Overdosed America (18 page)

Research results cannot always be hidden when studies don’t come out in the drug company’s favor, but that doesn’t mean drug companies don’t try to influence researchers to minimize the damage. Dr. William Applegate, then from the University of Tennessee, was a principal investigator in a study of a new blood pressure pill, DynaCirc, sponsored by the drug maker Sandoz (now Novartis).
Not long before a dramatic meeting
at which researchers were going to be shown the results of their study, Applegate was offered a $30,000-a-year consulting position with the drug company. He turned down the offer. Then, when he saw the data, he told the
Baltimore Sun,
“I thought the company was trying to buy my favor and my opinion.” It was simple. Sandoz’s new blood pressure drug had a higher rate of complications than the older drug with which it had been compared. The company twice made offers of research grants to Applegate’s research center, each time asking whether he had reconsidered his conclusions about the study.

Applegate eventually resigned from the project along with three of his colleagues. In a letter to JAMA,
explaining the reason for their departure
, the investigators stated: “We believed that the sponsor of the study was attempting to wield undue influence on the nature of the final paper. This effort was so oppressive that we felt it inhibited academic freedom and led to substantial differences . . . with regard to the ultimate presentation and interpretation of the results.” Dr. Applegate and his three colleagues endorsed the ultimate presentation of the study in JAMA, but most likely their willingness to resign on principle in the face of drug-company pressure played an important role in the publication of a fair report.

As the function
of medical research in our society has been transformed from a fundamentally academic and scientific activity to a fundamentally commercial activity, the context in which the research is done has similarly changed: first in universities funded primarily by public sources, then in universities funded primarily by commercial sources, then by independent for-profit research organizations contracting directly with drug companies. And most recently, the
three largest advertising agencies
, Omnicom, Interpublic, and WPP, have bought or invested in the for-profit companies that perform clinical trials. These advertising agencies are now full-service operations, as an executive for one of the biggest health care marketing companies told the
New York Times:
“We provide services that go from the beginning of drug development all the way to the launch of your products.” The dialectic of the market rolls along.

There is nothing illegal or unethical about these commercial arrangements, but both the public’s interest and the commercial sponsor’s interest cannot always be served simultaneously: Either a study is designed to maximize sales or it is designed to determine the best way to prevent or treat a particular health problem. Certainly commercially sponsored research has produced important findings. But at best, the medical knowledge produced by commercial interests is restricted to the medical problems that are most profitable to study. And at worst, research is manipulated, misrepresented, or withheld, with the goal of maximizing sales. The most visible consequence of this is ignoring diseases like malaria, which causes millions of unnecessary deaths each year but has little appeal to industry because the disease occurs in the third world, where there are relatively few paying customers. Much less obvious is the extent to which it has become accepted as “normal” to sacrifice the well-known standards of medical science to achieve commercial goals.

The drug companies pour billions of dollars each year into medical research, and they need to have a number of successes in order to stay in business. Nonetheless, as
Drs. Bruce Psaty and Drummond Rennie
said in a JAMA editorial, “Medical research, even if it is conducted by the pharmaceutical industry, is not solely a commercial enterprise designed to maximize personal gain or company profits. The responsible conduct of medical research involves a social duty and a moral responsibility that transcends quarterly business plans or the changing of chief executive officers.”

If it weren’t
so important, my struggle to keep up with all the new developments in medicine that came across my desk would bring to mind the hilarious scene from
I Love Lucy
when Lucy and Ethel struggle in vain to package the chocolates flying by them on a conveyor belt. The sheer volume of new material is overwhelming. Perhaps if doctors had the time to critically analyze each article before adopting its conclusions and recommendations, they would see through the commercial bias; but there are not enough hours in the day. Even the most disciplined practitioner cannot keep up with more than one or two medical journals, let alone with all of the new drugs and developments in all of the different fields of medicine. Since few doctors have the time to figure out which new drugs or procedures are real improvements—and for which patients—it should come as no surprise that the medical industry, well aware that
doctors are responsible for about 80 percent
of all health care expenditures, is more than willing to lend a helping hand.

From the moment doctors enter medical school to the moment they retire, drug companies and medical-device manufacturers attempt to influence their medical decisions. Armed with their industry-generated medical research, marketing and sales departments rarely miss an opportunity to persuade doctors to incorporate new drugs and products into their practices. Medical students and residents are treated to free lunches while they listen to subtle and not so subtle infomercials. Company salespeople schmooze and muscle their way into doctors’ offices, leaving behind a trail of freebies emblazoned with their products’ names. Doctors are invited to learn about new medical breakthroughs at free suppers and conferences in tropical paradises. And most pernicious: companies lure doctors into becoming paid consultants, staff experts, or lecturers, leveraging their relationships and prestige to hawk the companies’ products to their peers.

Doctors tend to believe that they are immune to drug company influence. They don’t realize that at every step of the way, at every moment of information transfer, and with nearly unimaginable skill, the medical industry insinuates itself into their medical decision making. And often this influence is invisible. Even if a doctor wants to avoid these entanglements and relationships, the culture of American medicine is such that he or she has to make a special effort to maintain what appears to colleagues as an outsider, holier-than-thou code of ethics. Doctors finish their training at about age 30, with enormous medical school debts and in many cases young families. Accepting freebies or financial support from industry sponsors seems like a reasonable reward for their efforts. The practice is so pervasive and looks like such standard operating procedure that many doctors believe that it doesn’t adversely affect their patient care. Unfortunately, they are wrong.

According to the
editor of the
British Medical Journal
, Dr. Richard Smith, “The major journals try to counterbalance the might of the pharmaceutical industry, but it is an unequal battle—not least because journals themselves profit from publishing studies funded by the industry.”

The journals benefit from the publicity gained from publishing large drug company–sponsored studies. This increases the value of their advertising and enables them to sell back to the drug companies reprints of articles, which the drug companies then distribute as marketing tools to doctors. According to Dr. Smith, this can amount to more than $1 million for a single article. At the same time that medical journals are given incentives to please the drug companies, they are also given strong disincentives to go against drug company interests. According to
Dr. Marcia Angell
, former editor of NEJM, editors of medical journals exercise self-censorship—trying to avoid offending their chief advertisers, the drug companies.

Dr. Robert Fletcher
learned about this firsthand. In 1992, he was editor of the
Annals of Internal Medicine
when it published an article reporting that 44 percent of the drug ads in medical journals were written in a way that would lead doctors with no other source of information to prescribe improperly. The article also reported that 92 percent of these ads were in some violation of FDA rules. Writing in
The Lancet
in 2003, Dr. Fletcher said that as punishment for publishing this article, the pharmaceutical industry “withdrew many adverts” and showed that it was “willing to flex its considerable muscles when it felt its interests were threatened.” This is a price that medical journal editors would prefer not to pay.

Even if a doctor could keep up with all the studies that were published, he or she would still have a limited and skewed view of the real evidence. Notwithstanding all the potential ways that research can be tipped in favor of a sponsor’s product, clinical trials still tend to reveal the truth about whether a new therapy is effective—or not. The problem is that research that shows that a product is not effective or safe can be hidden away, that is, the “knowledge” can be filtered to let through findings that favor the sponsor’s product, making it difficult for even the most fastidious doctors to discover the truth. Positive studies tend to get published quickly, so sales of expensive drugs and new technologies get a jump-start. Negative studies have a much higher likelihood of not being published at all or being published only after a lag time that protects the company’s profits—the public’s health be damned.

These words may sound too harsh; surely no drug company would ever go that far. But when the truth finally comes out about how doctors’ access to the scientific evidence has been manipulated, we find that this is exactly what happens. One example stands out above all the rest for me because in this case I was seriously misled in the care of so many of my patients. In the 1980s, cardiologists had a low threshold for recommending 24-hour ambulatory heart monitor (“Holter monitor”) tests. The purpose of these tests was to identify heart patients who were having irregular heartbeats that put them at increased risk of fatal arrhythmias—like the one Mr. Peters almost suffered. The criteria for starting an antiarrhythmic drug to suppress extra heartbeats were well established, and the degree to which the particular drug and dose had succeeded in suppressing each patient’s extra heartbeats could be evaluated by repeating the 24-hour heart monitor test. Few diagnostic tests and therapeutic interventions seemed as important as decreasing these patients’ risk of sudden death.

These so-called class I antiarrhythmic drugs
*
were routinely prescribed into the 1990s. It turned out that even though these drugs do effectively decrease the frequency of extra heartbeats, they
increase
the risk of death. One study documenting a higher death rate in people treated with these drugs was completed in 1980. The results, however, weren’t published until 1993. According to
a 2003 article in JAMA
, had doctors been aware of these findings earlier, their use might have been stopped sooner. The JAMA article then presents a frightening calculation: “There are estimates that 20,000 to 75,000 lives were lost each year in the 1980s in the United States alone from inappropriate administration of [class I] antiarrhythmic drugs.” I wonder if any of those were my patients, taking medications that I had prescribed. And I wonder how much more money the drug company made as a result of the 13-year delay in the publication of these findings.

The mistakes of medicine are always easier to see through the “retrospectoscope.” What we think we now know about the new antidepressants provides a current example. In a recent survey, respected primary care doctors
ranked the new antidepressants
as the eighth most important medical innovation of the past 25 years. And well they should; the scientific evidence available to them left little doubt about the benefit of these drugs. There is, however, a lot of evidence that they couldn’t have known about.

When
application was made to the Swedish Drug Authority
for approval of five new antidepressant drugs, 28 separate clinical trials evaluating the drugs’ effectiveness had been published in medical journals. The results were overwhelmingly positive: Twenty-two studies showed that the new drugs were significantly more effective than a placebo, and only 6 showed no difference. In Sweden, drug applications must include
all
known studies—published or not—relevant to the new drug. When researchers from the Swedish Drug Authority went through the new drug applications for the five new antidepressants, they found that a total of 42 studies had been completed. It turned out that exactly half of these showed that the new antidepressants are more effective than the placebos and half found that they are not. The 22 positive articles that had been published represented 19 of the positive studies (three were published twice). In contrast, only six of the 21 studies with negative or inconclusive findings had been published. Even the most conscientious doctor could know only the results of the studies that had been published and would reasonably conclude that the weight of the evidence about the new antidepressants was overwhelmingly positive.

The Swedish researchers commented that their finding that 40 percent of the studies that had been completed on these drugs remained unpublished (as independent studies, not pooled with others) was consistent with the findings of other such reviews. In their conclusion, they warned that “for anyone who relies on published data alone to choose a specific drug, our results should be cause for concern.. . . Any attempt to recommend a specific drug is likely to be based on biased evidence.” What else can a practicing physician rely on but the published data? In an understated way, these researchers were telling doctors that they could not trust the published scientific evidence about antidepressants to be complete and unbiased.