Pharmageddon (33 page)

There might be less cause for concern if the FDA were the type of investigative agency most people imagine must have been put in place following the thalidomide scandal or if it were the kind of agency that was in the business of ensuring our medicines get progressively better. When we go to sleep at night with a child in the next room on some new medication, we expect the treatment will be at least marginally better and safer than treatments we may have been prescribed when we were children. After all, the music system is so much more advanced than the one around when we were young and there is a computer now where there was once a typewriter. But this is not the case for many drug treatments. There is every chance our family members will be taking a drug, whether an antibiotic or antidepressant, that is less effective than the one we were treated with or a new drug whose hazards remain to be discovered. All that is in place between our children and possible disaster is a set of auditors whose job it is to tick the boxes.

It is in fact a lot harder for the FDA to audit the books of Pfizer, Lilly, or GlaxoSmithKline than it was for the Arthur Andersen firm to audit Enron. In financial circles it is recognized that after a period of time auditors come to see the world the way their clients do. As a result it is regarded as good practice for major corporations to change their auditors every five years. But there are no changes of auditors when it comes to pharmaceuticals.

When a plane falls out of the sky, the Aviation Safety Board audits what has gone wrong rather than the Federal Aviation Board, the agency responsible for letting a plane fly in the first instance. But when a problem blows up with a drug, it is often the same FDA officials who have made the decision to let the drug on the market who are now called upon to make a further set of judgments that may reflect badly on their original decision.

When the crisis blew up around drugs like tolbutamide in the 1970s, one of the few safeguards in place was that regulators worldwide were paid from the public purse. But things have changed. Britain was one of the first countries in the 1980s to switch to a system where industry paid to be regulated, and the regulator was encouraged to become a business selling “regulatory services” to the industry and promoting itself as one of the fastest licensing authorities in the world for new drugs.
¹⁷
The United States moved to a similar system in 1992, with the passage of a Prescription Drug User Fee Act (PDUFA) that allowed the FDA to collect a fee from industry based on marketing applications reviewed. The intention was, by employing more reviewers in order to speed up processing of industry applications, to get rid of the bureaucratic delay that, ironically, had been the FDA's only contribution to averting a thalidomide disaster.

A new emphasis on partnership has blurred the boundary between the FDA and industry. Since drugs began to be regulated in the United States in 1906 there has always been a revolving door between the regulatory agency and industry; senior figures in the regulatory apparatus found jobs in pharmaceutical companies or consulted for them after they left government, or employees from industry moved into senior regulatory positions. This was later true of the regulatory agencies that followed in Europe. This revolving door makes it difficult to know how independent our regulators are. If the regulator knew he could be scrutinized because the data from the clinical trials used to get drugs on the market were publicly available, this might not be a big issue, but the data are not available so none of us can assess how much the lure of a future job might bias a regulator to give a company favorable treatment.

Whatever shuttling between industry and the regulatory apparatus there has been, until the new emphasis on partnership between industry and regulator was put in place it would have been considered scandalous to find senior regulators sitting down with industry representatives, academics enmeshed in industry, and patient groups that had been sponsored by industry to issue a ghostwritten consensus statement advocating the detection and treatment of disorders in a manner that can only increase the sales of drugs.

Thus in 2005, Tom Laughren, head of the FDA section responsible for licensing drugs that act on the central nervous system (known as the CNS section), was a co-author on an article advocating the detection and treatment of mood disorders in those with other medical illnesses, and indeed giving consideration to prophylactic antidepressant treatment in those who might be put on other medical drugs at risk of triggering depression.
¹⁸
The article was in fact written by Scientific Therapeutics Information.

In 2003, Laughren was a participant in a “consensus conference” convened under the auspices of the American Academy of Child and Adolescent Psychiatry but organized by Best Practices, a marketing firm whose website states that “we bring together opinion leadership and direct services to the pharmaceutical and biotechnology industries.”
¹⁹
Its services include “Consensus Development Conferences…in areas of clinical controversy.” In this case the meeting was aimed at increasing the recognition and treatment of childhood bipolar disorder, a condition that few psychiatrists outside the United States believed existed.
²⁰

In 2007, Laughren was named as an “author” of an article promoting antipsychotic drug studies in children labeled with “Impulsive Aggression.”
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This article, like the others above, came out of a sponsored meeting; in this case by Abbott Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, INC Research, Janssen, Johnson & Johnson, Eli Lilly, Novartis, Pfizer, Solvay, Annie E. Casey Foundation, Forest Research Institute, Jazz, Otsuka, and Sanofi Synthelabo.

In these cases, Laughren endorsed a treatment option when, in his FDA capacity, he might later be called on to adjudicate whether companies should have a license for marketing the use of antipsychotics for children who ostensibly have bipolar disorder or impulsive aggression disorder. There is no reason to believe that this quite extraordinary situation is anything other than standard behavior within the FDA now.

When we are ill, we are at our most vulnerable and need someone to look after us. Someone who ensures we get treatments that work, treatments that are as safe as they can be. For a century this figure, in the shape of doctors like Alfred Worcester and Richard Cabot, used to be our doctor. After the thalidomide tragedy in 1962 many of us also looked to the FDA as a guardian of our well-being, but if the regulator ever was a truly independent safeguard, the reality now is that he is more like a Wizard of Oz figure, pulling the strings of publicity rather than capable of making any meaningful changes—a figure who has made his accommodations with the witches of the East and North.

THE CUTTING EDGE OF CARING

In marked contrast to the increasingly cozy partnerships between regulators and industry in other countries of the world, there have been individuals within the FDA who in recent years have spoken out when they felt that critical health information was being suppressed or unnecessarily delayed. In 2004, David Graham from the FDA's safety department went public with news that as early as 2000 the scientific data had pointed to a seven-fold increase in the risk of a heart attack among people on Vioxx though the FDA were still refusing to require Merck to warn doctors and patients about this risk.
²²
He estimated there might already have been thirty thousand unnecessary heart attacks that could be linked to Vioxx. Graham also pointed to the risks of death from asthma inhalers. Andy Mosholder, another FDA staffer, in 2004 similarly presented an analysis suggesting that the available company trials pointed to a risk of suicide from antidepressants. Both Graham and Mosholder were threatened and both needed support from the Whistleblowers Act. Terrible though such efforts to gag them are, it is unimaginable that anyone within the regulatory apparatus in Europe would step out of line in the way Graham or Mosholder did.

But why should a regulator have to lead the way? Drugs are available by prescription only in part so that doctors will sing out should there appear to be a problem. It's not the job of a regulator to go to the wall for patients—but it is close to the definition of good medical care for a doctor to do so. And even if all the doctors in a particular specialty have been cajoled by a pharmaceutical company's line or its perks, or fall short in their duty to provide safe care, still in the case of drugs such as Vioxx and Prozac the published data in major journals like the
Journal of the American Medical Association
and the
British Medical Journal
point to clear increases in risk that should have alerted the medical profession to look for problems. David Graham and Andy Mosholder were not dealing with confidential data that only the FDA had access to—they appealed to data that was within reach for thousands of doctors—but almost none spoke up.
²³
Why not?

When doctors speak out about a treatment hazard, they often encounter antagonism from colleagues; the revelation is likely to be perceived as bad for medical business and to reflect badly on other doctors who have prescribed this treatment. This antagonism may be even more likely now as company marketing has become adept at ensuring that other doctors do not only see a product being attacked but see their own views being challenged. In addition, most doctors have accepted prescription privileges as a God-given right to a monopoly in drug treatments of people at their most desperate and most vulnerable and have divorced this right from a sense of duty to do something about the hazards of treatment. In this respect, doctors have become one more link in the drug distribution chain rather than the people who once took charge of medical treatments. Something quite extraordinary must have happened to produce such a change in the practice of medicine. The tolbutamide and, later, Prozac and Vioxx cases bring out what has changed.

Concerns that the blockbuster antidepressant Prozac might make people taking the drug suicidal broke in 1990, following the publication of a set of clinical cases in the
American Journal of Psychiatry
, as discussed in
chapter 3
.
²⁴
As this article made clear, within days of starting Prozac some patients became more agitated and suicidal. The agitation got worse if the dose of the drug was increased. It cleared up if the treatment was stopped and reappeared if the treatment was restarted. While depression can cause suicidality, both the treating doctors and the affected patients identified the new state as quite different from their previous experience. In at least one case, the drug led to a completed suicide in a child being treated for anxiety. Finally, intervening with an antidote that blocked the effects of Prozac brought about an improvement. In this series of cases and in others published in the months that followed, according to the rules Robert Koch set out in the 1880s to determine when a bacterium or a drug might have brought about some effect (see
chapter 3
), there was a cast-iron argument that Prozac had caused the problem it stood accused of.

The main way hazards may be hidden right under the noses of doctors centers around Ronald Fisher's efforts in the 1930s to investigate whether fertilizers worked or not, as outlined in
chapter 3
. Fisher, quite arbitrarily, set up a standard—if on nineteen occasions out of twenty plants in a fertilized patch did better than those in an otherwise equal but nonfertilized patch, this was said to be statistically significant and the fertilizer could be said to be effective. If the result came out indicating that the fertilized patch did better only seventeen or eighteen times out of twenty, in Fisher's view, proper scientists should conclude they either had not designed the experiment correctly or they were dealing simply with the play of chance.

Soon after Fisher outlined his view of statistical significance, Jerzy Neyman, another early statistician, argued Fisher was throwing common sense out the window and offering a recipe for scientific sterility, not scientific progress. For most people, having a drug prove its worth in a study in which thousands of patients participate sounds more impressive than demonstrating a benefit in a handful of people. But as was discussed in
chapter 3
, the drug to go for is the one that consistently shows up as working in a small sample. Snake oil, which contains omega-3 and other fatty acids, could be shown to have statistically significant effects on depression rating scales or for pain relief purposes and possibly for some other conditions as well—provided several hundred patients are recruited to the trial. As Neyman was first to point out, we can be fooled by the fact that having hundreds of patients in a study can make a trivial finding statistically significant. Fooled to the extent that these hints of effectiveness can be sold by drug companies as convincing evidence their drug works and should all but be put in the drinking water.

Neyman's beef with Fisher becomes even clearer if we turn to drug hazards. To see this, let us move from fertilized fields to a hazard analogue, such as being faced with a loaded gun. If Fisher had said that it was only when there were bullets in nineteen chambers of a twentychambered gun that the gun could be said to be loaded this would make no sense to any of us. In the experiment that is real life, a lot of us wouldn't go near a gun with even one bullet in its twenty chambers. One bullet is significant enough for most of us. Fisher's approach makes sense in situations where skepticism is called for—as when faced with claims by a huckster or a company trying to make money out of a remedy for sick and vulnerable people. It might indeed be reasonable in this case to suspend skepticism if a treatment “worked” nineteen times out of twenty. But it makes no sense for doctors or patients to be skeptical when hazards are involved—only pharmaceutical companies have an interest in being skeptical about the existence of hazards.

But when it comes to drug hazards, pharmaceutical companies can now confidently bank on the medical community and the FDA following Fisher, not Neyman. The studies of Prozac, and later of other antidepressants, threw up double the number of suicidal acts than were found in patients on placebo, but the numbers involved were not statistically significant. Merck was happy to report over four times more heart attacks on Vioxx than on placebo, again because the numbers were not statistically significant. For Fisher, Merck, and Lilly, this essentially meant the suicides and heart attacks were not happening, whereas for Neyman the onus was on Merck and Lilly to show their gun wasn't loaded.