Good Drugs, Bad Rap

These are turbulent times for the pharmaceutical industry and for its regulator, the FDA. Lately, both have focused increasingly on issues of safety. First there were claims that the labeling of certain antidepressants failed to warn doctors that the drugs caused some adolescents to commit suicide. Then the agency was blind-sided by contamination that made half the nation’s flu vaccine supply unavailable, and revelations about previously unknown side effects of several widely prescribed anti-inflammatory analgesic drugs. <?xml:namespace prefix = o ns = “urn:schemas-microsoft-com:office:office” />

Regulators’ increasing sensitivity to safety concerns—sometimes at the expense of the availability of essential drugs—may have become contagious: Drug manufacturers, too, seem to have begun to “err on the side of safety” to a degree that causes safe and effective drugs to be taken off the market voluntarily.

Consider Tysabri, only the sixth medication approved—and the first in several years—for the treatment of Multiple Sclerosis (MS), a debilitating autoimmune disease that affects the central nervous system. The stunning results of the drug’s testing in clinical trials—the frequency of clinical relapses was cut by more than half—induced FDA to grant accelerated approval last fall. MS patients eagerly put their names on waiting lists to get the medicine.

But this ray of hope for MS sufferers was short-lived. By the time that several thousand patients were being treated with Tysabri, three confirmed cases of a rare neurological disorder caused by a virus were reported. (Because the drug suppresses certain aspects of the immune response, regulators, clinicians and the drug’s developers had from the beginning been sensitive to the possibility of infections as a side effect.)

Immediately—some would say prematurely—the manufacturers of the medicine voluntarily halted production and distribution and withdrew Tysabri from the market. MS victims and many neurologists were bitterly disappointed. Now they can only hope that regulators’ consideration of a recently completed comprehensive review of all the clinical data will permit a return of the drug to the market, presumably with new labeling.

Another wrinkle on the voluntary withdrawal from the market of a useful drug concerns financial risk. Drug and medical device companies are especially likely to become the targets of product-liability litigation because they make products that, by their very nature, are intimately involved in life and death situations. Claims for damages are often designed to appeal to the sympathy of jurors prone to picking the proverbially deep pockets of large drug companies. Even when no causal relationship between the product and injury or illness in patients is demonstrated, or when the alleged injury is only a trivial side-effect listed on the product’s label, companies are at risk.

For example, from the 1970s through the mid-1980s, almost 2,000 lawsuits were filed against Merrell Dow Pharmaceuticals, alleging that the company’s drug Bendectin had caused birth defects in the offspring of women who took the drug to prevent morning sickness during pregnancy. No judgments against the company were ever upheld, but ultimately, Merrell Dow discontinued manufacturing the extraordinarily useful drug because it felt an unreasonable and hostile jury might some day award huge damages.

Public policy toward vaccines is a long-standing problem. The CDC’s policy of demanding large discounts on pediatric vaccines and risk-averse FDA regulation have limited vaccines’ profitability and, consequently, their attractiveness to drugmakers. Consider, for example, the travails of the vaccine against rotavirus, a common diarrheal disease which is spread by the fecal-oral route. The virus infects some 2.7 million American children under age five annually — infections that cause half a million physician visits, 50,000 hospitalizations, and dozens of deaths. Direct medical costs are almost $300 million, and overall societal costs amount to several times that. The first live oral vaccine against rotavirus was approved in 1998 and was soon added to the list of recommended childhood vaccinations. After approximately 800,000 children in the <?xml:namespace prefix = st1 ns = “urn:schemas-microsoft-com:office:smarttags” />United States had received a million and a half doses, public health surveillance detected what appeared to be a statistical association between vaccination and a rare bowel abnormality called intussusception (a kind of telescoping of a portion of the bowel that cuts off the blood supply). Although the condition affected only about one in 11,000 vaccinees and is readily correctable with surgery, in response to a public outcry the FDA forced the company to withdraw the vaccine from the market.

Consequently, we are without a rotavirus vaccine and children are dying from the disease. Ironically, more recent data suggest that the vaccine does not actually increase the overall incidence of intussusception, but only concentrates the occurrences of this side effect into a shorter time period following vaccination; in other words, the overall frequency of intussusception is not greater in vaccinated children, although it seems to occur more frequently shortly after the shot.

This situation might finally be remedied in early 2006, when Merck expects to introduce a new rotavirus vaccine. However, FDA regulators, gun-shy about possible side effects, are requiring huge clinical trials—more than 70,000 children—in order to be able to detect even relatively rare side effects before approval.

The result of these actions by FDA and CDC is that innovation has suffered and vaccine producers have abandoned the field in droves, leaving only four major manufacturers and a few dozen products. As of the last flu season, for example, there were only two producers of injectable flu vaccine for the U.S. market, a situation that is especially worrisome at a time when we might need large amounts of vaccine to protect against a pandemic of avian flu.

Another challenge for the drug industry is that various self-styled experts have taken to publicly bashing various important drugs, including Arava for rheumatoid arthritis and Accutane for severe acne. Inexplicably, some have even called for the withdrawal from the market of Natrecor, an important treatment for severe breathing difficulties caused by congestive heart failure. The rationale? That in order to keep patients out of the hospital, some physicians may have prescribed it for less severe heart failure. Even if that’s true, the drug isn’t to blame. Moreover, the medical literature and common medical practice often anticipate formal changes in drug labeling.

The withdrawal of Natrecor would deprive doctors of a critical tool to manage an often fatal disease in the most seriously ill patients, relegating them to alternatives that have been shown to have poor long-term outcomes. As is the case for other drugs that have been shown to be safe and effective, physicians—not journalists or activists—should be permitted to decide which patients will benefit most from Natrecor.

If America’s aging population is to get the new drugs it needs, policy makers must make decisions based on data, and resist speculation and public pronouncements by special interests.