactics employed by drug companies to tap into that lucrative market and influence which medicines your doctor prescribes
With the NHS drug bill topping £10 billion in 2013, this investigation examines the tactics employed by drug companies to tap into that lucrative market and influence which medicines your doctor prescribes.
Strict rules govern drug company spending in the UK, but still they pay out millions to doctors to attend and speak at conferences. Panorama goes undercover to see this subtle persuasion at work and asks whether you should have the right to know who is paying your doctor.
And as Britain’s most profitable drug company, GlaxoSmithKline, waits to hear whether it will face criminal charges following allegations of bribery in China, the programme reveals new evidence that GSK was recently paying doctors to boost prescriptions much closer to home, in Europe.
The controversy surrounding antidepressants and pregnancy
” Last December, the Supreme Court of British Columbia set a bold precedent: it green-lit the first class action suit in Canada alleging that an antidepressant taken by a woman during pregnancy caused a birth defect in her child. Faith Gibson of Surrey, B.C., named “representative plaintiff,” had been prescribed Paxil, a selective serotonin reuptake inhibitor (SSRI), in December 2002. Her daughter, Meah Bartram, was born in September 2005 with a hole in her heart. The defect was repaired months later, but Meah remains a “sickly” child, prone to infection. Two weeks after her birth, Health Canada and Paxil’s manufacturer, GlaxoSmithKline Inc. (GSK), issued an advisory stating that paroxetine (Paxil’s generic name) taken in the first trimester may pose “an increased risk” of cardiovascular defects. ”