A Review by:  Marcia Angell

Read more: http://www.nybooks.com/articles/2009/01/15/drug-companies-doctorsa-story-of-corruption/

Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial

by Alison Bass Algonquin Books of Chapel Hill, 260 pp., $24.95

Our Daily Meds: How the Pharmaceutical Companies Transformed Themselves into Slick Marketing Machines and Hooked the Nation on Prescription Drugs

by Melody Petersen Sarah Crichton/Farrar,  Straus and Giroux, 432 pp., $26.00

Shyness: How Normal Behavior Became a Sickness

by Christopher Lane, Yale University Press, 263 pp., $27.50; $18.00 (paper)

Indeed, most doctors take money or gifts from drug companies in one way or another. Many are paid consultants, speakers at company-sponsored meetings, ghost-authors of papers written by drug companies or their agents,⁴ and ostensible “researchers” whose contribution often consists merely of putting their patients on a drug and transmitting some token information to the company.

Still more doctors are recipients of free meals and other out-and-out gifts. In addition, drug companies subsidize most meetings of professional organizations and most of the continuing medical education needed by doctors to maintain their state licenses.

No one knows the total amount provided by drug companies to physicians, but I estimate from the annual reports of the top nine US drug companies that it comes to tens of billions of dollars a year.

By such means, the pharmaceutical industry has gained enormous control over how doctors evaluate and use its own products. Its extensive ties to physicians, particularly senior faculty at prestigious medical schools, affect the results of research, the way medicine is practiced, and even the definition of what constitutes a disease.

Consider the clinical trials by which drugs are tested in human subjects.⁵ Before a new drug can enter the market, its manufacturer must sponsor clinical trials to show the Food and Drug Administration that the drug is safe and effective, usually as compared with a placebo or dummy pill.

The results of all the trials (there may be many) are submitted to the FDA, and if one or two trials are positive—that is, they show effectiveness without serious risk—the drug is usually approved, even if all the other trials are negative.

Drugs are approved only for a specified use—for example, to treat lung cancer—and it is illegal for companies to promote them for any other use.

But physicians may prescribe approved drugs “off label”—i.e., without regard to the specified use—and perhaps as many as half of all prescriptions are written for off-label purposes.

After drugs are on the market, companies continue to sponsor clinical trials, sometimes to get FDA approval for additional uses, sometimes to demonstrate an advantage over competitors, and often just as an excuse to get physicians to prescribe such drugs for patients. (Such trials are aptly called “seeding” studies.)

Since drug companies don’t have direct access to human subjects, they need to outsource their clinical trials to medical schools, where researchers use patients from teaching hospitals and clinics, or to private research companies (CROs), which organize office-based physicians to enroll their patients.

Although CROs are usually faster, sponsors often prefer using medical schools, in part because the research is taken more seriously, but mainly because it gives them access to highly influential faculty physicians—referred to by the industry as “thought-leaders” or “key opinion leaders” (KOLs). These are the people who write textbooks and medical journal papers, issue practice guidelines (treatment recommendations), sit on FDA and other governmental advisory panels, head professional societies, and speak at the innumerable meetings and dinners that take place every year to teach clinicians about prescription drugs. Having KOLs … on the payroll is worth every penny spent.

A recent survey found that about two thirds of academic medical centers hold equity interest in companies that sponsor research within the same institution.⁶ A study of medical school department chairs found that two thirds received departmental income from drug companies and three fifths received personal income.

Because drug companies insist as a condition of providing funding that they be intimately involved in all aspects of the research they sponsor, they can easily introduce bias in order to make their drugs look better and safer than they are.

Before the 1980s, they generally gave faculty investigators total responsibility for the conduct of the work, but now company employees or their agents often design the studies, perform the analysis, write the papers, and decide whether and in what form to publish the results. Sometimes the medical faculty who serve as investigators are little more than hired hands, supplying patients and collecting data according to instructions from the company.

In view of this control and the conflicts of interest that permeate the enterprise, it is not surprising that industry-sponsored trials published in medical journals consistently favor sponsors’ drugs—largely because negative results are not published, positive results are repeatedly published in slightly different forms, and a positive spin is put on even negative results.

The suppression of unfavorable research is the subject of Alison Bass’s engrossing book, Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial. This is the story of how the British drug giant GlaxoSmithKline buried evidence that its top-selling antidepressant, Paxil, was ineffective and possibly harmful to children and adolescents.

Bass, formerly a reporter for the Boston Globe, describes the involvement of three people—a skeptical academic psychiatrist, a morally outraged assistant administrator in Brown University’s department of psychiatry (whose chairman received in 1998 over $500,000 in consulting fees from drug companies, including GlaxoSmithKline), and an indefatigable New York assistant attorney general. They took on GlaxoSmithKline and part of the psychiatry establishment and eventually prevailed against the odds.

Many drugs that are assumed to be effective are probably little better than placebos, but there is no way to know because negative results are hidden.

One clue was provided six years ago by four researchers who, using the Freedom of Information Act, obtained FDA reviews of every placebo-controlled clinical trial submitted for initial approval of the six most widely used antidepressant drugs approved between 1987 and 1999 — Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor.¹⁰ They found that on average, placebos were 80 percent as effective as the drugs.

The difference between drug and placebo was so small that it was unlikely to be of any clinical significance. The results were much the same for all six drugs: all were equally ineffective. But because favorable results were published and unfavorable results buried (in this case, within the FDA), the public and the medical profession believed these drugs were potent antidepressants.

Clinical trials are also biased through designs for research that are chosen to yield favorable results for sponsors. For example, the sponsor’s drug may be compared with another drug administered at a dose so low that the sponsor’s drug looks more powerful. Or a drug that is likely to be used by older people will be tested in young people, so that side effects are less likely to emerge.

A common form of bias stems from the standard practice of comparing a new drug with a placebo, when the relevant question is how it compares with an existing drug.

In short, it is often possible to make clinical trials come out pretty much any way you want.

Conflicts of interest affect more than research. They also directly shape the way medicine is practiced, through their influence on practice guidelines issued by professional and governmental bodies, and through their effects on FDA decisions.

A few examples: in a survey of two hundred expert panels that issued practice guidelines, one third of the panel members acknowledged that they had some financial interest in the drugs they considered.¹¹

In 2004, after the National Cholesterol Education Program called for sharply lowering the desired levels of “bad” cholesterol, it was revealed that eight of nine members of the panel writing the recommendations had financial ties to the makers of cholesterol-lowering drugs.¹²

Of the 170 contributors to the most recent edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM), ninety-five had financial ties to drug companies, including all of the contributors to the sections on mood disorders and schizophrenia.¹³

Perhaps most important, many members of the standing committees of experts that advise the FDA on drug approvals also have financial ties to the pharmaceutical industry.¹⁴

In recent years, drug companies have perfected a new and highly effective method to expand their markets. Instead of promoting drugs to treat diseases, they have begun to promote diseases to fit their drugs.

The strategy is to convince as many people as possible (along with their doctors, of course) that they have medical conditions that require long-term drug treatment. Sometimes called “disease-mongering,” this is a focus of two new books: Melody Petersen’s Our Daily Meds: How the Pharmaceutical Companies Transformed Themselves into Slick Marketing Machines and Hooked the Nation on Prescription Drugs and Christopher Lane’s Shyness: How Normal Behavior Became a Sickness.

To promote new or exaggerated conditions, companies give them serious-sounding names along with abbreviations. Thus, heartburn is now “gastro-esophageal reflux disease” or GERD; impotence is “erectile dysfunction” or ED; premenstrual tension is “premenstrual dysphoric disorder” or PMMD; and shyness is “social anxiety disorder” (no abbreviation yet).

Note that these are ill-defined chronic conditions that affect essentially normal people, so the market is huge and easily expanded.

Melody Petersen, who was a reporter for The New York Times, has written a broad, convincing indictment of the pharmaceutical industry.¹⁶ She lays out in detail the many ways, both legal and illegal, that drug companies can create “blockbusters” (drugs with yearly sales of over a billion dollars) and the essential role that KOLs play.

Her main example is Neurontin, which was initially approved only for a very narrow use—to treat epilepsy when other drugs failed to control seizures. By paying academic experts to put their names on articles extolling Neurontin for other uses—bipolar disease, post-traumatic stress disorder, insomnia, restless legs syndrome, hot flashes, migraines, tension headaches, and more—and by funding conferences at which these uses were promoted, the manufacturer was able to parlay the drug into a blockbuster, with sales of $2.7 billion in 2003.

The following year, in a case covered extensively by Petersen for the Times, Pfizer pleaded guilty to illegal marketing and agreed to pay $430 million to resolve the criminal and civil charges against it. A lot of money, but for Pfizer, it was just the cost of doing business, and well worth it because Neurontin continued to be used like an all-purpose tonic, generating billions of dollars in annual sales.

er their other properties, are sedating, and nearly all of which have potentially serious side effects.

Similar conflicts of interest and biases exist in virtually every field of medicine, particularly those that rely heavily on drugs or devices. It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.

One result of the pervasive bias is that physicians learn to practice a very drug-intensive style of medicine. Even when changes in lifestyle would be more effective, doctors and their patients often believe that for every ailment and discontent there is a drug.

Physicians are also led to believe that the newest, most expensive brand-name drugs are superior to older drugs or generics, even though there is seldom any evidence to that effect because sponsors do not usually compare their drugs with older drugs at equivalent doses.

In addition, physicians, swayed by prestigious medical school faculty, learn to prescribe drugs for off-label uses without good evidence of effectiveness.

It is easy to fault drug companies for this situation, and they certainly deserve a great deal of blame. Most of the big drug companies have settled charges of fraud, off-label marketing, and other offenses.

Physicians, medical schools, and professional organizations have no such excuse, since their only fiduciary responsibility is to patients. The mission of medical schools and teaching hospitals—and what justifies their tax-exempt status—is to educate the next generation of physicians, carry out scientifically important research, and care for the sickest members of society. It is not to enter into lucrative commercial alliances with the pharmaceutical industry.

As reprehensible as many industry practices are, I believe the behavior of much of the medical profession is even more culpable.¹⁹ Drug companies are not charities; they expect something in return for the money they spend, and they evidently get it or they wouldn’t keep paying.

So many reforms would be necessary to restore integrity to clinical research and medical practice …. Members of medical school faculties who conduct clinical trials should not accept any payments from drug companies except research support, and that support should have no strings attached, including control by drug companies over the design, interpretation, and publication of research results.

Medical schools and teaching hospitals should rigorously enforce that rule, and should not enter into deals with companies whose products members of their faculty are studying.

Finally, there is seldom a legitimate reason for physicians to accept gifts from drug companies, even small ones, and they should pay for their own meetings and continuing education.

After much unfavorable publicity, medical schools and professional organizations are beginning to talk about controlling conflicts of interest, but so far the response has been tepid. They consistently refer to “potential” conflicts of interest, as though that were different from the real thing, and about disclosing and “managing” them, not about prohibiting them.

But if the medical profession does not put an end to this corruption voluntarily, it will lose the confidence of the public.

Source: http://www.nybooks.com/articles/2009/01/15/drug-companies-doctorsa-story-of-corruption/