TCS Daily

Nuclear Medicine

By Iain Murray - April 4, 2005 12:00 AM

Users of the popular eczema medications Elidel and Protopic will have been stunned by the recent announcement that the Food and Drug Administration is to require the medicines to carry "a strong advisory about a cancer risk" (Reuters, March 11). An FDA panel recommended a "black box" warning be included on the ointments' packaging. A "black box" is the strongest warning carried on medicines. Yet the reasoning for the warning is hotly disputed by not only the manufacturers, but also by independent bodies like the American Academy of Dermatology and the National Eczema Association for Science and Education. In fact, there is no real clinical evidence for any association with cancer. The FDA appears to have deployed its "nuclear option" for other reasons.

The FDA officially based its reasoning for the cancer warning on animal studies that found "the risk of cancer increased as the amount of the drug given increased." Yet the animal studies are hardly convincing. In one study of mice, the researchers found no skin cancer in animals that were exposed for two years to twenty seven times the normal human dose. A study of monkeys that found cancers increased as the dose increased had the animals given the medicine at even higher levels than the mice. The dose was also administered orally when the medicine is meant for external use only. The animal data clearly cannot be generalized to typical human use of the products.

The FDA also referred to "a small number of reports of cancers in children and adults treated with Elidel or Protopic." The FDA should know that the plural of anecdote is not data. Clinical trials of the products showed no evidence of an increased risk of malignancies compared with steroid creams like hydrocortisone. Since Elidel went on the market in December 2001, there have been only six spontaneous reports of cancers among the product's users. The verdict of independent experts who looked at three of these cases was that Elidel use was unlikely to be the cause. Several members of the FDA panel agreed that the link between the medications and cancer was not strong enough to warrant action.

Given the weak clinical case, then, why did the FDA panel choose to deploy their "nuclear option?" Wading through the 413-page transcript of their day-long deliberations available on the FDA web site gives plenty of clues. The panel considered lesser options like amendment of the informational insert that goes in all medications, but agreed that this would not achieve anything as these inserts are generally "tossed." One might ask, if this is the judgment of an FDA panel, why does the FDA continue to impose such an onerous requirement upon pharmaceutical suppliers?

The panel's primary concern, however, was over the success of the products in penetrating the market. When they were approved for use by the FDA, the label suggested that they be a second-choice option behind the corticosteroids. Yet Elidel alone has been prescribed to over 5 million patients.

The panel regarded this as inappropriate. They were particularly concerned about the aggressive marketing of the product both to physicians and consumers. Yet they were also informed by FDA experts that the marketing was perfectly legal. Products with "black box" warnings, however, have certain restrictions put on their marketing. They cannot use what are termed "reminder ads" -- the sort of ads that tend to show happy people who are obviously users of a medication without telling you what the medication does (which would mean they would have to list potential side effects), normally closing with a reminder to "ask your doctor" if the medication "is right for you." This restriction clearly had a bearing in the panel's decision to go for the "black box" option.

By taking the decision on at least partly this basis, the panel denigrated the entire field of general practice. They essentially decided that the nation's doctors, who go through many years of training and whose intellectual capabilities are among the finest in the nation, are unable to make informed decisions about what medicine is in the best interests of their patients. If the FDA believes that "off-label" prescription is a problem it should seek powers to deal with the problem directly rather than using this end-around to restrict legal advertising.

By using the "nuclear option," the FDA has undoubtedly created other problems. Some people for whom Elidel was the most appropriate medicine will no longer be prescribed it. And the warning has also opened the door for trial lawyers (try a search for Elidel and cancer on Google and see what pops up first), creating massive extra liabilities for the drugs companies at the same time as reducing their income and thereby increasing the price of all medication.

This case reveals some serious institutional problems in the FDA. There is clearly something wrong with its requirements for drug information if the documents it requires are regarded as inconsequential by its advisory panels, while it is happy to use a serious clinical warning simply to restrain marketing. The FDA's regulations are clearly out of step with the powers it feels it requires. Perhaps this would be a good time to step back and consider what powers and regulations are really necessary for the safe and timely approval of the medicines that continue to improve our nation's health.


TCS Daily Archives