by David Healy
It would be an easy matter to remedy this—by ensuring that the consent forms for a trial tell us whether the company will sequester our data. Without this any participation in such studies is more likely to jeopardize the health and well-being of our friends, children, and communities than to widen the compass of freedom from disease because companies will parade clinical trials where injurious side effects are hidden, artfully coded, or simply eliminated as evidence that their drug could not have caused the injury, and if doctors or the courts believe them, any effort on our part to seek redress will fail at the first hurdle.
Evidence-based medicine as first conceived was a highly moral enterprise. It takes courage to subject all our preconceptions to testing, and then to treat the people who come to us for care on the basis of the data. But what passes for evidence-based medicine has now been subverted by companies into an exercise that skirts conflicting values by appealing to preselected “data” that are supposedly value neutral. We need to recover the perspective that science, far from being value free, values data and does so with a passion. “Controlled trials” that involve restricted access to data are not science, and following selected “data” can only diminish both the carers and the cared-for.
If all the data on the benefits and hazards of treatment were available, the exuberance that companies can engender by marketing agents of supposedly extraordinary efficacy and almost no risks would to some extent be curbed, and if curbed the vast profits that support the most sophisticated marketing on the planet, that conjures diseases out of vicissitudes and can reconfigure our very selves to suit its purposes, would in some measure be limited. If this happened clinical practice would have a better chance of returning to something closer to what it once was, when one person consulted another.
We might require companies to post all records from clinical trials, with suitable safeguards to protect individual patient identities, to an Internet site, before any analysis of the evidence was published. This would simply replicate for medicine the common scientific practice of journals like Nature or Science that require the relevant genetic sequence to be posted to the Internet before any claims are published.
But the simple idea of posting the data reveals a profound ambiguity in the notion of evidence-based medicine. While most people assume medicine has been data-based for the last twenty years or so, there are vanishingly few articles in journals or presentations at meetings—other than, ironically, some good case reports—that offer data. In the course of clinical trials things happen to patients, but these things are assembled and analyzed using models that come with assumptions including that if a finding is not statistically significant it essentially does not exist. It is the “results” of these analyses that are published—rather than any account of what in fact happened to patients. When it comes to results, he who controls the program giving rise to the results can control everything.3
When we have Pierre Touery drinking ten times the lethal dose of strychnine in front of our eyes and surviving because he had previously taken activated charcoal or when a child with bacterial endocarditis gets up off her deathbed and walks after being given penicillin, we have data-based medicine. When you are put on a statin, a biphosphonate, or a psychotropic drug because in some trial that has recruited hundreds or even thousands of subjects so that a finding on a blood test or rating scale that suits some company has become statistically significant, you are being subjected to results-based medicine rather than cared for with data-based medicine.
When it comes to the hazards of drugs as reported by their makers we are invariably dealing with results rather than data. Consider the following excerpt from the deposition of Ian Hudson, then head of Global Safety at GSK:
Q: Okay. So, your view is: It's simply impossible for SmithKline Beecham to decide whether Paxil did or did not contribute to the homicidal or suicidal behavior of any one given individual; is that your testimony?
A: We would certainly gather all the information, but on an individual case basis it would be impossible to decide whether paroxetine caused an event or not…. It is impossible, on an individual case basis, from individual reports, to assign causality especially in a very complicated area such as this. That's why, when we have issues, we review all the available data and make a determination, on the basis of all the available data, whether there is an issue or not.
Q: Okay. Do you believe that it is possible that Paxil has caused any person, worldwide, to commit an act of homicide or suicide?
A: I have seen no evidence to suggest that at all.4
Hudson is demonstrating the standard company approach to determining whether there is any link between an adverse effect and the company's drug. In brief, the company position is that unless an adverse event has been statistically significantly associated with the company's drug in a controlled trial, that event cannot be said to have been caused by the drug. And companies can ensure their drug never causes anything by making sure that trials are organized so that important adverse events cannot become statistically significant.
Taking this approach, even when faced with assessments by doctors or their own personnel that the company's drug has caused some problem, based perhaps on a temporal link between a Vioxx or a Paxil, say, and a side effect that emerges on treatment, clears when the treatment is stopped, and reappears when the treatment is restarted, the company will still not concede a link.
What, then, about the long list of side effects reported in ads for the drug or in the Physicians' Desk Reference (PDR)? The company view is that these have been reported but this is not the same thing as being caused. These reports are merely anecdotal unless or until they have occurred enough times in clinical trials to have their link to the drug come out as statistically significant. Drug company personnel will of course warn doctors about all proven hazards their treatment causes (conveniently, none as no trials are done to establish a linkage)—it would be inhuman to do otherwise in such a sensitive domain as medicine. But they will not, as they put it, spread rumors about their drug—that would be good neither for the company nor for the patient. In adhering to this kind of “science” company personnel—and doctors—have found a way to live with themselves that has echoes of a totalitarian regime where people have learned to live with themselves on the basis that they are obeying orders or keeping to the rule of law.
What these doctors miss is that companies are working from assumptions or results rather than from data. There may have been thousands of reports of a problem to the company as clinically significant as Pierre Touery's use of activated charcoal, but these never stand a chance of becoming statistically significant.
When John Snow, investigating the outbreak of cholera in London in 1856, found a cluster of deaths from the disease on Broad Street, he was not inhibited by considerations of statistical significance because this concept hadn't been invented. He was free to recognize a cluster. Clinical prudence dictated a course of action—remove the handle of the pump. Science mandates efforts to go behind the data in an attempt to establish what has given rise to the cluster. But if companies had controlled the pump and took an Ian Hudson approach, they would not countenance the removal of the handle or any investigation of what the mechanisms giving rise to the cluster might be—unless the findings were statistically significant, which in all likelihood at Broad Street they weren't.
This account of what happens when our deaths or injuries on treatment are hidden or disguised may also help explain why doctors neglect what is happening to the person in front of them—in a manner that seems close to the antithesis of what good care should be. Anything that happens to the patient in front of a doctor has been degraded to an anecdote rather than an event that the doctor needs to pay heed to. If the doctor, using standard methods to decide if treatment has caused a particular problem, attempts to report it to a journal, the report will be turned down on the basis that journals no longer take case reports. If the doctor tried to report it to either the company or the FDA,
it disappears into a statistical black hole that can swallow thousands of such events without the slightest indigestion. In the case of Vioxx it is estimated that there were at least 30,000 heart attacks linked to this drug from the time clinical trials first showed an increase in risk to the point where it was conceded there might be a problem and Merck drew back from its marketing blitzkrieg.5
The result is that, astonishingly, in the midst of this emphasis on evidence, medicine is collecting even less evidence on those harmed by treatments than it has done in the past. Although we now have the ability to register all patients with particular diagnoses or patients receiving any drug and could track all outcomes and assemble the data on what actually happens when treatments are given, there is in fact a yawning hole—through which Cora and others in the prime of life are abducted by Hades. Those who love them, who are left behind, have a right to complain to Zeus that there has been a fundamental breach here in the contract between heaven and hell.
But in addition to frustrating the giving of decent and reliable medical care, the neglect of data on the problems treatment may cause is cutting off our ability to develop new drugs. The single most fruitful source for the discovery of new drugs continues to be observations that a drug given for one purpose in some cases is doing something else. It is perhaps no coincidence that as the possibility of reporting “adverse” events has dried up, with journals unwilling to take reports on unexpected outcomes in individual cases and companies hiding effects that do not fit with the business plan for a drug, so also drug discovery has dried to a trickle.
In response to questions as to whether major medical journals should insist on access to the raw data from controlled trials, the editorial staff of the New England Journal of Medicine (NEJM) said in April 2009 they do not see this happening in the near future—“that would be a large step outside our role”—while at the same time maintaining that the NEJM offers transparency.6 As things stand we might all be safer if clinical trials were published in the New York Times rather than the NEJM, as the Times makes some effort to check the integrity of the primary sources for its stories, whereas the NEJM does nothing. When a Times story turns out to have been invented, as in the case some years ago of a series of articles written by Jayson Blair, it is national news, and the editor's job is on the line; not so when a drug trial such as Study 329 turns out to have been bogus.
Study 329 was the 1997 trial, discussed initially in chapter 4, in which Paxil was found to be no more effective yet more dangerous than placebo but from which GlaxoSmithKline (GSK) decided to select and publish the good bits, concealing the fact that six times more children became suicidal on Paxil than on placebo. The ghostwritten article was published in the most influential journal in child psychiatry, the Journal of the American Association of Child and Adolescent Psychiatry, whose editor at the time was Mina Dulcan. Dulcan had this to say in 2004 when interviewed by Shelley Jofre of the BBC after the history of the paper had become clear, and at a time when the paper was the basis of a fraud case taken by New York State against GSK:
SJ: The interesting thing is that GlaxoSmithKline actually acknowledged internally three years before you even published Study 329 that it had failed to show that Paxil was better than placebo. They took a marketing decision to effectively pick out the best bits of the study and see if they could get it published.
MD: That may be. That's not something that journals have any access to, that information.
SJ: Do you have no regrets about publishing the study?
MD: I don't have any regrets about publishing at all. It generated all sorts of useful discussion, which is the purpose of a scholarly journal. The purpose of a scholarly journal is not to tell people what to do. The purpose of a scholarly journal is to put out the data….
SJ: I can tell you that GlaxoSmithKline thought [publication] was fantastic and their sales reps were using your journal's name and influence to then say to doctors, here look, there's a published study, it works.
MD: Well, I think we all see salesmen of a whole variety of kinds, whether they are drug company salesmen or insurance salesmen and we certainly have no control over how they use something.
SJ: But, given what you know now about this drug and what it can do to children, don't you have any regrets that that published article was able to use your journal's good name to basically, as a cloak of respectability to say look, I have been in this journal. It must be true, look at the authors.
MD: I can't control the authors. No, I don't have regrets…. If someone misuses our journal we really have very little control over that….
SJ: Are you aware that 329 was ghost written?
MD: I have no way of knowing that. It doesn't surprise me to know it happens, but we have no way of259 having that information.
SJ: Does it worry you, do you think it matters?
MD: Well, certainly if I were an author I would not put my name on anything that I didn't feel was accurate. I can't speak to what those authors, to the extent, how much they saw the data. Someone can write something and you may or may not agree with it. The fact that someone puts the words together may be a good thing or a bad thing depending on what the words are….7
In contrast to what one imagines the position of the editor of the New York Times might be had they published Study 329, Mina Dulcan seems completely unfazed by her role in the publication of one of the most notorious studies of all time. At some point it is going to take a gutsy academic editor to risk being shut down by industry or the rest of us to consider whether we would be safer if publication of clinical trials happened in the New York Times and academic journals were reclassified as periodicals and academic meetings as trade fairs.
The response of many to these issues may be that we need a beefedup FDA to police what is going on. We don't. It would do no harm to beef up, or exit, those in the FDA who are weak and bureaucratic. But the FDA's primary brief is to regulate the wording of advertisements rather than to care about patients. When these drugs were made available by prescription only it was because legislators thought to put them in the hands of an institution that looked a lot more powerful than the FDA and a lot more concerned about the welfare of patients—medical doctors. If medicine and its academics have been neutered, any other beefed-up agency or set of regulations can be too. Any regulations should follow from our values rather than substitute for them—and the values in this case are that if the data aren't available it's not science.
When it comes to the risks of treatment, the company trials that now dictate clinical practice are like the subprime mortgage market, in which risk was so cut up that all parties could act as though the hazards of lending had somehow vanished. By running small studies, the pharmaceutical industry has similarly cut up the appearance of risk to patients, using statistical significance to make these risks vanish. It then has come as a huge shock when large and independent studies show the risks to be alive and flourishing for Vioxx, Avandia, Advair, and other drugs. These shocks have been handled by denial.
Faced with these scenarios both doctors and patients cast around for a wizard for help but it has been as difficult to spot any influence for the good from the FDA as it was to spot any good from the financial regulators in the recent financial turmoil. In this case, doctors are the scarecrows, tin men, and lions who need to be told that they have the brains, hearts, and courage for the job. In the case of the FDA, we need a Dorothy to pull back the curtain and reveal the wizard as a simple auditor. But we have instead—to the benefit of no one except industry—drifted slowly into the position where professional bodies within medicine have turned to the FDA for a lead on the safety and efficacy of drugs where in the Kefauver hearings of 1962 it was envisaged that medicine would offer the FDA a lead. Given the failure of medicine to step up to the plate and the fact that the current regulations governing drugs have been in place for an extraordinary length of time—over fifty years, it is perhaps time to revisit what might be done.
PRESCRIPTION
-ONLY STATUS
The problem within medicine, unlike the financial crisis, is not that we have abandoned regulations, but rather that the current regulations aren't working or are being manipulated to our disadvantage, in particular prescription-only regulations. Prescription-only status makes doctors, not patients, the primary consumers of our blockbuster drugs but this is a consumer group that in the 1950s effectively disbanded one of its only consumer bodies when the AMA stopped running its independent program of drug assessments. Medicine ever since has been like a frigate or tanker adrift on the high seas whose rudder is not functioning, a clear target for pirates.
Because doctors have always written prescriptions, and because today's doctors have only practiced in a prescription-only world, they think key medicines have always been available by prescription only. But prescription-only status is very recent, and just as with the French Revolution it may still be too early to judge all the consequences.
The initial prescription-only arrangements introduced in 1914 were a police function aimed at controlling the use of substances like heroin and cocaine. This seemed incompatible with the practice of medicine to many. We have since lost any perspective we once had that giving a doctor exclusive control over access to something as important as life-saving remedies might corrupt the doctor. The subsequent impetus to prescription-only status ironically first arose in the United States, the home of the free market, rather than in Europe or elsewhere. This restriction on the availability of drugs assumed that the doctors who prescribed medicines would be like Philippe Pinel in Paris two hundred years ago, Alfred Worcester a century ago in Massachusetts, or Nancy Olivieri in Toronto today (who lost her job after speaking out about the hazards of deferiprone as a treatment for thalassemia), doctors who were skeptical that all treatments were as beneficial as companies claimed and who were not afraid to speak out in defense of their patients.8 If these hopes had been realized, we might not have the degradation of medical care we now have.