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Excerpt from Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients, by Ben Goldacre. Published by Faber and Faber, Inc. © 2013 Ben Goldacre. Excerpted with permission from the publisher. All Rights Reserved.
Before we get going, we need to establish one thing beyond any doubt: industry-funded trials are more likely to produce a positive, flattering result than independently funded trials. This is our core premise, and you're about to read a very short chapter, because this is one of the most well-documented phenomena in the growing field of "research about research". It has also become much easier to study in recent years, because the rules on declaring industry funding have become a little clearer.
We can begin with some recent work: in 2010, three researchers from Harvard and Toronto found all the trials looking at five major classes of drug—antidepressants, ulcer drugs and so on—then measured two key features: were they positive, and were they funded by industry? They found over five hundred trials in total: 85 per cent of the industry-funded studies were positive, but only 50 per cent of the government funded trials were. That's a very significant difference.
In 2007, researchers looked at every published trial that set out to explore the benefit of a statin. These are cholesterol lowering drugs which reduce your risk of having a heart attack, they are prescribed in very large quantities, and they will loom large in this book. This study found 192 trials in total, either comparing one statin against another, or comparing a statin against a different kind of treatment. Once the researchers controlled for other factors (we'll delve into what this means later), they found that industry-funded trials were twenty times more likely to give results favoring the test drug. Again, that's a very big difference.
We'll do one more. In 2006, researchers looked into every trial of psychiatric drugs in four academic journals over a ten-year period, finding 542 trial outcomes in total. Industry sponsors got favorable outcomes for their own drug 78 per cent of the time, while independently funded trials only gave a positive result in 48 per cent of cases. If you were a competing drug put up against the sponsor's drug in a trial, you were in for a pretty rough ride: you would only win a measly 28 per cent of the time.
These are dismal, frightening results, but they come from individual studies. When there has been lots of research in a field, it's always possible that someone—like me, for example—could cherry-pick the results, and give a partial view. I could, in essence, be doing exactly what I accuse the pharmaceutical industry of doing, and only telling you about the studies that support my case, while hiding the reassuring ones from you.
To guard against this risk, researchers invented the systematic review. We'll explore this in more detail soon, since it's at the core of modern medicine, but in essence a systematic review is simple: instead of just mooching through the research literature, consciously or unconsciously picking out papers here and there that support your pre-existing beliefs, you take a scientific, systematic approach to the very process of looking for scientific evidence, ensuring that your evidence is as complete and representative as possible of all the research that has ever been done.
Systematic reviews are very, very onerous. In 2003, by coincidence, two were published, both looking specifically at the question we're interested in. They took all the studies ever published that looked at whether industry funding is associated with pro-industry results. Each took a slightly different approach to finding research papers, and both found that industry-funded trials were, overall, about four times more likely to report positive results. A further review in 2007 looked at the new studies that had been published in the four years after these two earlier reviews: it found twenty more pieces of work, and all but two showed that industry sponsored trials were more likely to report flattering results.
I am setting out this evidence at length because I want to be absolutely clear that there is no doubt on the issue. Industry sponsored trials give favorable results, and that is not my opinion, or a hunch from the occasional passing study. This is a very well-documented problem, and it has been researched extensively, without anybody stepping out to take effective action, as we shall see.
There is one last study I'd like to tell you about. It turns out that this pattern of industry-funded trials being vastly more likely to give positive results persists even when you move away from published academic papers, and look instead at trial reports from academic conferences, where data often appears for the first time (in fact, as we shall see, sometimes trial results only appear at an academic conference, with very little information on how the study was conducted).
Fries and Krishnan studied all the research abstracts presented at the 2001 American College of Rheumatology meetings which reported any kind of trial, and acknowledged industry sponsorship, in order to find out what proportion had results that favored the sponsor's drug. There is a small punch-line coming, and to understand it we need to cover a little of what an academic paper looks like. In general, the results section is extensive: the raw numbers are given for each outcome, and for each possible causal factor, but not just as raw figures. The 'ranges' are given, subgroups are perhaps explored, statistical tests are conducted, and each detail of the result is described in table form, and in shorter narrative form in the text, explaining the most important results. This lengthy process is usually spread over several pages.
In Fries and Krishnan [2004] this level of detail was unnecessary. The results section is a single, simple, and—I like to imagine—fairly passive-aggressive sentence:
The results from every RCT (45 out of 45) favored the drug of the sponsor.
This extreme finding has a very interesting side effect, for those interested in time-saving shortcuts. Since every industry sponsored trial had a positive result, that's all you'd need to know about a piece of work to predict its outcome: if it was funded by industry, you could know with absolute certainty that the trial found the drug was great.
How does this happen? How do industry-sponsored trials almost always manage to get a positive result? It is, as far as anyone can be certain, a combination of factors. Sometimes trials are flawed by design. You can compare your new drug with something you know to be rubbish—an existing drug at an inadequate dose, perhaps, or a placebo sugar pill that does almost nothing. You can choose your patients very carefully, so they are more likely to get better on your treatment. You can peek at the results halfway through, and stop your trial early if they look good (which is—for interesting reasons we shall discuss—statistical poison). And so on.
But before we get to these fascinating methodological twists and quirks, these nudges and bumps that stop a trial from being a fair test of whether a treatment works or not, there is something very much simpler at hand.
Sometimes drug companies conduct lots of trials, and when they see that the results are unflattering, they simply fail to publish them. This is not a new problem, and it's not limited to medicine. In fact, this issue of negative results that go missing in action cuts into almost every corner of science. It distorts findings in fields as diverse as brain imaging and economics, it makes a mockery of all our efforts to exclude bias from our studies, and despite everything that regulators, drug companies and even some academics will tell you, it is a problem that has been left unfixed for decades.
In fact, it is so deep-rooted that even if we fixed it today—right now, for good, forever, without any flaws or loopholes in our legislation—that still wouldn't help, because we would still be practicing medicine, cheerfully making decisions about which treatment is best, on the basis of decades of medical evidence which is—as you've now seen—fundamentally distorted.
But there is a way ahead.
Why missing data matters
Reboxetine is a drug I myself have prescribed. Other drugs had done nothing for this particular patient, so we wanted to try something new. I'd read the trial data before I wrote the prescription, and found only well-designed, fair tests, with overwhelmingly positive results. Reboxetine was better than placebo, and as good as any other antidepressant in head-to-head comparisons. It's approved for use by the Medicines and Healthcare products Regulatory Agency (the MHRA) in the UK, but wisely, the U.S. chose not to approve it. (This is no proof of the FDA being any smarter; there are plenty of drugs available in the U.S. that the UK never approved.) Reboxetine was clearly a safe and effective treatment. The patient and I discussed the evidence briefly, and agreed it was the right treatment to try next. I signed a prescription saying I wanted my patient to have this drug.
But we had both been misled. In October 2010 a group of researchers were finally able to bring together all the trials that had ever been conducted on reboxetine.6 Through a long process of investigation—searching in academic journals, but also arduously requesting data from the manufacturers and gathering documents from regulators—they were able to assemble all the data, both from trials that were published, and from those that had never appeared in academic papers.
When all this trial data was put together it produced a shocking picture. Seven trials had been conducted comparing reboxetine against placebo. Only one, conducted in 254 patients, had a neat, positive result, and that one was published in an academic journal, for doctors and researchers to read. But six more trials were conducted, in almost ten times as many patients. All of them showed that reboxetine was no better than a dummy sugar pill. None of these trials was published. I had no idea they existed.
It got worse. The trials comparing reboxetine against other drugs showed exactly the same picture: three small studies, 507 patients in total, showed that reboxetine was just as good as any other drug. They were all published. But 1,657 patients' worth of data was left unpublished, and this unpublished data showed that patients on reboxetine did worse than those on other drugs. If all this wasn't bad enough, there was also the side effects data. The drug looked fine in the trials which appeared in the academic literature: but when we saw the unpublished studies, it turned out that patients were more likely to have side effects, more likely to drop out of taking the drug, and more likely to withdraw from the trial because of side effects, if they were taking reboxetine rather than one of its competitors.
If you're ever in any doubt about whether the stories in this book make me angry—and I promise you, whatever happens, I will keep to the data, and strive to give a fair picture of everything we know—you need only look at this story. I did everything a doctor is supposed to do. I read all the papers, I critically appraised them, I understood them, I discussed them with the patient, and we made a decision together, based on the evidence. In the published data, reboxetine was a safe and effective drug. In reality, it was no better than a sugar pill, and worse, it does more harm than good. As a doctor I did something which, on the balance of all the evidence, harmed my patient, simply because unflattering data was left unpublished.
If you find that amazing, or outrageous, your journey is just beginning. Because nobody broke any law in that situation, reboxetine is still on the market, and the system that allowed all this to happen is still in play, for all drugs, in all countries in the world. Negative data goes missing, for all treatments, in all areas of science. The regulators and professional bodies we would reasonably expect to stamp out such practices have failed us.
In a few pages, we will walk through the literature that demonstrates all of this beyond any doubt, showing that "publication bias"—the process whereby negative results go unpublished—is endemic throughout the whole of medicine and academia; and that regulators have failed to do anything about it, despite decades of data showing the size of the problem. But before we get to that research, I need you to feel its implications, so we need to think about why missing data matters.
Evidence is the only way we can possibly know if something works—or doesn't work—in medicine. We proceed by testing things, as cautiously as we can, in head-to-head trials, and gathering together all of the evidence. This last step is crucial: if I withhold half the data from you, it's very easy for me to convince you of something that isn't true. If I toss a coin a hundred times, for example, but only tell you about the results when it lands heads-up, I can convince you that this is a two-headed coin. But that doesn't mean I really do have a two-headed coin: it means I'm misleading you, and you're a fool for letting me get away with it. This is exactly the situation we tolerate in medicine, and always have. Researchers are free to do as many trials as they wish, and then choose which ones to publish.
The repercussions of this go way beyond simply misleading doctors about the benefits and harms of interventions for patients, and way beyond trials. Medical research isn't an abstract academic pursuit: it's about people, so every time we fail to publish a piece of research we expose real, living people to unnecessary, avoidable suffering.
In March 2006, six volunteers arrived at a London hospital to take place in a trial. It was the first time a new drug called TGN1412 had ever been given to humans, and they were paid £2,000 each. Within an hour these six men developed headaches, muscle aches, and a feeling of unease. Then things got worse: high temperatures, restlessness, periods of forgetting who and where they were. Soon they were shivering, flushed, their pulses racing, their blood pressure falling. Then, a cliff: one went into respiratory failure, the oxygen levels in his blood falling rapidly as his lungs filled with fluid. Nobody knew why. Another dropped his blood pressure to just 65/40, stopped breathing properly, and was rushed to an intensive care unit, knocked out, intubated, mechanically ventilated. Within a day all six were disastrously unwell: fluid on their lungs, struggling to breathe, their kidneys failing, their blood clotting uncontrollably throughout their bodies, and their white blood cells disappearing. Doctors threw everything they could at them: steroids, antihistamines, immune-system receptor blockers. All six were ventilated on intensive care. They stopped producing urine; they were all put on dialysis; their blood was replaced, first slowly, then rapidly; they needed plasma, red cells, platelets. The fevers continued. One developed pneumonia. And then the blood stopped getting to their peripheries. Their fingers and toes went flushed, then brown, then black, and then began to rot and die. With heroic effort, all escaped, at least, with their lives.
The Department of Health convened an Expert Scientific Group to try to understand what had happened, and from this two concerns were raised. First: can we stop things like this from happening again? It's plainly foolish, for example, to give a new experimental treatment to all six participants in a 'first-in-man' trial at the same time, if that treatment is a completely unknown quantity. New drugs should be given to participants in a staggered process, slowly, over a day. This idea received considerable attention from regulators and the media.
Less noted was a second concern: could we have foreseen this disaster? TGN1412 is a molecule that attaches to a receptor called CD28 on the white blood cells of the immune system. It was a new and experimental treatment, and it interfered with the immune system in ways that are poorly understood, and hard to model in animals (unlike, say, blood pressure, because immune systems are very variable between different species). But as the final report found, there was experience with a similar intervention: it had simply not been published. One researcher presented the inquiry with unpublished data on a study he had conducted in a single human subject a full ten years earlier, using an antibody that attached to the CD3, CD2 and CD28 receptors. The effects of this antibody had parallels with those of TGN1412, and the subject on whom it was tested had become unwell. But nobody could possibly have known that, because these results were never shared with the scientific community. They sat unpublished, unknown, when they could have helped save six men from a terrifying, destructive, avoidable ordeal.
That original researcher could not foresee the specific harm he contributed to, and it's hard to blame him as an individual, because he operated in an academic culture where leaving data unpublished was regarded as completely normal. The same culture exists today. The final report on TGN1412 concluded that sharing the results of all first-in-man studies was essential: they should be published, every last one, as a matter of routine. But phase 1 trial results weren't published then, and they're still not published now. In 2009, for the first time, a study was published looking specifically at how many of these first-in-man trials get published, and how many remain hidden. They took all such trials approved by one ethics committee over a year. After four years, nine out of ten remained unpublished; after eight years, four out of five were still unpublished.
In medicine, as we shall see time and again, research is not abstract: it relates directly to life, death, suffering and pain. With every one of these unpublished studies we are potentially exposed, quite unnecessarily, to another TGN1412. Even a huge international news story, with horrific images of young men brandishing blackened feet and hands from hospital beds, wasn't enough to get movement, because the issue of missing data is too complicated to fit in one sentence.
When we don't share the results of basic research, such as a small first-in-man study, we expose people to unnecessary risks in the future. Was this an extreme case? Is the problem limited to early, experimental, new drugs, in small groups of trial participants?
In the 1980s, U.S. doctors began giving anti-arrhythmic drugs to all patients who'd had a heart attack. This practice made perfect sense on paper: we knew that anti-arrhythmic drugs helped prevent abnormal heart rhythms; we also knew that people who've had a heart attack are quite likely to have abnormal heart rhythms; we also knew that often these went unnoticed, undiagnosed and untreated. Giving anti-arrhythmic drugs to everyone who'd had a heart attack was a simple, sensible preventive measure.
Unfortunately, it turned out that we were wrong. This prescribing practice, with the best of intentions, on the best of principles, actually killed people. And because heart attacks are very common, it killed them in very large numbers: well over 100,000 people died unnecessarily before it was realized that the fine balance between benefit and risk was completely different for patients without a proven abnormal heart rhythm.
Could anyone have predicted this? Sadly, yes, they could have. A trial in 1980 tested a new anti-arrhythmic drug, lorcainide, in a small number of men who'd had a heart attack—less than a hundred—to see if it was any use. Nine out of forty-eight men on lorcainide died, compared with one out of forty-seven on placebo. The drug was early in its development cycle, and not long after this study it was dropped for commercial reasons. Because it wasn't on the market, nobody even thought to publish the trial. The researchers assumed it was an idiosyncrasy of their molecule, and gave it no further thought. If they had published, we would have been much more cautious about trying other anti-arrhythmic drugs on people with heart attacks, and the phenomenal death toll—over 100,000 people in their graves prematurely—might have been stopped sooner. More than a decade later, the researchers finally did publish their results, with a mea culpa, recognizing the harm they had done by not sharing them earlier:
When we carried out our study in 1980, we thought that the increased death rate that occurred in the lorcainide group was an effect of chance. The development of lorcainide was abandoned for commercial reasons, and this study was therefore never published; it is now a good example of 'publication bias'. The results described here might have provided an early warning of trouble ahead.10
As we shall shortly see, this problem of unpublished data is widespread throughout medicine, and indeed the whole of academia, even though the scale of the problem, and the harm it causes, have been documented beyond any doubt. We will see stories on basic cancer research, Tamiflu, cholesterol blockbusters, obesity drugs, antidepressants and more, with evidence that goes from the dawn of medicine to the present day, and data that is still being withheld, right now, as I write, on widely used drugs which many of you reading this book will have taken this morning. We will also see how regulators and academic bodies have repeatedly failed to address the problem.
Because researchers are free to bury any result they please, patients are exposed to harm on a staggering scale throughout the whole of medicine, from research to practice. Doctors can have no idea about the true effects of the treatments they give. Does this drug really work best, or have I simply been deprived of half the data? Nobody can tell. Is this expensive drug worth the money, or have the data simply been massaged? No one can tell. Will this drug kill patients? Is there any evidence that it's dangerous? No one can tell.
This is a bizarre situation to arise in medicine, a discipline where everything is supposed to be based on evidence, and where everyday practice is bound up in medico-legal anxiety. In one of the most regulated corners of human conduct we've taken our eyes off the ball, and allowed the evidence driving practice to be polluted and distorted. It seems unimaginable. We will now see how deep this problem goes.
Why we summarize data
Missing data has been studied extensively in medicine. But before I lay out that evidence, we need to understand exactly why it matters, from a scientific perspective. And for that we need to understand systematic reviews and "meta-analysis." Between them, these are two of the most powerful ideas in modern medicine. They are incredibly simple, but they were invented shockingly late.
When we want to find out if something works or not, we do a trial. This is a very simple process, and the first recorded attempt at some kind of trial was in the Bible (Daniel 1:12, if you're interested). First, you need an unanswered question: for example, 'Does giving steroids to a woman delivering a premature baby increase the chances of that baby surviving?' Then you find some relevant participants, in this case, mothers about to deliver a premature baby. You'll need a reasonable number of them, let's say two hundred for this trial. Then you divide them into two groups at random, give the mothers in one group the current best treatment (whatever that is in your town), while the mothers in the other group get current best treatment plus some steroids. Finally, when all two hundred women have gone through your trial, you count up how many babies survived in each group.
This is a real-world question, and lots of trials were done on this topic, starting from 1972 onwards: two trials showed that steroids saved lives, but five showed no significant benefit. Now, you will often hear that doctors disagree when the evidence is mixed, and this is exactly that kind of situation. A doctor with a strong pre-existing belief that steroids work—perhaps preoccupied with some theoretical molecular mechanism, by which the drug might do something useful in the body—could come along and say: "Look at these two positive trials! Of course we must give steroids!" A doctor with a strong prior intuition that steroids were rubbish might point at the five negative trials and say: "Overall the evidence shows no benefit. Why take a risk?"
Up until very recently, this was basically how medicine progressed. People would write long, languorous review articles—essays surveying the literature—in which they would cite the trial data they'd come across in a completely unsystematic fashion, often reflecting their own prejudices and values. Then, in the 1980s, people began to do something called a "systematic review". This is a clear, systematic survey of the literature, with the intention of getting all the trial data you can possibly find on one topic, without being biased towards any particular set of findings. In a systematic review, you describe exactly how you looked for data: which databases you searched, which search engines and indexes you used, even what words you searched for. You pre-specify the kinds of studies that can be included in your review, and then you present everything you've found, including the papers you rejected, with an explanation of why. By doing this, you ensure that your methods are fully transparent, replicable and open to criticism, providing the reader with a clear and complete picture of the evidence. It may sound like a simple idea, but systematic reviews are extremely rare outside clinical medicine, and are quietly one of the most important and transgressive ideas of the past forty years.
When you've got all the trial data in one place, you can conduct something called a meta-analysis, where you bring all the results together in one giant spreadsheet, pool all the data and get one single, summary figure, the most accurate summary of all the data on one clinical question. The output of this is called a "blobbogram," and you can see one on the following page, in the logo of the Cochrane Collaboration, a global, non-profit academic organization that has been producing gold-standard reviews of evidence on important questions in medicine since the 1980s.
This blobbogram shows the results of all the trials done on giving steroids to help premature babies survive. Each horizontal line is a trial: if that line is further to the left, then the trial showed steroids were beneficial and saved lives. The central, vertical line is the 'line of no effect': and if the horizontal line of the trial touches the line of no effect, then that trial showed no statistically significant benefit. Some trials are represented by longer horizontal lines: these were smaller trials, with fewer participants, which means they are prone to more error, so the estimate of the benefit has more uncertainty, and therefore the horizontal line is longer. Finally, the diamond at the bottom shows the 'summary effect': this is the overall benefit of the intervention, pooling together the results of all the individual trials. These are much narrower than the lines for individual trials, because the estimate is much more accurate: it is summarizing the effect of the drug in many more patients. On this blobbogram you can see—because the diamond is a long way from the line of no effect—that giving steroids is hugely beneficial. In fact, it reduces the chances of a premature baby dying by almost half.
The amazing thing about this blobbogram is that it had to be invented, and this happened very late in medicine's history. For many years we had all the information we needed to know that steroids saved lives, but nobody knew they were effective, because nobody did a systematic review until 1989. As a result, the treatment wasn't given widely, and huge numbers of babies died unnecessarily; not because we didn't have the information, but simply because we didn't synthesize it together properly.
In case you think this is an isolated case, it's worth examining exactly how broken medicine was until frighteningly recent times. The diagram on the following page contains two blobbograms, or "forest plots," showing all the trials ever conducted to see whether giving streptokinase, a clot-busting drug, improves survival in patients who have had a heart attack.
Look first only at the forest plot on the left. This is a conventional forest plot, from an academic journal, so it's a little busier than the stylized one in the Cochrane logo. The principles, however, are exactly the same. Each horizontal line is a trial, and you can see that there is a hodgepodge of results, with some trials showing a benefit (they don't touch the vertical line of no effect, headed '1') and some showing no benefit (they do cross that line). At the bottom, however, you can see the summary effect—a dot on this old-fashioned blobbogram, rather than a diamond. And you can see very clearly that overall, streptokinase saves lives.
So what's that on the right? It's something called a cumulative meta-analysis. If you look at the list of studies on the left of the diagram, you can see that they are arranged in order of date. The cumulative meta-analysis on the right adds in each new trial's results, as they arrived over history, to the previous trials' results. This gives the best possible running estimate, each year, of how the evidence would have looked at that time, if anyone had bothered to do a meta-analysis on all the data available to them. From this cumulative blobbogram you can see that the horizontal lines, the "summary effects", narrow over time as more and more data is collected, and the estimate of the overall benefit of this treatment becomes more accurate. You can also see that these horizontal lines stopped touching the vertical line of no effect a very long time ago—and crucially, they do so a long time before we started giving streptokinase to everyone with a
heart attack.
In case you haven't spotted it for yourself already—to be fair, the entire medical profession was slow to catch on—this chart has devastating implications. Heart attacks are an incredibly common cause of death. We had a treatment that worked, and we had all the information we needed to know that it worked, but once again we didn't bring it together systematically to get that correct answer. Half of the people in those trials at the bottom of the blobbogram were randomly assigned to receive no streptokinase, I think unethically, because we had all the information we needed to know that streptokinase worked: they were deprived of effective treatments. But they weren't alone, because so were most of the rest of the people in the world at the time.
These stories illustrate, I hope, why systematic reviews and meta-analyses are so important: we need to bring together all of the evidence on a question, not just cherry-pick the bits that we stumble upon, or intuitively like the look of. Mercifully the medical profession has come to recognize this over the past couple of decades, and systematic reviews with meta-analyses are now used almost universally, to ensure that we have the most accurate possible summary of all the trials that have been done on a particular medical question.
But these stories also demonstrate why missing trial results are so dangerous. If one researcher or doctor "cherry-picks," when summarizing the existing evidence, and looks only at the trials that support their hunch, then they can produce a misleading picture of the research. That is a problem for that one individual (and for anyone who is unwise or unlucky enough to be influenced by them). But if we are all missing the negative trials, the entire medical and academic community, around the world, then when we pool the evidence to get the best possible view of what works—as we must do—we are all completely misled. We get a misleading impression of the treatment's effectiveness: we incorrectly exaggerate its benefits; or perhaps even find incorrectly that an intervention was beneficial, when in reality it did harm.
Now that you understand the importance of systematic reviews, you can see why missing data matters. But you can also appreciate that when I explain how much trial data is missing, I am giving you a clean overview of the literature, because I will be explaining that evidence using systematic reviews.
How much data is missing?
If you want to prove that trials have been left unpublished, you have an interesting problem: you need to prove the existence of studies you don't have access to. To work around this, people have developed a simple approach: you identify a group of trials you know have been conducted and completed, then check to see if they have been published. Finding a list of completed trials is the tricky part of this job, and to achieve it people have used various strategies: trawling the lists of trials that have been approved by ethics committees (or "institutional review boards" in the USA), for example; or chasing up the trials discussed by researchers at conferences.
In 2008 a group of researchers decided to check for publication of every trial that had ever been reported to the U.S. Food and Drug Administration for all the antidepressants that came onto the market between 1987 and 2004. This was no small task. The FDA archives contain a reasonable amount of information on all the trials that were submitted to the regulator in order to get a license for a new drug. But that's not all the trials, by any means, because those conducted after the drug has come onto the market will not appear there; and the information that is provided by the FDA is hard to search, and often scanty. But it is an important subset of the trials, and more than enough for us to begin exploring how often trials go missing, and why. It's also a representative slice of trials from all the major drug companies.
The researchers found seventy-four studies in total, representing 12,500 patients' worth of data. Thirty-eight of these trials had positive results, and found that the new drug worked; thirty-six were negative. The results were therefore an even split between success and failure for the drugs, in reality. Then the researchers set about looking for these trials in the published academic literature, the material available to doctors and patients. This provided a very different picture. Thirty-seven of the positive trials—all but one—were published in full, often with much fanfare. But the trials with negative results had a very different fate: only three were published. Twenty-two were simply lost to history, never appearing anywhere other than in those dusty, disorganized, thin FDA files. The remaining eleven which had negative results in the FDA summaries did appear in the academic literature, but were written up as if the drug was a success. If you think this sounds absurd, I agree: we will see in Chapter 4, on 'bad trials', how a study's results can be reworked and polished to distort and exaggerate its findings.
This was a remarkable piece of work, spread over twelve drugs from all the major manufacturers, with no stand-out bad guy. It very clearly exposed a broken system: in reality we have thirty-eight positive trials and thirty-seven negative ones; in the academic literature we have forty-eight positive trials and three negative ones. Take a moment to flip back and forth between those in your mind: "thirty-eight positive trials, thirty-seven negative"; or "forty-eight positive trials and only three negative".
If we were talking about one single study, from one single group of researchers, who decided to delete half their results because they didn't give the overall picture they wanted, then we would quite correctly call that act 'research misconduct'. Yet somehow when exactly the same phenomenon occurs, but with whole studies going missing, by the hands of hundreds and thousands of individuals, spread around the world, in both the public and private sector, we accept it as a normal part of life. It passes by, under the watchful eyes of regulators and professional bodies who do nothing, as routine, despite the undeniable impact it has on patients.
Even more strange is this: we've known about the problem of negative studies going missing for almost as long as people have been doing serious science.
This was first formally documented by an American psychologist called Theodore Sterling in 1959. He went through every paper published in the four big psychology journals of the time, and found that 286 out of 294 reported a statistically significant result. This, he explained, was plainly fishy: it couldn't possibly be a fair representation of every study that had been conducted, because if we believed that, we'd have to believe that almost every theory ever tested by a psychologist in an experiment had turned out to be correct. If psychologists really were so great at predicting results, there'd hardly be any point in bothering to run experiments at all. In 1995, at the end of his career, the same researcher came back to the same question, half a lifetime later, and found that almost nothing had changed.
Sterling was the first to put these ideas into a formal academic context, but the basic truth had been recognized for many centuries. Francis Bacon explained in 1620 that we often mislead ourselves by only remembering the times something worked, and forgetting those when it didn't. Dr. Thomas Fowler in 1786 listed the cases he'd seen treated with arsenic, and pointed out that he could have glossed over the failures, as others might be tempted to do, but had included them. To do otherwise, he explained, would have been misleading.
Yet it was only three decades ago that people started to realize that missing trials posed a serious problem for medicine. In 1980 Elina Hemminki found that almost half the trials conducted in the mid-1970s in Finland and Sweden had been left unpublished. Then, in 1986, an American researcher called Robert Simes decided to investigate the trials on a new treatment for ovarian cancer. This was an important study, because it looked at a life-or-death question. Combination chemotherapy for this kind of cancer has very tough side effects, and knowing this, many researchers had hoped it might be better to give a single "alkylating agent" drug first, before moving on to full chemotherapy. Simes looked at all the trials published on this question in the academic literature, read by doctors and academics. From this, giving a single drug first looked like a great idea: women with advanced ovarian cancer (which is not a good diagnosis to have) who were on the alkylating agent alone were significantly more likely to survive longer.
Then Simes had a smart idea. He knew that sometimes trials can go unpublished, and he had heard that papers with less 'exciting' results are the most likely to go missing. To prove that this has happened, though, is a tricky business: you need to find a fair, representative sample of all the trials that have been conducted, and then compare their results with the smaller pool of trials that have been published, to see if there are any embarrassing differences. There was no easy way to get this information from the medicines regulator (we will discuss this problem in some detail later), so instead he went to the International Cancer Research Data Bank. This contained a register of interesting trials that were happening in the USA, including most of the ones funded by the government, and many others from around the world. It was by no means a complete list, but it did have one crucial feature: the trials were registered before their results came in, so any list compiled from this source would be, if not complete, at least a representative sample of all the research that had ever been done, and not biased by whether their results were positive or negative.
When Simes compared the results of the published trials against the pre-registered trials, the results were disturbing. Looking at the academic literature—the studies that researchers and journal editors chose to publish—alkylating agents alone looked like a great idea, reducing the rate of death from advanced ovarian cancer significantly. But when you looked only at the pre-registered trials—the unbiased, fair sample of all the trials ever conducted—the new treatment was no better than old-fashioned chemotherapy.
Simes immediately recognized—as I hope you will too—that the question of whether one form of cancer treatment is better than another was small fry compared to the depth charge he was about to set off in the medical literature. Everything we thought we knew about whether treatments worked or not was probably distorted, to an extent that might be hard to measure, but that would certainly have a major impact on patient care. We were seeing the positive results, and missing the negative ones. There was one clear thing we should do about this: start a registry of all clinical trials, demand that people register their study before they start, and insist that they publish the results at the end.
That was 1986. Since then, a generation later, we have done very badly. In this book, I promise I won't overwhelm you with data. But at the same time, I don't want any drug company, or government regulator, or professional body, or anyone who doubts this whole story, to have any room to wriggle. So I'll now go through all the evidence on missing trials, as briefly as possible, showing the main approaches that have been used. All of what you are about to read comes from the most current systematic reviews on the subject, so you can be sure that it is a fair and unbiased summary of the results.
One research approach is to get all the trials that a medicines regulator has record of, from the very early ones done for the purposes of getting a license for a new drug, and then check to see if they all appear in the academic literature. That's the method we saw used in the paper mentioned above, where researchers sought out every paper on twelve antidepressants, and found that a 50/50 split of positive and negative results turned into forty-eight positive papers and just three negative ones. This method has been used extensively in several different areas of medicine:
- Lee and colleagues, for example, looked for all of the 909 trials submitted alongside marketing applications for all ninety new drugs that came onto the market from 2001 to 2002: they found that 66 per cent of the trials with significant results were published, compared with only 36 per cent of the rest.
- Melander, in 2003, looked for all forty-two trials on five antidepressants that were submitted to the Swedish drug regulator in the process of getting a marketing authorization: all twenty-one studies with significant results were published; only 81 percent of those finding no benefit were published.
- Rising et al., in 2008, found more of those distorted write-ups that we'll be dissecting later: they looked for all trials on two years' worth of approved drugs. In the FDA's summary of the results, once those could be found, there were 164 trials. Those with favorable outcomes were a full four times more likely to be published in academic papers than those with negative outcomes. On top of that, four of the trials with negative outcomes changed, once they appeared in the academic literature, to favor the drug.
If you prefer, you can look at conference presentations: a huge amount of research gets presented at conferences, but our current best estimate is that only about half of it ever appears in the academic literature. Studies presented only at conferences are almost impossible to find, or cite, and are especially hard to assess, because so little information is available on the specific methods used in the research (often as little as a paragraph). And as you will see shortly, not every trial is a fair test of a treatment. Some can be biased by design, so these details matter.
The most recent systematic review of studies looking at what happens to conference papers was done in 2010, and it found thirty separate studies looking at whether negative conference presentations—in fields as diverse as an aesthetics, cystic fibrosis, oncology, and A&E—disappear before becoming fully fledged academic papers. Overwhelmingly, unflattering results are much more likely to go missing.
If you're very lucky, you can track down a list of trials whose existence was publicly recorded before they were started, perhaps on a register that was set up to explore that very question. From the pharmaceutical industry, up until very recently, you'd be very lucky to find such a list in the public domain. For publicly funded research the story is a little different, and here we start to learn a new lesson: although the vast majority of trials are conducted by the industry, with the result that they set the tone for the community, this phenomenon is not limited to the commercial sector.
- By 1997 there were already four studies in a systematic review on this approach. They found that studies with significant results were two and a half times more likely to get published than those without.
- A paper from 1998 looked at all trials from two groups of trialists sponsored by the U.S. National Institutes of Health over the preceding ten years, and found, again, that studies with significant results were more likely to be published.
- Another looked at drug trials notified to the Finnish National Agency, and found that 47 per cent of the positive results were published, but only 11 per cent of the negative ones.
- Another looked at all the trials that had passed through the pharmacy department of an eye hospital since 1963: 93 per cent of the significant results were published, but only 70 per cent of the negative ones.
The point being made in this blizzard of data is simple: this is not an under-researched area; the evidence has been with U.S. for a long time, and it is neither contradictory nor ambiguous.
Two French studies in 2005 and 2006 took a new approach: they went to ethics committees, and got lists of all the studies they had approved, and then found out from the investigators whether the trials had produced positive or negative results, before finally tracking down the published academic papers. The first study found that significant results were twice as likely to be published; the second that they were four times as likely. In Britain, two researchers sent a questionnaire to all the lead investigators on 101 projects paid for by NHS R&D: it's not industry research, but it's worth noting anyway. This produced an unusual result: there was no statistically significant difference in the publication rates of positive and negative papers.
But it's not enough simply to list studies. Systematically taking all the evidence that we have so far, what do we see overall?
It's not ideal to lump every study of this type together in one giant spreadsheet, to produce a summary figure on publication bias, because they are all very different, in different fields, with different methods. This is a concern in many meta-analyses (though it shouldn't be overstated: if there are lots of trials comparing one treatment against placebo, say, and they're all using the same outcome measurement, then you might be fine just lumping them all in together).
But you can reasonably put some of these studies together in groups. The most current systematic review on publication bias, from 2010, from which the examples above are taken, draws together the evidence from various fields. Twelve comparable studies follow up conference presentations, and taken together they find that a study with a significant finding is 1.62 times more likely to be published. For the four studies taking lists of trials from before they started, overall, significant results were 2.4 times more likely to be published. Those are our best estimates of the scale of the problem. They are current, and they are damning.
All of this missing data is not simply an abstract academic matter: in the real world of medicine, published evidence is used to make treatment decisions. This problem goes to the core of everything that doctors do, so it's worth considering in some detail what impact it has on medical practice. First, as we saw in the case of reboxetine, doctors and patients are misled about the effects of the medicines they use, and can end up making decisions that cause avoidable suffering, or even death. We might also choose unnecessarily expensive treatments, having been misled into thinking they are more effective than cheaper older drugs. This wastes money, ultimately depriving patients of other treatments, since funding for health care is never infinite.
It's also worth being clear that this data is withheld from everyone in medicine, from top to bottom. Most countries have organizations to create careful, unbiased summaries of all the evidence on new treatments to determine whether they are cost effective. In the UK the organization is called NICE (the National Institute for Health and Clinical Excellence); in Germany it is called IQWiG, while in the U.S. insurers may make their own assessments. But these organizations are unable either to identify or to access data that has been withheld by researchers or companies on a drug's effectiveness; they have no more legal right to that data than you or I do. In fact, as we shall see, some regulators, despite having access to this information, have refused to share it with the public or doctors. Others have hidden the information they hold behind walls of chaos. This is an extraordinary and perverse situation.
So, while doctors are kept in the dark, patients are exposed to inferior treatments, ineffective treatments, unnecessary treatments, and unnecessarily expensive treatments that are no better than cheap ones; governments pay for unnecessarily expensive treatments, and mop up the cost of harms created by inadequate or harmful treatment; and individual participants in trials, such as those in the TGN1412 study, are exposed to terrifying, life-threatening ordeals, resulting in lifelong scars, again quite unnecessarily.
At the same time, the whole of the research project in medicine is retarded, as vital negative results are held back from those who could use them. This affects everyone, but it is especially egregious in the world of "orphan diseases," medical problems that affect only small numbers of patients, because these corners of medicine are already short of resources, and are neglected by the research departments of most drug companies, since the opportunities for revenue are thinner. People working on orphan diseases will often research existing drugs that have been tried and failed in other conditions, but that have theoretical potential for the orphan disease. If the data from earlier work on these drugs in other diseases is missing, then the job of researching them for the orphan disease is both harder and more dangerous: perhaps they have already been shown to have benefits or effects that would help accelerate research; perhaps they have already been shown to be actively harmful when used on other diseases, and there are important safety signals that would help protect future research participants from harm. Nobody can tell you.
Finally, and perhaps most shamefully, when we allow unflattering data to go unpublished, we betray the patients who participated in these studies: the people who have given their bodies, and sometimes their lives, in the implicit belief that they are doing something to create new knowledge, that will benefit others in the same position as them in the future. In fact, their belief is not implicit: often it's exactly what we tell them, as researchers, and it is a lie, because the data might be withheld, and we know it.


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Want to celebrate Earth Day in your gluten free cooking? Here are a few ways you can use less energy:
1. Boiling eggs.
Bring your water to a boil, add your eggs and allow the water to come back to a boil. Then turn off your burner. Let the eggs sit for about 10 minutes and you will have perfectly boiled eggs without using your burner for the whole cooking period. You can use the same technique for some gluten free rice pastas, rice & potatoes.
2. Letting bread rise the old fashioned way.
To quick rise a yeast bread, we turn on the oven and turn it off and then allow bread to rise in the hot oven for about 30-40 minutes. This is a great method when you're short on time... but if you want to do it the old fashioned way, just let it rise on the counter. If it's not super warm in your house this can take several hours, but I think it makes a better tasting bread because the yeast develops more slowly and you don't use the energy from your oven to let it rise.
3. Use homemade cleaners for countertops and glass stovetops.
My husband makes a cleaner from about 1/4 cup vinegar, 1 tbsp. earth-friendly dish detergent, and fills up the rest of the spray bottle with water. We use this to clean counters, bathtubs, sinks, windows, etc... it works great. If I have something that needs to be scrubbed we add baking soda. Works like a charm. Green & cheap.
4. Plan ahead and use your crockpot instead of your oven.
Your crockpot uses less energy and doesn't heat up the area surrounding it (like heating up your whole kitchen) to cook something. Cooking with your crockpot can also save you time and money! :-) Both good reasons to give it a try!
5. Shop locally & eat seasonally.
Know of a local farm or CSA that you can buy fresh vegetables, eggs, chicken, or meat from? Check out Local Harvest to find a farm that has community supported agriculture shares, fresh eggs, meats, handmade soaps, jams & jellies, etc... You will be eating foods that are fresh, local, usually organic, and you will save energy by not purchasing products that come from a long distance and use lots of fuel to get to your grocery store.
6. Check out all these ways to save energy in your kitchen this week:
What ways do you try to save energy when you're cooking?


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ESV1200 5 Year WarrantyESV1200-5
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Protect your investment with our new Extended Limited Warranty available for select Good-Lite products listed below. Available in a three or five-year plan, the Limited Warranty covers any defects in material or workmanship under normal use during the warranty period. During this period, the Good-Lite Co. will repair or replace, at no charge, products or parts of a product that proves defective because of improper material or workmanship, under normal use and maintenance.


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Used Motor Vehicle Dealer Educational Seminar Requirements
- Who should attend a Dealer Educational Seminar?
- How do I become an approved Dealer Educational Seminar provider?
- What are the requirements after I become an approved Dealer Educational Seminar provider?
- Who are the approved providers of Dealer Educational Seminars?
Who should attend a Dealer Educational Seminar?
Senate Bill 747 requires all used motor vehicle dealers applying for a motor vehicle dealer's license for the first time on or after August 28, 2006, to provide proof of attending a Dealer Educational Seminar approved by the Department of Revenue (department).
Used motor vehicle dealers applying for a license for the first time are exempt from the seminar requirement if they currently hold a new or used dealer license for a separate dealership.
The following dealer types are exempt from the Dealer Educational Seminar requirement:
- Used motor vehicle dealers licensed prior to August 28, 2006;
- New motor vehicle franchise dealers;
- New franchise powersport dealers;
- Wholesale dealers; and
- Wholesale and retail auto auctions.
A Dealer Educational Seminar will include, but is not limited to, the dealer licensing requirements of Sections 301.550 to 301.573 RSMo, the rules promulgated to implement, enforce, and administer these sections and any other rules and regulation promulgated by the department.
If you are required to attend a Dealer Educational Seminar, you must have attended an approved seminar within the last twelve months of applying for the dealer license. A certificate of Dealer Educational Seminar completion, issued by the seminar provider in the dealership name, must be attached to the Application for Dealer, Auction, or Manufacturer License and Number Plates(s) (Form 4682) when submitted to the department.
How do I become an approved Dealer Educational Seminar provider?
Complete an Application for Dealer Educational Seminar Certification (Form 5110). Application is free. Submit the completed and signed application to the address on the form. Applicants are not required to submit any further information on the seminar other than the Form 5510.
What are the requirements after I become an approved Dealer Educational Seminar provider?
After you have been approved to be a Dealer Educational Seminar provider, you may begin providing dealer educational seminars. The Dealer Educational Seminar must include the topics listed on the Form 5510, which include but are not limited to, dealer requirements of Sections 301.550 to 301.573 RSMo, and the rules promulgated to implement, enforce and administer these sections.
All approved Dealer Educational Seminar providers will be added to the department's website of approved providers with a link to the provider's website.
Dealer Educational Seminar providers are required to issue a certificate of seminar completion in the name of the potential dealership. The certificate should not be issued in the individual attendee's name. The provider must maintain copies of the certificates for 12 months.
Dealer Educational Seminar providers must also electronically submit an Excel file with the names of the dealerships that have completed the seminar. The spreadsheet must contain the date of seminar completion and be emailed to the department within five working days of the dealership's completion of the seminar. The file must be emailed to firstname.lastname@example.com.
Dealer Educational Seminar providers are required to recertify each year by submitting a new Application for Dealer Educational Seminar Certification to the department by September 1.
Certification of the Dealer Educational Seminar can be canceled if the department receives complaints or becomes aware that the seminar does not comply with all the requirements of the certification.


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France's New Law: Control Immigration Flows, Court the Highly Skilled
France's new immigration and integration law, adopted on July 25, 2006, aims to overhaul France's immigration system by giving the government new powers to encourage high-skilled migration, fight illegal migration more effectively, and restrict family immigration.
Although the new law does not take effect until early 2007, one of its pillars is already making itself felt. The number of people deported for not having the required documents reached nearly 13,000 by the end of July 2006, more than halfway to the Interior Ministry's 2006 goal of 25,000, inciting protests from tens of thousands of French citizens.
The unrest illustrates that France will not have an easy transition to a selective immigration system that 1) emphasizes employment-driven immigration at the expense of the 113,000 immigrants who arrive in France annually for family-related reasons and 2) that carries out a robust campaign against illegal migration.
Political Context and Debate
After years of debate, Nicolas Sarkozy, France's interior minister and leading presidential contender for the 2007 election, succeeded in passing a law that he argues will finally allow the government to control immigration. Addressing fellow government officials in July, Sarkozy argued that "selective immigration … is the expression of France's sovereignty. It is the right of our country, like all the great democracies of the world, to choose which foreigners it allows to reside on our territory."
However, immigrant rights organizations, African leaders, and many French citizens have criticized the law's limits on family reunification and its greater stringency in giving legal status to illegally resident immigrants. Politicians in France were not always in agreement either: The bill underwent over 300 amendments in the National Assembly and Senate before finally being passed.
Nevertheless, most policymakers agreed that France's immigration system is failing. Sarkozy argues that the failure can be traced to 1974, when migration inflows shifted from being worker-dominated to family dominated. The oil price shocks and resultant high unemployment in the early 1970s caused France to stop recruiting immigrant workers, yet migrants continued to enter France in large numbers to rejoin family members.
Today, family reunification accounts for nearly 65 percent of immigration to France — a major reason that the government wants to gain control over the numbers and types of migrants coming to the country (see Figure 1). Furthermore, the number of unauthorized migrants—an estimated 200,000 to 400,000 — fuels concerns over the rise in poverty, unemployment (8.9 percent), and social tensions.
As last fall's riots in the Paris suburbs illustrated, France has fallen short in its efforts to integrate its immigrants and their children, many of whom are French by birthright. More controlled migration, Sarkozy argues, will lead to better integration of migrants.
Finally, France is well-aware that it must compete with other global players for international talent. Countries such as Canada, the United Kingdom, and Australia all actively recruit migrants and select them according to criteria that range from education and language skills to adaptability and age.
The July 24, 2006, Law
The new immigration and integration law has four main objectives:
- recruiting skilled workers;
- facilitating foreign students' stay;
- tightening the rules on family reunification; and
- limiting access to residence and citizenship.
Recruiting skilled workers
The new law authorizes the government to identify particular professions and geographic zones of France that are "characterized by recruitment difficulties." For those identified employers, the government plans to facilitate the recruitment of immigrant workers with needed skills or qualifications. However, this means employers who are not on the government-selected list may have more difficulty (or may face longer waiting periods) obtaining residence permits for migrant workers they wish to employ.
Under the new law, foreigners who possess skill sets of interest to French employers in the designated areas will be granted "skills and talents" visas, valid for three years. In a uniquely French twist, eligible candidates must be able to demonstrate that they will contribute to the economic or intellectual and cultural development of both France and their country of origin.
The new law's emphasis on "skills and talents" has already created tensions with those who are concerned that it will negatively impact developing countries, whose highest-skilled nationals will likely seek to emigrate.
In an attempt to ease fears about "brain drain," the government will only issue this visa to qualified immigrants from a developing country if the sending country has signed a "co-development" agreement with France or if the immigrants in question agree to return to their country of origin within six years. By doing so, the government aims to reframe the issue about the loss of some of sending countries' most skilled nationals by emphasizing the "circulation of skills."
Facilitating foreign students' stay
In addition to high-skilled workers, foreign students seeking to stay on in France after they complete their studies will also benefit from the new law by being given greater opportunities to do so.
With the new law, the government hopes to continue to attract foreign students coming to France to pursue higher education. Already, their numbers are growing. Between 2001 and 2003, the number of foreign students increased by 50 percent — a significantly larger increase than that which occurred in Italy, Germany, the United Kingdom, or the United States (see Figure 2).
During the 2004-2005 academic year, France admitted approximately 250,000 foreign students (in "degree/diploma track courses"), according to the Embassy of France in the United States. The French government reports that about half of France's foreign students come from francophone Africa.
The new law would require foreign students to receive approval to study in France from their country of origin. Once in France, foreign students who receive a masters or higher degree would be allowed to pursue a "first professional experience" that contributes to the economic development of both France and the student's country of origin. The student will be granted a six-month renewable visa to look for and take up work in France.
Tightening the rules on family reunification
The government's objective in modifying family reunification policy is three-fold: to ensure that immigrants respect French values, to promote their integration into French society, and to fight forced or polygamous marriages.
According to the president, the new law better defines conditions for family reunification. Accordingly, a family member of an immigrant who does not respect the basic principles of family life in France (recognition of the secular state, equality between a man and a woman, and monogamy) will not be allowed to enter France. Furthermore, an immigrant must now wait 18 months, instead of 12, to apply to bring a family member to France.
In an effort to prevent immigrant families from becoming dependent on France's welfare system, the law also requires immigrants to prove they can independently support all family members who seek to come to France. Specifically, they must earn at least the French minimum wage and not be reliant on assistance from the French state. Access to government assistance is also limited to European Union citizens. Those who reside in France longer than three months without working or studying must be able to support themselves without relying on social or medical benefits from the French government.
Another modification to the family reunification policy is that spouses of French citizens must wait three years (instead of two) before applying for a 10-year residence permit. Four years of marriage are required for the spouse of a French citizen to apply for French citizenship. Finally, an immigrant found to be practicing polygamy can have his or her visa revoked.
Limiting access to residence and citizenship
Sarkozy argued that the previous (1998) law "rewarded" immigrants who broke the law by offering them legal status after being residents for 10 years. The new law changes this by simplifying the procedure whereby the government can directly deport unauthorized migrants who are refused the right to stay in France.
Key exceptions were made for some illegal immigrants this summer when public outrage erupted over the deportation of immigrant families with school-aged children. In order to avoid deportation, these immigrants had to meet several criteria, including having a child enrolled in the French school system and demonstrating a "real will" to integrate.
Still, out of the 30,000 people who applied for regularization, less than 7,000 were granted legal status by mid-September 2006. Illegally resident immigrants who disturb the "public order" would also be vulnerable to deportation — a measure Sarkozy deems necessary to fight "delinquency" among foreigners.
Access to both citizenship and legal residence is dependent on the newly defined requirements of integration. For the first time in French history, a law explicitly states the integration responsibilities of immigrants.
Specifically, immigrants must sign a "welcome and integration" contract and take French language and civic courses. Before applying for permanent residence, immigrants must accordingly prove that they are "well-integrated" into French society. The government understands integration in this regard to mean that the immigrant respects and complies with the principles of the French Republic and has a sufficient knowledge of the French language.
Toward a Selective Migration System
As the French government prepared to pass the immigration and integration law in June, the Minister of Town and Country Planning, Christian Estrosi, appealed to fellow policymakers: "After 30 years of renunciation and blindness in front of the crucial challenge of immigration, after 30 years of uncertainty and non-choice, the moment has come to act!"
Bennhold, Katrin Bennhold (2006). "Sarkozy shores up support." International Herald Tribune, September 3.
EU Observer (2006). "Migrants keep coming as EU seeks new border plans." September 4.
Embassy of France. "Studying in France (a few facts on...)" Available online
Expatica (2006). "France to amnesty 7,000 immigrant families." September 18.
Jamet, S (2006). "Improving Labor Market Performance in France." OECD Working Papers, No. 504.
Journal Officiel de la Republique francaise: Article 6, Chapter 1 of Lois nº 2006-911 du 24 juillet 2006.
Communique du Conseil des ministres du President de la Republique, March 29, 2006.
Journal Officiel de la Republique francaise: Article 18, Chapter 3 of Lois nº 2006-911 du 24 juillet 2006.
Journal Officiel de la Republique francaise: Chapter 5 of Lois nº 2006-911 du 24 juillet 2006.
La vie publique: loi du 24 juillet 2006 relative à l'immigration et à l'intégration (La documentation française).
Migration News (2006). "France, Germany, Benelux." Vol. 13, No. 3. UC Davis, July. Available online
Ministry of Foreign Affairs, France. "Welcoming foreign students to France — some figures."
Ministry of the Interior, Intervention de M. Nicolas Sarkozy, press conference, July 24, 2006.
Ministry of the Interior: Vote du projet de loi relative à l'immigration et à l'intégration, June 30, 2006.
INSEE, August 2006.
Ministry of the Interior, Intervention de M. Nicolas Sarkozy, July 24, 2006.
OECD International Migration Outlook 2006 (data approximated from 2004). UMP: Les grands discours, Nicolas Sarkozy à l'Assemblée nationale, June 9, 2005.


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If you've uttered this phrase yourself, I'm sure that your intentions were good, but let me explain why this expression is, more often than not, unwelcome. Savor every moment you say? How exactly does one savor the sleepless nights, inconsolable crying, postpartum recovery, breastfeeding pains, and emotional roller coasters of new motherhood? For the first 6 weeks, the baby doesn't even smile back at you! Talk about being emotionally and physically drained.
By telling a new mother to "savor every moment," you are more likely than not telling an already overwhelmed new mother one more thing she is doing wrong! Because, I can assure you that she is more concerned about diapers, feeding, naps, and bathing than savoring every moment...let alone savoring a couple of minutes to herself.
Now, I understand that your intentions are good. You want this new mother to savor the everyday moments. The moments that we so easily take for granted. One of my favorite takeaways from parenting magazines and blogs is that you never know when a milestone will end...the last bath in the sink, the last midnight feeding, the last swaddle. One moment you think you will be stuck on the couch for eternity with a baby stuck to your breast and the next he begs for the bottle instead of begging for you.
So, new moms, if someone tells you to "savor every moment," rest assured that her intentions are good. She doesn't want you to miss out on the every day moments. She wants you to relish when your baby falls asleep in your arms, squeals with joy when you come home from work, or drags his favorite stuffed animal over to you for a cuddle. Those moments might seem few and far between, but when they occur, savor them. Take mental photos. Pause. Because one day, without warning, they will stop. And those moments are gone forever.
If you know a new mother, I challenge you to point these moments out...for she may be so sleep deprived and overwhelmed to fully comprehend them: "Look at him. He just loves knocking down block towers!" "Her coo is adorable. I've never heard a baby 'chat' with her mother so energetically at such a young age. What a sweetheart!"
It is by savoring these moments that we new mothers can get through the fevers, teething, ER visits, and other not so joyful moments of parenting.


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Wolf outdoor gas grills use two types of heat, direct and radiant, to achieve the ideal temperature range and uniform heat distribution that are the keys to flawless grilling. Direct heat from the gas burners delivers high, searing temperatures (via a total of 130,000 Btu on the 54" model) and rapid preheating, while radiant heat sources distribute temperatures evenly.
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text: To celebrate the re-release of the AUTO-CINEMATIC VIDEO MIX TAPE, Peripheral Produce is happy to announce a full bore experimental film blow out at the historic Hollywood Theatre. Highlighting the work of local filmmakers made over the past 20 years, the show is both a celebration and retrospective of Portland's energetic film community. Featured artists include Miranda July, Vanessa Renwick, Andrew Blubaugh, Jon Raymond, Orland Nutt, Ashby Lee Collinson, Jim Blashfield, Chel White, Karl Lind, Matt McCormick, and many many more. The show show is one night only, 8:00PM Saturday August 4th. Tickets and additional information can be found here.


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a friend...6:35 AM Tuesday, May 29, 2007
... hears the song in my heart, and sings it to me when my memory fails. (Anonymous)
My second confinement for this month (acute gastroenteritis) which lasted for some 5 days found me in the lowest of lows. I was just too tired and feeling too dumb and helpless. The fact that I actually got sick enough to require confinement (which I may not have needed had I not been pregnant) was just too much to bear, along with the guilt over the expense, my capacity as a mother, the safety of my unbonr, and the burden I was putting on my husband.
It was just too much. I literally cried and cried buckets because there was nothing else I could do. I was just tired. And I was ready to give up... the old usual escape of wishing I could just curl up and die was too tempting.
I'm going to sound overly redundant but really, I was just too tired.
Then my friend Jaejay pays me a visit in the hospital. He wanted to bring me his pasalubongs from the US, push incentives really: a Discovery Channel documentary on the Human Body, a 2-gig hi-speed SD card for my cam (for taking lots of pics once my little one is out) and an I Hope You Dance Journal.
He was a friend I met over the net around some four years ago... we've seen each other about once or twice a year at most. We mainly chat or e-mail each other... or text. He was one of two friends who went to Pyro's wake to console me, and condole with my family. And he remembered how touched I was before when a friend shared with me the inspirational song I blogged about.
He reminded me to dance. And as if woken from a dream, I slowly got myself together enough to express myself better and get my significant others to really be able to help me.
Jaejay heard the song in my heart... and sang it to me when my memory failed. Hopefully, I don't fail him and really keep on dancing this time.
For the mp3 of the song, click here.
Labski, hope you're finding Texas a lot friendlier and rewarding the second time around. And that you'd get yourself a date for that something you've already bought tickets for. Mwah!
One other thing that greatly humbled me while I was at the labor room, having my contractions monitored lest they really trigger premature labor, was the fact that during the time Py was sick, all of us who loved him dearly wished we could suffer the cancer in his stead. It's still heartbreaking to think of all those times he had to be poked and prodded and tampered with just so he can be saved...
And I thought then... my illness and the pregnancy discomforts that had me so compromised the past months are still nothing compared to what he had to go thru. And I had a chance to do for my baby what his mother couldn't do for him. I could take better care of myself, and I could suffer the confinement, just so I could save my baby.
I also thought then... that maybe this is some kind of life deposit I was making. Suffering now would spare my child. Or at least teach me important lessons i'd need to be a better parent.
But then, depression struck me... and it was only after being able to bounce back that I realized how Py still has much to teach me. I wrote in my IHYDJ (I hope you dance journal):
"Pyro kept dancing till the end, despite the tears and the trauma, he didn't stop being a child, he didn't lose his sense of wonder. Even his morose, whimpering attitude on his last few days don't seem to me as if he stopped dancing. I know he was just sad he couldn't dance to the beat we wanted anymore."
I face more trials and challenges and stumbling blocks and unknowns... I vow to dance around and over them to get to the opportunities and rewards and bliss.
addendum: June 01, 2007
Around a month before we found out Py was sick, I blogged about dancing with him. I was reminded of that entry by MommyBa's comment about how Py is still dancing with me.


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Recipe by: Vegan Handbook
Servings: 4
one 10.5 oz package lite silken tofu
1/3 C natural no sugar added strawberry jam
1 tsp vanilla extract
8 fresh ripe figs
– In blender or food processor, combine tofu, jam, and vanilla until smooth. Refrigerate 1 hour.
– When ready to serve, split figs and place on dessert dishes. Top with chilled cream.


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I'll bet you think that the earthworm is only good for fishbait. Well, think again. The earthworm is one of nature's top "soil scientists." The earthworm is responsible for a lot of the things that help make our soil good enough to grow healthy plants and provide us food.
Worms help to increase the amount of air and water that gets into the soil. They break down organic matter, like leaves and grass into things that plants can use. When they eat, they leave behind castings that are a very valuable type of fertilizer.
Earthworms are like free farm help. They help to "turn" the soilbringing down organic matter from the top and mixing it with the soil below. Another interesting job that the worm has is that of making fertilizer. If there are 500,000 worms living in an acre of soil, they could make 50 tons of castings. That's like lining up 100,000 one pound coffee cans filled with castings. These same 500,000 worms burrowing into an acre of soil can create a drainage system equal to 2,000 feet of 6-inch pipe. Pretty amazing for just a little old worm, don't you think?
Having worms around in your garden is a real good sign that you have a healthy soil.


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GoldCore offices are closed this Friday and Monday, March 29th and April 1st, for the Irish national holidays of Easter.
Today's AM fix was USD 1,602.50, EUR 1,253.13 and GBP 1,057.41 per ounce.
Yesterday's AM fix was USD 1,591.00, EUR 1,243.75 and GBP 1,052.39 per ounce.
Silver is trading at $28.60/oz, €22.44/oz and £18.97/oz. Platinum is trading at $1,583.00/oz, palladium at $768.00/oz and rhodium at $1,200/oz.
Spot gold and silver closed at $1,606.40/oz and $28.79/oz.
Precious Metals and Currencies Table – (Bloomberg)
Gold continues to consolidate above $1,600 an ounce today supported by widespread concerns that the expropriation of Cyprus deposits could become a blueprint for solving banking crises in the Eurozone.
This is increasing gold's safe haven appeal and will continue to do so in the coming months. As will the real risk of deepening financial instability in the euro zone stoked by the crisis in Cyprus where hundreds of anxious depositors are withdrawing as much of their savings as they can after their banks reopened.
Depositors in Luxembourg, Slovenia, Spain, Italy, Portugal and Ireland will be made more nervous by the scenes of queues outside banks in Cyprus today.
Gold is on track for a 1.6% gain in March, its first monthly rise in six.
For the quarter, gold is 4.3% lower in dollar terms and 1.4% lower in euros. However, signalling that the demise of gold is greatly exaggerated, gold is 3.7% higher in Japanese yen and 2.6% higher in sterling.
Gold in USD, YTD – (Bloomberg)
The quarter or year to date charts suggest that gold is consolidating and given that the major fiscal, financial and monetary challenges that continue to face the EU and all major economies, we continue to be believe gold remains in a secular bull market.
Currency debasement is set to continue and this allied to the risk of wealth confiscation makes physical bullion a vital asset to own.
Gold in Sterling, YTD – (Bloomberg)
GoldCore have been very busy on the sell side in recent weeks which suggests we are close to a bottom. This week was the first week in three where there were more buyers than sellers.
There were a lot of new account openings after the Cyprus crisis began and in recent days, particularly from Spain and Italy, but there have been no huge flows into gold and nothing on the scale of the Lehman panic.
There are real and growing concerns out there among the European public but as of yet the mass of retail and savers and investors are not concerned enough or more likely not aware enough to diversify into gold.
Gold in Euros, YTD – (Bloomberg)
Whoever thought we'd see the issue of safety of deposits come into question?
We did. Since the Lehman Brothers debacle and near collapse of the world's financial system, we said that there was a possibility that what happened in Argentina and Russia – capital controls including deposit withdrawal restrictions and other draconian measures- would likely be seen in massively indebted periphery nations.
However, we thought such regressive moves would come from misguided and desperate national governments – not from supranational organisations such as the EU and the IMF and from the ECB.
We believe that growing awareness of the risk for individuals and businesses of keeping all their savings and capital in deposit accounts and a gradual realisation of the importance of diversification will lead to significant capital flows into gold.
As one astute financial journalist said to me " 'cash in the bank' doesn't have quite the same ring to it anymore."
In most European countries, except for Germany, Austria and Switzerland, cash has been 'king' for some time, but that has now changed. This is especially the case as the expropriation was not the doings of the Cypriot government rather it was that of the Troika – the EU, the ECB and the IMF.
Gold is financial insurance which protects against inflation and expropriation of financial assets – such as pensions and now deposits.
Recent events show the wisdom of the old Wall Street adage to always keep 10% of one's wealth in gold and hope it does not work.
Gold holds above $1,600 as Cyprus fallout supports – Reuters
Cyprus Banks to Reopen: container trucks loaded with cash arrive – Reuters
Russia to ban cash transactions over $10,000 – Forbes
Central Banks Bought Just $3 Billion Of Gold In 2013: UBS – Forbes
How Safe Are Your Savings? – The Tuam Herald
Russia, South Africa plan OPEC-type cartel for platinum and palladium – Market Watch
Faber: Deposits At Risk Everywhere Including US As Seen With MF Global – Bloomberg
Cyprus Shows Your Savings Will be Stolen! UK Theft is by Means of High Inflation – Market Oracle
Keiser Report: 'Yes, No, Maybe' World Order – Max Keiser
US National Debt – Nearly $17 Trillion – U.S. Debt Clock
Gold Price Isn't Irrelevant But Financial Journalism Is – GATA
For breaking news and commentary on financial markets and gold, follow us on Twitter.


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Scientists have developed a new optical chip for a telescope that enables astronomers to have a clear view of alien planets that may support life.
Seeing a planet outside the solar system which is close to its host sun, similar to Earth, is very difficult with today's standard astronomical instruments due to the brightness of the sun.
Associate Professor Steve Madden from The Australian National University's Research School of Physics and Engineering said the new chip removes light from the host sun, allowing astronomers for the first time to take a clear image of the planet.
"The ultimate aim of our work with astronomers is to be able to find a planet like Earth that could support life," said Madden.
"To do this we need to understand how and where planets form inside dust clouds, and then use this experience to search for planets with an atmosphere containing ozone, which is a strong indicator of life."
Physicists and astronomers at ANU worked on the optical chip with researchers at the University of Sydney and the Australian Astronomical Observatory.
Madden said the optical chip worked in a similar way to noise cancelling headphones.
"This chip is an interferometer that adds equal but opposite light waves from a host sun which cancels out the light from the sun, allowing the much weaker planet light to be seen," he said.
PhD student Harry-Dean Kenchington Goldsmith, who built the chip at the ANU Laser Physics Centre, said the technology works like thermal imaging that fire fighters rely on to see through smoke.
"The chip uses the heat emitted from the planet to peer through dust clouds and see planets forming. Ultimately the same technology will allow us to detect ozone on alien planets that could support life," said Kenchington Goldsmith.
The innovation builds on over 10 years of research on specialized optical materials and devices that has been supported through CUDOS, a centre of excellence funded by the Australian Research Council.
The research is being presented at the Australian Institute of Physics Congress in Brisbane this week.
Filed Under: Aerospace + defense


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Our program philosophy goes much further than just a fitness workout.
We designed Kaia to fit into your schedule, and we welcome you to start anytime.
Our year-round program includes three yearly BRIKs that we believe are the cornerstones of health & fitness and can be incorporated into our daily lives. By building a solid foundation of strength, endurance, and nutrition during these six-week BRIK programs, we train our bodies and our minds to take on multiple challenges simultaneously. We carry these foundations [or start building new ones!] into our five-week Core sessions (two in between each Brik Boot Camp). Each session is loaded with innovative workouts and nutritional support that are specific to the season.
The Kaia FIT program is designed to increase your fitness level and/or to get you excited about exercising and eating healthy. Finding camaraderie during these sessions is a vital component to everyone's success. The women beside you each day feel exactly what you are feeling and give you the motivation to keep you coming back to class.


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Why Israel is holding out in Lebanon
| Jerusalem
His voice dropping to denote displeasure with the thought, Israeli Defense Minister Ariel Sharon looked earnestly at his audience of American Jews. ''Imagine the situation,'' he said, ''if we withdraw - after everything that has happened - and our northern towns and cities are shelled. What are we going to do? Go again into Lebanon?''
Moments later, matter-of-factly but no less bluntly, Israeli Foreign Minister Yitzhak Shamir told delegates to the Israel Bonds convention: ''We are concerned what will happen the day after our withdrawal. The PLO will try to return. The Lebanese Army is too weak to stop them.''
Enduring security - that is the overriding theme expressed by Israeli government officials as the Israeli-Lebanese-American negotiations on the future of Lebanon continue, deadlocked, into their second month.
Besides the universally agreed upon need for secure borders for Israel, the government's own credibility is at stake. The speeches Jan. 26 by the second and third most important men in the Israeli Cabinet, coming at a time of strained relations with the United States, provide a valuable insight into official Israeli thinking. And they seem to indicate little give in the Israeli position.
The costly, image-tarnishing war in Lebanon was conducted, the Israeli leaders have contended, to drive the Palestine Liberation Organization out of Lebanon once and for all and to achieve the much-promised ''peace for Galilee.'' If the north of Israel is harassed in the future (there have been three incidents of Katayusha rockets being fired, harmlessly, into Galilee from southern Lebanon in the past three weeks), the Menachem Begin government is in trouble. Mr. Sharon, in particular, has been associated with the war in Lebanon as the architect of the invasion.
Mr. Sharon told his audience Israel is holding fast to four basic conditions necessary before the Israelis agree to a settlement. He indicated there is little room for compromise on these conditions since they involve matters of ''life and death'' for Israel:
1. No PLO guerrillas or political operatives may remain in Lebanon, nor may any forces from any country - Arab or otherwise - remain in Lebanon unless that country has relations with Israel. Mr. Sharon estimated there are 8,000 Palestinian guerrillas still in Lebanon and claimed some are ''coming back into the camps in west Beirut'' and operating against Israeli forces ''from behind the lines of the multinational forces.''
2. The PLO must leave first, then Israel and Syria can remove their troops simultaneously.
3. A 30-mile security zone must be established in southern Lebanon, to be patrolled by Maj. Saad Haddad's pro-Israeli militia. The Haddad forces, whether integrated back into the main Lebanese Army or not, would remain in control of southern Lebanon until the Lebanese Army is strong and reliable enough to take over. And, Mr. Sharon candidly added, ''that may take years.''
4. In this zone there must be placed three temporary Israeli outposts, which Mr. Sharon described as ''anti-terrorist supervision stations,'' to give Israel ''very specific information about any attempt by terrorists to reestablish infrastructure in southern Lebanon.''
Mr. Sharon said these outposts could be staffed by less than 750 Israeli soldiers, but they would be necessary until the Lebanese secret police are sufficiently strong to take over ''anti-terrorist'' operations themselves. The posts would ''not need to be equipped with electronic devices'' for cross-border snooping on Syria or Jordan, said Mr. Sharon, since existing Israeli outposts already perform that function adequately. He said neither the United Nations nor the multinational peacekeeping troops, nor the US Marines on their own could do the job Israel needs done.
5. Lebanon and Israel must have peaceful and normal relations, including open borders and open trade. Foreign Minister Shamir stated, ''We must come to a peace treaty between Israel and Lebanon.''
Mr. Sharon said that normalization is necessary so that ''on both sides of the border people will know they have something to lose if they do not stick to this peaceful situation.'' He pointed to the cross-bridge traffic between Israel and Jordan and the close coexistence, across the Jordan River valley, of Israeli and Jordanian farmers as an example of how de-facto normalcy ensures peace.
Each of these points is controversial, particularly those involving Major Haddad and the early-warning stations.
As the US sees it, these reflect on Lebanon's basic right to control activities within its own borders. US officials argue that Israel cannot call the shots inside the Lebanese Army and that if the Israelis have early-warning stations in Lebanon the Syrians can demand the same. Furthermore, the US argues, a peace treaty could cause problems with Lebanon's Arab neighbors.
Sharon and Shamir both cited the differences Israel and the US have on these issues. Both noted that these involved vital Israeli national interests, while to the US they were simply items on a huge global agenda. Mr. Shamir seemed most critical of the American attitude, calling it a contradiction that ''our American friends are stressing the argument for Lebanon's sovereignty and independence but disregard the surrender of Lebanese sovereignty to Arab pressure.''
Both men also rejected the Sept. 1 Reagan plan, which calls for ''self-rule'' for Palestininans of the West Bank and Gaza ''in association with Jordan.''
Mr. Sharon argued that the ability of Palestinian guerrillas to ''give us real problems from among the 270,000 Palestinians in Lebanon'' was an indicator of how difficult it would be to maintain security if the 1.1 million Palestinians in the West Bank and Gaza were not under Israeli control. Mr. Shamir rejected any peace process other than the Camp David autonomy plan.