Pharmageddon (32 page)

In 1961 a long-term study by the National Institutes of Health (NIH) involving over a thousand patients began in which Upjohn's tolbutamide was compared to insulin, placebo, and an amphetamine derivative developed by Smith Kline & French, phentermine, which it was thought might help because it suppressed appetite and led to weight loss. In 1967, a problem came to light: more patients were dying on tolbutamide than on phentermine, insulin, or placebo. The result ran completely against expectation, as the trial protocol excluded anyone thought to be at risk of dying, and controlling blood sugars should have reduced the risk of complications.
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Had some of the treatment centers failed to adhere to the protocol or was there some other explanation of the findings? The investigators could find no explanation aside from some possible side effect of tolbutamide, and in 1969, the study was terminated so as not to put any patients on tolbutamide at further risk. The investigators consulted with Upjohn and the FDA, and an FDA meeting to discuss the study was organized for May 1970. The results of the study were not expected to be made public until an American Diabetics Association meeting the following month.

However, the study results appeared first in the business section of the
Washington Post
, just prior to the FDA meeting. The study, it seemed, had implications for the health of Upjohn that were of concern to many in the commercial sector. The first that many physicians knew of the issue was when anxious patients faced them in the clinic that day with the news. Close to a million people were on tolbutamide in the United States—a lot of anxious patients. This was not the way anyone was used to things happening in medicine.

Patients in many cases found that their doctors seemed personally offended, as if their judgments in putting the patient on this treatment were being questioned. But the doctors were stymied. Their patients didn't know what was going on, but neither did the doctors.
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These doctors flooded the FDA with letters suggesting the bureaucrats had no idea how much distress this was causing patients. The FDA scrambled to respond but they too were faced with a novel situation. It had never been part of the FDA's brief to tell doctors how to practice medicine. They left the NIH academics to fight it out with academics recruited by or otherwise taking Upjohn's side.

Patients also sought out the FDA—asking the agency whether it was still safe to take tolbutamide. Some had worked out from the figures given in the media that over a decade tolbutamide may have killed more Americans than had then been killed in the Vietnam War. How could such a drug still be on the market? The FDA directed patients back to their doctor, still, the agency said, the person best placed to decide the right course of action for them.

The FDA was at pains to insist it was not involved in the practice of medicine and did not wish to subvert clinical judgment. As Senator Kefauver put it in the debate surrounding the 1962 Kefauver-Harris amendments to the FDA bill, introduced after the thalidomide crisis and aimed at controlling the pharmaceutical industry's inappropriate marketing of drugs, “It should be made very clear to Senators and to the country; this is not a Federal control bill. This is a Federal information bill…. I am not talking about regulating medicine between the physician and the patient.”
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Many clinicians simply refused to believe the findings on tolbutamide. They were not used to having data trump their common sense. Perhaps there were more dead bodies in a trial of the drug, but these doctors had given tolbutamide to hundreds of patients, few if any of whom had dropped dead. Besides, how could trials like this take into account all the people whose lives must have been saved by having their blood sugars better controlled? It didn't make sense that a drug doing something so obviously right could be causing problems, no matter what a fancy controlled trial cooked up by some academics might have shown.

Upjohn moved quickly to mobilize a coalition of experts to cast doubt on the NIH research. These company-recruited academics pointed to a number of tolbutamide trials in which, they claimed, there had been no hint of a problem. While these trials were smaller, there were many trials on one side, with only one, albeit larger, trial pointing to a serious problem on the other. The insults began to fly between the academics, with one side accusing the other of being hysterical publicity seekers, attempting only to advance their careers, and the other pointing to the conflicts of interest stemming from participation in Upjohn-convened panels.
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Tolbutamide remained on the market without warnings until the 1980s.

In the meantime, the availability of tolbutamide had put a new premium on detecting elevations of blood sugar. Because of this, when any of us have the most basic of blood screens, the results will include blood sugar levels. Studies of those results concluded that, as of 2008, 30 percent of Western populations have either diabetes or prediabetes. In the wake of such findings, majority medical opinion supported treatment for such patients as early as possible with the hypoglycemic successors to tolbutamide.
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A further National Institutes of Health trial, however, reported in 2008 that tight control of blood sugars with tolbutamide's hypoglycemic successors led in fact to a higher death rate than was found in patients whose blood sugar control was allowed to vary more.
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By 2008 a series of blood-sugar-lowering drugs from Rezulin to Avandia either had to be withdrawn from the market or were required to carry warnings after evidence emerged that they too were linked to excess mortality. Nevertheless, the hypoglycemic market remains one of the blockbuster markets, in 2010, worth over $25 billion per annum and showing growth of 10 percent per annum. This has been a market in which the best teamwork and care in medicine has been harnessed to company sales, but if the data are to be believed, this teamwork is in fact now delivering at least some patients to an earlier death than they might have otherwise had.

The story of tolbutamide prefigures a series of crises that developed around Prozac in the 1990s and Vioxx in 2005. But in 1970, the issues were new for the regulators. Before the amendments to the US Food and Drugs Act triggered by thalidomide in 1962, such conflicts would have been straight contests between doctors and industry. It was in fact the number of doctors who spoke out, at a risk to their careers, that brought the problems with thalidomide originally to light. The public, however, attributed the discovery to the actions of the FDA and as a result for the first time saw in the FDA a third party whom they might turn to for help.

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.