Pharmageddon

by David Healy

  THE WIZARD OF OZ

  When asked what a regulatory agency does, many involved in healthcare respond that agencies like the FDA, either in a commissioning capacity or in conjunction with universities, even if supported by pharmaceutical companies, are responsible for the clinical trials that bring drugs to market. In this view, the agency, directly or through independent investigators cooperating with them, designs the protocols for trials, arranges for the conduct of the research, collects, tabulates, and analyzes the data that academics then write up in articles that faithfully represent the data. These articles are peer-reviewed, and especially if outlining notable advances, they are likely to appear in the most distinguished journals, offering further assurance, so it is thought, of the validity of the data and the conclusions presented. It is also commonly assumed that the FDA in some way houses the raw data so that should a problem develop with a drug after marketing, someone independent of the pharmaceutical industry can consult the data and determine whether there is cause for concern. None of this is the case.

  What most people think the FDA now does is very much what the American Medical Association used to do with all new drugs from the 1940s to the mid- 1950s but does not do now. Once the AMA stopped doing this, except in the increasingly rare instances, such as the NIH tolbutamide studies, in which the government or an independent institution decides to do a study itself, there is no independent research done on new drugs. When it comes to the study of drug treatments, the medical profession has been eclipsed. The public think the FDA has stepped into the breach but in fact pharmaceutical companies now control everything.

  Companies decide which trials to conduct, which ones to make public, and what data to release. The trials are designed not only to gain regulatory approval but also to test for characteristics that fit company marketing requirements and may bear little relationship to what some of the drug's most telling effects are. Thus the “benefit” of SSRIs for premature ejaculation was so clear-cut that trials were almost unnecessary. In contrast, the effects of the drugs on mood were so weak that in the clinical trials of SSRIs as antidepressants, hundreds of patients were needed to come up with statistically significant results. Yet, the drugs were licensed for depression and have since been called antidepressants, while the effects on sexual functioning, if acknowledged at all, are labeled side effects. It is not the job of the FDA, or any regulator worldwide, to tell a company what its business should be.

  Drug trials are increasingly conducted in settings and by notional investigators that suit company interests. When it came to testing antidepressants in children, the first wave of trials took place in North America, recruiting heavily among children in foster care, before a second wave moved to South Africa, Brazil, and elsewhere. It is not the job of the FDA, or any other regulator, to note this and wonder if trials done in circumstances such as these will produce results that should be allowed to dictate the treatment of the child across the road—or at least the regulators have not read their safety brief in this way.

  In the case of tolbutamide, the study was run by the NIH, but now private companies known as clinical research organizations (CROs) run almost all trials. These trials may only have had ethics clearance from the CROs' own panels, and they may include nonexistent patients (one convenient aspect to these bogus patients, unlike those taking tolbutamide, is that they can't die). Also in contrast to the patients dying on tolbutamide, patients suffering adverse effects in company trials may be coded as dropouts for noncompliance rather than injured by treatment. Finally, in contrast to the tolbutamide trials, the publications stemming from company trials will likely be ghostwritten.

  Of even greater importance is that in the case of tolbutamide, the investigators had the data, but today's investigators for statins, asthma drugs, hypoglycemics for diabetes, or antidepressants don't. The file of data from company trials of these drugs notionally goes to the FDA but the regulators in fact work from tables of the raw data already made up for them and company reports as to what the trials have shown. Furthermore, as of the 1990s, the FDA has been encouraged by both Congress and the executive branch of both Republican and Democratic administrations to see itself as a partner of industry; in this climate a zealous commitment to safety is not likely to be viewed with favor by their new partners.

  There are no academics now who can speak out about a problem in the way the academics from NIH did in the case of tolbutamide. This shifts the burden to the FDA—but this agency is not equipped to be a scientific arbiter. The FDA acts essentially as an auditor for drug company data and no more. When the raw data are submitted to them, the agency typically samples the clinical records to determine whether they correspond with figures in various tables that have been constructed by the company.

  FDA officials may analyze some of these tables themselves but usually will simply comment on the methods used by the company. If further analyses are deemed necessary, the company is asked to perform these. Should a problem arise with the drug after it has been approved for marketing, the FDA will typically write to the company and inquire what the company's database might reveal about the issue. They will ordinarily trust the report that is prepared by the company, despite a series of cases in which company reports have borne little relationship to the underlying raw data, as we shall see below.

  The companies, not the regulators, write the labels and any warnings for the drug, though the FDA must approve them. There are a number of technical issues that are considered, such as the precise meanings the FDA has given to words like “rare” and “frequent.” These have been tied down to rates that may be, for example, greater than 1 in 100 (frequent) or less than1in 10,000 (rare), and the FDA will ensure that such words are used in their technically correct fashion.

  The FDA's role in a drug's regulation can be brought out by considering the agency's role in regulating a food like butter. While one officer in one part of the FDA may have to decide whether a drug can be labeled as a treatment for asthma or osteoporosis, another may be faced with a slab of yellow material a company wishes to label as butter. Is it butter or lard colored to look like butter? The regulator has a set of criteria for butter, dealing with what it should contain and what it cannot contain. If the yellow material meets the criteria, the regulator has no option but to let it on the market labeled as butter. In the case of butter or other foods words such as “organic,” “fresh,” and “local” are defined by the regulator, and the challenge for companies is often to find a way around the definitions in order to make use of these premium descriptive terms. It is not the job of the regulator to decide if this is good butter or not. Nor is it considered the job of the FDA to decide if butter is good for our health. Consumer agencies survey available butters to answer the first point, while medical associations or others in healthcare will issue guidance from time to time on whether we should be eating as much butter as we do.

  But unlike butter, in the case of drugs FDA approval is now taken to mean that these treatments are good treatments and that treatment is good for you—with no consumer groups scrutinizing just how good these products are, and above all, no groups of physicians reviewing the issue of whether it is appropriate to be on as much treatment as we are.

  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 w
ere 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.”21 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 ens
uring 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.