Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients

by Ben Goldacre Narrated by Jonathan Cowley

Overview

Medicine is broken. We like to imagine that it's based on evidence and the results of fair tests. In reality, those tests are often profoundly flawed. We like to imagine that doctors are familiar with the research literature surrounding a drug, when in reality much of the research is hidden from them by drug companies. We like to imagine that doctors are impartially educated, when in reality much of their education is funded by industry. We like to imagine that regulators let only effective drugs onto the market, when in reality they approve hopeless drugs, with data on side effects casually withheld from doctors and patients.

All these problems have been protected from public scrutiny because they're too complex to capture in a sound bite. But Dr. Ben Goldacre shows that the true scale of this murderous disaster fully reveals itself only when the details are untangled. He believes we should all be able to understand precisely how data manipulation works and how research misconduct on a global scale affects us. In his own words, "the tricks and distortions documented in these pages are beautiful, intricate, and fascinating in their details." With Goldacre's characteristic flair and a forensic attention to detail, Bad Pharma reveals a shockingly broken system and calls for something to be done. This is the pharmaceutical industry as it has never been seen before.

Editorial Reviews

The New York Times Book Review - Cara Parks

…an eye-opening glance into a world of experts who have failed us…the book distinguishes itself by looking primarily at the poorly designed trials and outright testing manipulations that have led to "a market flooded with drugs that aren't very good."

Publishers Weekly - Audio

In his latest, British physician and author Goldacre tackles the misdeeds of the pharmaceutical industry. As Goldacre presents a laundry list of flawed research projects, narrator Jonathan Cowley handles the author’s academic style with ease, never missing a beat. His precise annunciation matches the seriousness of the issues at hand, and he successfully balances the shifting tones of the narrative. Yet, as Goldacre recounts his adventures uncovering greed and corruption, Cowley ably takes on the author’s populist persona. Cowley especially entertains in sections devoted to industry schmoozing and networking, providing doses of humor to help bring home the author’s underlying messages. And if technical and scientific sections of the book make for a sometimes-demanding listening experience, Cowley’s winning reading helps broaden the appeal. A Faber & Faber hardcover. (Feb.)

Publishers Weekly

In this searing expose´ of the pharmaceutical industry, physician and journalist Goldacre (Bad Science) uncovers a cesspool of corrupt practices designed to sell useless ordangerous drugs to an unsuspecting public. His main focus is the distortion of the science on which evidence-based medicine relies: drug companies, he argues, deploy deliberately biased clinical trials and twisted statistics to exaggerate their drugs' benefits, while suppressing countless studies that show negative results or deadly side effects. Big Pharma's malign influence doesn't stop there, he contends; doctors' prescribing practices are determined not by patients' needs but by the insidious bribes and blandishments of sales representatives, the industry's ubiquitous "educational" programs, and fake research articles, journals, and even textbooks signed by independent academics but authored by industry-hired ghost writers. Goldacre's indictment fingers many culprits-profit-hungry industry executives, lax regulatory agencies that collude in hiding crucial information from the public, and complaisant journal editors and university officials who put their imprimatur on blatant misconduct. Drawing on a wealth of research but writing squarely for laypeople, Goldacre conveys complicated scientific, medical, and ethical issues in simple, clear, plainspoken language that pulls no punches. The result is a smart, infuriating diagnosis of the rotten heart of the medical-industrial complex. Agent: Zoe¨ Pagnamenta, the Zoe¨ Pagnamenta Agency.
(c) Copyright PWxyz, LLC. All rights reserved.

From the Publisher

Slightly technical, eminently readable, consistently shocking, occasionally hectoring and unapologetically polemical . . . This is a book that deserves to be widely read, because anyone who does read it cannot help feeling both uncomfortable and angry.” —The Economist

“Ben Goldacre has done it again . . . This is a morbidly fascinating and dispiriting account, yet one which deserves (and needs) to be read and acted upon without delay.” —Dennis Rosen, Dennis Rosen, The Boston Globe

“Read this book. It will make you mad, it will make you scared. And, hopefully, it will bring about some change. ” —Chris Lee, Ars Technica

“A thorough piece of investigative medical journalism. What keeps you turning its pages is the accessibility of Goldacre's writing, . . . his genuine, indignant passion, his careful gathering of evidence and his use of stories, some of them personal, which bring the book to life.” —Luisa Dillner, The Guardian

“Goldacre's research is scrupulous, and lay readers may find themselves converted by his geeky ardor. ” —The New Yorker

“[A]n eye-opening glance into a world of experts who have failed us.” —The New York Times Book Review

“In this searing exposé of the pharmaceutical industry, physician and journalist Goldacre uncovers a cesspool of corrupt practices designed to sell useless or dangerous drugs to an unsuspecting public . . . Goldacre conveys complicated scientific, medical, and ethical issues in simple, clear, plainspoken language that pulls no punches. The result is a smart, infuriating diagnosis of the rotten heart of the medical-industrial complex.” —Publishers Weekly

“A useful guide for policymakers, doctors and the patients who need protection against deliberate disinformation.” —Kirkus Reviews

“Goldacre's essential exposé will prompt readers to ask more questions before automatically popping a doctor-prescribed pill.” —Karen Springen, Booklist

“Smart, funny, clear, unflinching: Ben Goldacre is my hero.” —Mary Roach, author of Stiff, Spook, and Bonk, on Bad Science

“Ben Goldacre is exasperated . . . He is irked, vexed, bugged, ticked off at sometimes inadvertent (because of stupidity) but more often deliberate deceptions perpetrated in the name of science . . . You'll get a good grounding in the importance of evidence-based medicine . . . ‘Studies show' is not good enough, he writes: ‘The plural of "anecdote" is not data.'” —Katherine Bouton, The New York Times, on Bad Science

“One of the best books I've ever read. It completely changed the way I saw the world. And I actually mean it. ” —Tim Harford, author of The Undercover Economist, on Bad Science

“Ben Goldacre lucidly, and irreverently, debunks a frightening amount of pseudoscience, from cosmetics to dietary supplements to alternative medicine. If you want to read one book to become a better-informed consumer and citizen, read Bad Science.” —Sandeep Jauhar, author of Intern, on Bad Science

“This is a much-needed book. Ben Goldacre shows us—with hysterical wit—how to separate the scam artists from real science. In a world of misinformation, this is a rare gem.” —Timothy Ferriss, author of The 4-Hour Workweek, on Bad Science

“Ben Goldacre uses a brilliant mix of science and wit to challenge and investigate alternative therapists and the big pharmaceutical corporations. Bad Science is an invaluable tool for anybody who wants to protect themselves from the snake-oil salesmen of the twenty-first century.” —Simon Singh, author of Big Bang and Fermat's Last Theorem, on Bad Science

“British physician and journalist Ben Goldacre takes aim at quack doctors, pharmaceutical companies and poorly designed studies in extraordinary fashion in Bad Science . . . Goldacre shines in a chapter about bad scientific studies by writing it from the perspective of a make-believe big pharma researcher who needs to bring a mediocre new drug to market. He explains exactly how to skew the data to show a positive result. 'I'm so good at this I scare myself,' he writes. 'Comes from reading too many rubbish trials.'” —Rachel Saslow, The Washington Post, on Bad Science

“Funny and biting . . . While it is a very entertaining book, it also provides important insight into the horrifying outcomes that can result when willful anti-intellectualism is allowed equal footing with scientific methodology.” —Dennis Rosen, The Boston Globe, on Bad Science

“I hereby make the heretical argument that it is time to stop cramming kids' heads with the Krebs cycle, Ohm's law, and the myriad other facts that constitute today's science curricula. Instead, what we need to teach is the ability to detect Bad Science—BS, if you will. The reason we do science in the first place is so that 'our own atomized experiences and prejudices' don't mislead us, as Ben Goldacre of the London School of Hygiene and Tropical Medicine puts it in his new book, Bad Science: Quacks, Hacks, and Big Pharma Flacks. Understanding what counts as evidence should therefore trump memorizing the structural formulas for alkanes.” —Sharon Begley, Newsweek.com, on Bad Science

“Dr. Ben Goldacre's UK bestseller Bad Science: Quacks, Hacks, and Big Pharma Flacks is finally in print in the USA, and Americans are lucky to have it. Goldacre writes a terrific Guardian column analyzing (and debunking) popular science reporting, and has been a star in the effort to set the record straight on woowoo 'nutritionists,' doctors who claim that AIDS can be cured with vitamns, and vaccination/autism scares. Bad Science is more than just a debunking expose (though it's that): it's a toolkit for critical thinking, a primer on statistics and valid study design, a guide to meta-analysis and other tools for uncovering and understanding truth . . . The book should be required reading for everyone who cares about health, science, and public policy.” —BoingBoing.net on Bad Science

From the Publisher - AUDIO COMMENTARY

"A useful guide for policymakers, doctors and the patients who need protection against deliberate disinformation."" —Kirkus

Library Journal - Audio

Goldacre (Bad Science) here turns his attention to medical research and the pharmaceutical industry. He explains that negative or no-result studies of drugs are less likely to be published anywhere in the professional literature than positive ones. The author further explains that medical professionals are manipulated by planted articles, drug vendors, and the selective use of statistics. All true, if not exactly new ideas. Unfortunately, despite his claims of nonbias, Goldacre supports his opinions with interesting anecdotes and carefully selected metadata studies. This fact-filled book is scientifically no better than the studies it critiques. The audiobook, competently read by Jonathan Cowley, has its own problems. It comes with so-called bonus materials—PDF files of graphs. In several places, people are expected to go to their computer and look at figures while listening to the text, not easy for those who listen while driving, exercising, etc. VERDICT While not an impartial exposé, this is an enjoyable and informative book, best read in print form. Recommended for individuals interested in medical issues who are good at mental data manipulations. ["Goldacre's recommendations for much larger, simpler trials and for more access to clinical trial data, as well as educating people about risk assessment, clinical trial design, and statistical literacy, make this much more than a condemnation of the pharmaceutical industry," read the review of the Faber & Faber hc, LJ Xpress Reviews, 3/22/13.—Ed.]—I Pour-El, Des Moines Area Community Coll., Ames, IA

Library Journal

British epidemiologist Goldacre (Bad Science: Quacks, Hacks, and Big Pharma Flacks), who writes the popular Guardian column “Bad Science,” is unabashedly polemical in his latest book. He addresses biases against publishing negative results, the limitations of current clinical trials, and the growing (but still limited) use of evidence-based medicine and comparative effectiveness research, along with the challenges and uncertainties of medicine. Published originally in the UK, the book also includes a number of examples from the United States. Building upon work such as Iain Chambers’s Testing Treatments: Better Research for Better Healthcare (for which Goldacre wrote the foreword), Jerry Avorn’s Powerful Medicines, and Marcia Angell’s The Truth About Drug Companies, Goldacre’s in-your-face rhetoric will capture attention and should spark important conversations about ways to improve medicine, clinician education, drug safety monitoring, and drug regulation and marketing.

Verdict Goldacre’s recommendations for much larger, simpler trials and for more access to clinical trial data, as well as educating people about risk assessment, clinical trial design, and statistical literacy make this much more than a condemnation of the pharmaceutical industry. Recommended for academic, health industry, and lay audiences.—Mary Chitty, Cambridge Healthtech, Neeedham, MA

(c) Copyright 2013. Library Journals LLC, a wholly owned subsidiary of Media Source, Inc. No redistribution permitted.

MAY 2013 - AudioFile

Listeners to this audiobook will likely feel betrayed by pharmaceutical companies—who manipulate test results so only favorable tests are made public—and by government regulators—who rubber-stamp these specious findings and fail to properly monitor or investigate. The result is that consumers and doctors are misled. For example, the author, a physician, describes how he has prescribed medicines, unaware of the shoddy testing of them as well as their undisclosed side effects and contraindications. Although the book's content is absorbing, some of the material—particularly the statistical information—may not be ideal for the audiobook format. The author is a popular lecturer and Internet blogger, and narrator Jonathan Cowley channels his emphatic tone and English accent. (Cowley also narrated Goldacre's previous book.) The high-density onslaught of information will prove convincing for some while others may find the insistent tone fatiguing. R.W.S. © AudioFile 2013, Portland, Maine

Kirkus Reviews

An explanation of why pharmaceutical companies have come under increasing scrutiny in recent years. As both a physician and medical correspondent (Bad Science, 2010), Goldacre has been in the catbird seat in regard to the detection of medical fraud. Here, he discusses the gray area in which drug companies can legally manipulate data in order to package experimental results in the most attractive way. Although Goldacre practices medicine in the U.K., his book is applicable to the U.S. pharmaceutical industry. He explains what should be an obvious flaw in the system: The majority of experiments validating the safety and benefits of new drugs are funded by the pharmaceutical industry, either directly or indirectly, through grants to universities and other methods. Because of this, writes Goldacre, "industry-sponsored studies are more likely to produce results that flatter the sponsor's drug." The author cites the conclusion by three researchers from Harvard and Toronto, who conducted a meta-analysis of data on antidepressants and other drugs in 2010. They found major discrepancies in results related to reported effectiveness between research conducted by industry-funded and government-funded trials. Goldacre believes that such reviews should be conducted routinely, backdated and made easily available to the public. Currently, pharmaceutical companies are not obligated to publish results that are unfavorable to their product. Another shady tactic is touting the short-term performance of drugs that become less effective over time. The author supports enforceable government regulation. A useful guide for policymakers, doctors and the patients who need protection against deliberate disinformation.

Product Details

BN ID:	2940170691807
Publisher:	Tantor Audio
Publication date:	02/05/2013
Edition description:	Unabridged

Read an Excerpt

1

 

Missing Data

Sponsors get the answer they want

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?1 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.2 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 favouring 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 favourable 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.3

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 (here), 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.4 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.5

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 favourable 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 favoured the sponsor’s drug. There is a small punchline 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. It may be that companies are more likely to run trials when they’re most confident their treatment is going to ‘win’: this sounds reasonable, although even it conflicts with the ethical principle that you should only do a trial when there’s genuine uncertainty about which treatment is best (otherwise you’re exposing half of your participants to a treatment you already know to be inferior). Sometimes the chances of one treatment winning can be increased by outright design flaws. 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 practising 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 US FDA chose not to approve it. (This is no proof of the FDA being any smarter; there are plenty of drugs available in the US that the UK never approved.) Reboxetine was clearly a safe and 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.

TGN1412

In March 2006, six volunteers arrived at a London hospital to take part 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.7 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.8 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.9 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? No.

In the 1980s, US 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 realised 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, recognising 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.

 

Copyright © 2012, 2013 by Ben Goldacre

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