TriHealth (Cincinnati) fires 150 workers who did not get their flu shot

Happy Thanksgiving:  You're fired.   Donald Trump couldn't have done it with more aplomb.

"Health system TriHealth had a message for 150 employees Wednesday: We really mean it this time.  

The 150 workers who didn’t get the required flu shots by the Nov. 16 deadline received termination notices the day before Thanksgiving..."

On November 20, FDA approved a new flu vaccine, grown in mammalian cells.  It appears to work in adults below age 50, but the manufacturer was only able to show it was no worse than a different flu vaccine at generating antibodies in those over 50.  That is a poor correlate for effectiveness.  According to FDA:

"The use of Flucelvax in people older than 49 is supported by antibody responses in about 1,700 adults which showed it to be comparable to Agriflu, an egg-based seasonal influenza vaccine approved by FDA for use in people 18 years and older..."

UPDATE:  AHRP on Cochrane findings re flu vaccine efficacy.

Only 6 weeks ago the University of Minnesota published a long report on the Flu Vaccine Enterprise.  Among its key findings are the two below:

1.   "During some influenza seasons vaccination
offers substantially more protection for most
of the population than being unvaccinated;
however, influenza vaccine protection is markedly
lower than for most routinely recommended
vaccines and is suboptimal.  
We reviewed all studies that evaluated influenza
vaccine efficacy and effectiveness published from 1967
to 2012 and summarized those that used rigorous
methodology and had specific infection outcome end
points. For TIV, results demonstrated: (1) evidence of
moderate protection (pooled estimate of 59%) for
healthy adults 18 to 64 years of age, (2) inconsistent
evidence of protection in children age 2 to 17 years,
and (3) a paucity of evidence for protection in adults 65
years of age and older. For LAIV, (the live vaccine used mostly in children) results demonstrated:
(1) evidence of high protection (pooled estimate of
83%) for young children 6 months to 7 years of age,
(2) inconsistent evidence of protection in adults 60
years of age and older, and (3) a lack of evidence for
protection in individuals between 8 and 59 years of
age. 

2.   Current policy goals for influenza vaccines focus
on increasing production capacity and have not
addressed key public health challenges related to
the effectiveness of current vaccines.
Current influenza vaccine public health policy
focuses on: (1) expanding current seasonal influenza
vaccination campaigns to vaccinate an increasing
proportion of the population each year using current
HA-head vaccines, (2) ensuring that capacity is
available to rapidly produce HA-head vaccines at the
onset of an influenza pandemic, and (3) improving
vaccine access, particularly in developing countries.
While these are all laudable goals, they provide only
for incremental improvements. Public health policy
has not yet recognized the critical limitations of the
current HA-head vaccines or the limited impact of our
current strategies. While officials are now recognizing
that better vaccines are needed, the current policy
focus and the lack of acknowledgment of the current
vaccines’ shortcomings have created an environment
lacking the political will to develop novel-antigen
game-changing vaccines. Public health policy leaders
must overcome these barriers and make development
of game-changing vaccines a national priority.

How Drug Company Money Is Undermining Science / Sci Am

This has been a big week for long articles about the role (read: SCANDAL) of money in the so-called science of medicine.  Scientific American has a very worthwhile article with a focus on drugs for osteoporosis.  I covered this subject once before.  Charles Seife, the author, is an academic who worked very hard to piece together information, and the story is compelling.

“There isn't a single sector of academic medicine, academic research or medical education in which industry relationships are not a ubiquitous factor,” says sociologist Eric Campbell, a professor of medicine at Harvard Medical School.

The Washington Post ran a long piece today on the Avandia scandal and how GSK managed the bad news, keeping the drug on the market for years after the bad news was known (and causing thousands of excess deaths in the process).

Over a year-long period ending in August, NEJM published 73 articles on original studies of new drugs, encompassing drugs approved by the FDA since 2000 and experimental drugs, according to a review by The Washington Post.Of those articles, 60 were funded by a pharmaceutical company, 50 were co-written by drug company employees and 37 had a lead author, typically an academic, who had previously accepted outside compensation from the sponsoring drug company in the form of consultant pay, grants or speaker fees. 

This was also the week when BMJ issued its new guidance for publishing clinical trials, requiring sharing of data by drug and device makers.

Maybe change is coming.  Maybe industry, which has conflated marketing and clinical research, will have its wings clipped.  We'll see.

Tiotropium (Spiriva) increases death rates in users compared to other COPD treatments/ BMJ

Spiriva had an unusual marketing strategy when it came out:  I was told (while eating a free lunch) it was a great drug, but could take a very long time to show benefit:  therefore, give it to patients for 6 months before concluding lack of benefit.  A six month trial cost the patient about $1,000.

Six months before seeing benefit in COPD?  That sounded dodgy to me.  The similar drug ipratropium had showed benefit quickly.  Thankfully, I chose not to prescribe it.

Fast forward.  After several years of papers questioning the drug's safety, Curt Furberg et al. have published a meta-analysis in the BMJ, showing the drug increases the death rate in users.  Using the low dose, there will be an estimated 1 excess death per year per 124 users, or a 52% overall increased risk of mortality in users:

Results Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P=0.02; I²=0%). Both 10 µg (2.15, 1.03 to 4.51; P=0.04; I²=9%) and 5 µg (1.46, 1.01 to 2.10; P=0.04; I²=0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P=0.04), limiting the analysis to three trials of one year’s duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.

Appropriately, the question is asked:  why is this drug still on the market?

US firm accused of manipulating journal articles and paying millions to authors/ BMJ

Another blockbuster article from the BMJ:  Medtronic paid hundreds of millions of dollars (most to doctors) to write its own articles on a spinal fusion device and genetically engineered protein to stimulate bone growth:

The US medical device company Medtronic was “heavily involved in drafting, editing, and shaping the content of medical journal articles authored by its physician consultants,” who were paid hundreds of millions of dollars by the company through royalties and consulting fees, a US Senate Finance Committee staff investigation has found.1

The committee investigated 13 journal articles related to Medtronic’s product Infuse, a bone growth stimulating protein approved by the US Food and Drug Administration (FDA) in 2002 for use in spinal fusion surgery.2 The protein is used in conjunction with a Medtronic spinal fusion device for treatment of degenerative disc disease in the lower spine.

The protein, a genetically engineered version of bone morphogenetic protein 2 (rh-BMP2), has been used to treat more than 500 000 patients. In Europe it is known as dibotermin alfa and it is marketed under the trade name InductOs.

According to the report, Medtronic employees inserted language into medical journal articles that promoted the product without disclosing to the journals “the company’s significant role in authoring or substantively editing” the manuscripts. The company paid “approximately $210 million dollars (£130m; €163m) to physician authors of Medtronic sponsored studies from November 1996 through December 2010,” the report alleges. 

The report also claims that Medtronic employees sought to downplay adverse events associated with the product while emphasising problems with competing procedures...

On compulsory flu vaccinations for medical personnel /Canadian Medical Association Journal

Dr. Flegel, a professor of medicine and senior associate editor of the CMAJ, last week weighed in to support compulsory flu vaccinations on the basis that the following was met:

"... there must be an outbreak of serious illness; immunity levels must be low; the
vaccine must be effective, safe and available; and vaccine uptake must be low."

That seems a reasonable bar for a compulsory medical procedure.  But does flu vaccination reach this bar?

First, how serious is flu?  If we put aside the "estimated" death rate and simply look at death certificates, there are less than 2,000 flu deaths/year in the US.  Some flu deaths are due to secondary conditions that occur as a result of flu, so flu may not be listed on the death certificate.  Sometimes mathematical models are used instead to infer flu's impact.

Flegel says there are 4-8,000 flu deaths/year in Canada, a country of 34 million people. His own journal, the CMAJ, said in 2003 that Canadian flu deaths had been estimated at 500-1500/year, but applying a new CDC model increased the estimate to 700-2500/year.

Flegel's numbers come from a 2007 paper by Schanzer et al. Based only on mathematical modeling and new assumptions, the authors concluded that the real rate of flu deaths was 4,000-8,000/year. However, this model is fatally flawed:  it predicted that over half the deaths during periods of influenza activity were due to influenza, when Simonsen et al. have reliably shown that less than 10% of winter deaths in any season were influenza-related.

In fact, Schanzer's Figure 2 attributes as many deaths to flu as to cancer in Canada! Think of how many people you knew who died of cancer, then think of how many you knew who died of flu. Schanzer needs to go back to the drawing board.

Second, it is hard to gauge the degree of immunity in a population, since we don't know which antibodies are protective, so we don't know which specific ones to measure.   Elderly people did not get much swine flu in 2009 because they had pre-existing immunity--but there was no way to know that till after the fact.  And there is no way to know how immune our population is to any one flu strain, because immunity from prior years' strains provides some degree of immunity to other strains.  But we only learn how much retrospectively.

Third, how safe and effective are flu vaccines?   With flu vaccines being made from new strain combinations almost every year, one never knows either how effective or how safe this year's version is going to be.  Flegel says efficacy is 86%, but others suggest efficacy is 60% or less, and related to the degree of match between vaccine strains and those circulating.

There was no mention of the interesting Canadian finding, supported by about 6 studies, showing that people who received the 2008 flu vaccine were twice as likely to become clinically ill from the 2009 swine flu virus as those who had not received flu vaccine in 2008. See this article, this one and this letter.   The finding raises a new safety issue for flu vaccines, one whose magnitude is uncertain.

Flegel apparently forgot to check his citations.  They failed to support several of his assertions, as pointed out in Letters to the editor by several well known flu experts, including an author of the Cochrane influenza vaccine review he cited.

IMHO, the editorial and letters are a welcome science-based addition to the discussion of mandatory, yearly flu inoculations for healthcare workers and others.

Clinical trial data for all drugs in current use / BMJ

Re: Clinical trial data for all drugs in current use

31 October 2012

Dr. Godlee's editorial (BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7304) underscores the importance of the GlaxoSmithKline decision to allow access to anonymized patient level data from its clinical trials. Meta-analysts can now work more efficiently in summarizing knowledge relating to the benefits and risks of drugs and other medical interventions. As a result, the pace of evidence-based medical practice should pick up.

Open availability of data on which journal and other publications are based is wise public policy and one that is consistent with the replicability tenet of empirical science. Now selective reporting of findings by researchers should not go unnoticed for so long and thus draw swift deserved criticism and reprimand.

Yet the hold-outs may well be government agencies when their interests are threatened. My correspondence via registered mail to US Center for Disease Control (CDC) co-authors of an anthrax safety report that they had published in Vaccine (1) has gone ignored for almost 8 months--despite citation of the CDC policy relating to data release and copying my concerns to Dr. Thomas Freiden, CDC Director. The US Department of Health and Human Services, of which the CDC is a part, has been advocating a test of the anthrax vaccine in children in face of substantial doubt about the safety of the anthrax vaccine in adults. (2)

John H Noble Jr, Emeritus Professor

State University of New York at Buffalo, 508 Rio Grande Loop, Georgetown, TX 78633, USA

(1) Stewart B, Zhang Y, Rose Jr CE, Tokars JI, Martin SM, Franzke LH, McNeil MM. Health-related quality of life in the Anthrax Vaccination Program for workers in the Laboratory Response Network. Vaccine 2012;30 (10): 1841-1846.
(2) Alliance for Human Research Protection (AHRP), 18 May 2012. Anthrax vaccine trial ethics? Science? See: www.ahrp.org/cms/content/view/851/9.

EDITORIAL: Clinical trial data for all drugs in current use must be made available for independent scrutiny/ BMJ

The courageous BMJ and editor Fiona Godlee have dared to suggest the only way forward through the quicksand of clinical trial data in which we find ourselves.  When only the manufacturer knows what is in a drug's database, and the manufacturer's primary duty is to shareholders, medicine progresses backwards to a new Dark Age.

Simply, governments, outside scientists and consumers have a dire need to know what the drug manufacturer knows, before the whole medical enterprise collapses.  As a physician I am tortured by the fact that I am not permitted to know the true efficacy and side effect profiles of the drugs I prescribe.

The BMJ will lose advertising and reprints worth millions--but unless its suggestion is followed we will lose the science of medicine.

The drug industry does many good things. It produces medicines that can improve health and save lives. It creates jobs and stimulates economic growth. Sadly it does bad things too. Persistently and systematically over decades it has withheld and misreported data from clinical trials.1 As a result, a whole range of widely used drugs across all fields of medicine have been represented as safer and more effective than they are, endangering people’s lives and wasting public money. Such wilful distortion is scientific misconduct.2 It is not something we can forgive because of the good things drug companies do. As Ben Goldacre says in the introduction to his new book Bad Pharma, “Drug companies around the world have produced some of the most amazing innovations of the past fifty years, saving lives on an epic scale. But that does not allow them to hide data, mislead doctors, and harm patients.”3

Hats off then to GlaxoSmithKline, which announced last month that it would allow access to anonymised patient level data from its clinical trials.4 An independent panel will assess all requests, and the company’s chief executive officer, Andrew Witty, says access will be granted on the basis of a reasonable scientific question, a protocol, and a commitment from the researchers to publish their results. Trial data collected since 2007 will be placed on a password protected website. Earlier data, not yet available in standard digitised formats, will be made available on “an ad hoc basis.”

Whether researchers will find it as easy to get past the panel as Witty suggests we will have to wait and see. It will be particularly important to know how many requests are turned down and for what reasons.

And amid the plaudits, a moment of doubt. Surely what this apparently brave and benevolent action really serves to highlight is the rank absurdity of the current situation. Why aren’t all clinical trial data routinely available for independent scrutiny once a regulatory decision has been made? How have commercial companies been allowed to evaluate their own products and then to keep large and unknown amounts of the data secret even from the regulators? Why should it be up to the companies to decide who looks at the data and for what purpose? Why should it take legal action (as in the case of GlaxoSmithKline’s paroxetine and rosiglitazone),5 6 strong arm tactics by national licensing bodies (Pfizer’s reboxetine),7 and

the exceptional tenacity of individual researchers and investigative journalists (Roche’s oseltamivir)8 to try to piece together the evidence on individual drugs?

Goldacre’s book makes it clear that the reasons are complex and there are no simple solutions. But there is no doubt that medical journals could do more. Rather than no longer publishing industry funded trials, as some have suggested, they could leverage their power and publish only where there is a commitment to make the relevant anonymised patient level data available on reasonable request. The International Committee of Medical Journal Editors has so far declined to take such a step. The BMJ will require this commitment for all clinical trials of drugs and devices—whether industry funded or not—from January 2013.

The BMJ is also intensifying its efforts to help resolve a three year battle to gain access to the full data on oseltamivir (Tamiflu). In 2009 the Cochrane respiratory group, led by Tom Jefferson, was commissioned by the UK government to update its systematic review of neuraminidase inhibitors. Despite a public promise to release “full study reports” (internal company reports) for each trial, each of which can run to thousands of pages,8 Roche has stonewalled, variously pleading patient or commercial confidentiality, or claiming that sufficient data have already been provided.9

In fact the Cochrane group has told the BMJ that about 60% of Roche’s data from phase III trials of oseltamivir have never been published. And although the European Medicines Agency (EMA) could have requested these data from Roche, it did not do so. This means that tax payers in the United Kingdom and around the world have spent billions of dollars stockpiling a drug for which no one except the manufacturer has seen the complete evidence base. Indeed the EMA’s unprecedented infringement proceedings launched against Roche last month suggest that even the manufacturer has never fully evaluated evidence it has collected on the drug’s adverse effects.10 What has Roche got to hide?

Two weeks ago in an attempt to break the deadlock, the BMJ wrote to one of the UK’s leading academics, John Bell, regius professor of medicine at Oxford University, who is a member of Roche’s board of directors. The letter is published this week.11

In a response not for publication, Bell said he has referred the matter to Roche and is awaiting a response.

Meanwhile, frustrated by the lack of progress, Jefferson and colleagues have given the BMJ their entire email correspondence with Roche, which is now published at bmj.com/tamiflu, as David Payne explains.12 They have also shared with us their correspondence with the World Health Organization and US Centers for Disease Control and Prevention. The emails show any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Please see the BMJ for footnotes.