Black box, black hole

More than three billion prescriptions are written per year, and each and every one of them comes with a complicated instruction manual known as a package insert.

"Package inserts were intended to inform physicians about the risks and benefits of a drug," AMA Trustee Cecil B. Wilson, MD, recently told a Senate panel investigating drug safety. "Unfortunately, today's package insert has become a long and complicated legal document rather than a useful resource for physicians."

Further obscuring matters is the fact that package inserts are intended to convey the gravest of alerts associated with about 500 drugs on the market -- the black-box warnings.

How to keep up with new drugs is difficult enough, but add to that the need to stay abreast of postmarketing prescribing changes, and information overload is likely to swamp even the most careful prescriber.

It is also becoming apparent that the health benefits promised by some pharmaceutical products could be overshadowing equally important safety concerns.

Promoting the safe use of drugs already marketed now has the attention of Congress, the Food and Drug Administration, pharmaceutical companies, physicians and patients -- thanks to the recent high-profile withdrawal of the popular pain medication Vioxx (rofecoxib) and the addition of black-box warnings to its close Cox-2 inhibitor relatives, Bextra (valdecoxib) and Celebrex (celecoxib).

The publicity generated by those changes would make it nearly impossible for physicians and patients to miss them. But often times, label changes receive far less public scrutiny. As a result, working to keep up with the advisories can lead to the prescriber's information overload. For example, last fall a label change was made to Strattera (atomoxeline hydrochloride), a drug for treating attention-deficit/hyperactivity disorder, and a black-box warning was added to the injectiable contraceptive Depo-Provera (medroxygrogesterone acetate).

Although black box warnings and other label changes go into effect as soon as the FDA determines they are necessary, it can take another six months for the information to appear on a printed package insert, said Raymond Woosley, MD, PhD, director of the Critical Path Institute at the University of Arizona Health Sciences Center in Tucson. Samples of drugs also might have been distributed without the new warning material.

In addition, the package insert can become outdated very quickly, said Michael Weber, MD, associate dean for research at State University of New York Downstate Medical Center College of Medicine, in Brooklyn, N.Y. "For a popular drug like Lipitor, there must have been a thousand papers written, but they are in no way summarized in that package insert."

He would like to see these inserts reviewed every year and updated if necessary. "Simplicity and brevity would be a virtue."

Not junk mail

The FDA did publish a proposal in December 2000 to streamline the format and content of package inserts but has not yet released a final rule. The FDA declined to respond to an AMNews request for a publication date.

The agency also requires that pharmaceutical companies send Dear Healthcare Professional letters to physicians and others to alert them to a prescribing change. Thousands are sent monthly. But the consensus is that they aren't very effective.

"Doctors have told me, 'We get so much junk mail that it's hard to find the really important stuff,' " Dr. Woosley said.

"Just look at what happened with cisapride," he added. A study in 2000 showed that the number of prescriptions written and filled for the heartburn medication did not decline substantially despite several Dear Healthcare Professionals letters warning about heart rhythm disorders and deaths in people taking it. The drug was withdrawn from the market in spring 2000.

So what's causing the difficulties? "My bottom line is our whole society doesn't fully appreciate how complex medicines are," said Dr. Woosley, who also directs the Center for Education and Research on Therapeutics at the University of Arizona. "We bar-code everything in the grocery store, but we still aren't bar-coding every pill that's taken."

When it comes to sorting through the information available, primary care physicians are in a bind, said Thomas J. Moore, a health policy analyst at George Washington University in Washington, D.C. "The only usable information comes from the drug sales force."

While some physicians would welcome safety information from sales reps who visit regularly to promote a new medication, others would consider such information suspect.

"I don't think marketing people are a source of unbiased information, and I think that what physicians need to make decisions on behalf of their patients is unbiased information," said Bruce Psaty, MD, PhD, professor of medicine and epidemiology at the University of Washington School of Medicine.

Dr. Woosley recommends that physicians tell patients to get a list of all the medications they take -- vitamins and herbal supplements included -- and ask their pharmacists to run a computer check for drug interactions. They should ask for a printout and take it home with them, he added.

Several physicians also recommend not being the first to prescribe a newly approved drug. "Use drugs with health benefits proven in large, long-term trials, because then we have good information about the benefits as well as the risks," Dr. Psaty said. "Those are the optimal therapies to use, and not the newest drug on the block."

Like other physicians, Dr. Psaty relies on a repertoire of familiar drugs. "I have maybe 50 or more drugs that I can reel off to you from a dozen different classes. I know them pretty well. I know the side effects, and I have a sense if there is a potential interaction problem with other drugs."

Bruce Bagley, MD, medical director for quality improvement at the American Academy of Family Physicians and, before that, a family physician for 28 years, also stuck with a panel of familiar drugs when he was in practice -- "a few antibiotics, a few antihypertensives and the diabetic medicines." A handheld computer and a subscription to a frequently updated database of drugs also was helpful, he said.

But drug safety issues are more of a systems problem than an individual physician problem, Dr. Psaty said. He would like to see the FDA use its authority on behalf of public health to discuss safety warnings more clearly.

"In America we have a chaotic form of care," he said. "Patients can go to six different doctors and 17 different pharmacies." A central system of care would allow for checks on all the drugs a person is taking as a step to prevent harmful interactions, a cause of many problems.

The FDA did take a step in the right direction by issuing a warning March 2 regarding the increased risk of serious muscle toxicity, especially among Asian-Americans, from high doses of Crestor (rosuvastatin), Dr. Psaty said.

But Sidney M. Wolfe, MD, director of Public Citizen's Health Research Group in Washington, D.C., said the black box warnings sometimes serve as a "less than full effort to separate patients from dangerous drugs." The full effort would be taking the drugs off the market, he said, which is what his group had petitioned the FDA to do with Crestor. The FDA declined to pull the drug.

Safety checks

The FDA has in place an Advisory Committee on Drug Safety and Risk Management, which is frequently called upon to grapple with such issues as black boxes, warning letters and package labels.

Although panel member Curt Furberg, MD, PhD, a professor of public health sciences at Wake Forest University Medical Center in Winston-Salem, N.C., agreed that black-box warnings and letters to physicians don't seem to get the attention of prescribers, he favored the warnings because they make it more difficult for manufacturers to develop direct-to-consumer ads for those drugs because ads must include the warnings.

To strengthen patient protections once a warning is issued about a particular drug or class of drugs, the committee also could advise that roadblocks be placed in the prescribing path, Dr. Furberg said. For example, patients could be required to sign forms saying they have been fully informed about the increased risk of heart attacks posed by Cox-2 inhibitors.

Another approach would be to mandate that physicians undertake special training before they are authorized to prescribe the drug. Or a registry of every user of the drug could be established to track any adverse consequences.

Ruth Day, PhD, an advisory committee member and professor of psychology at Duke University in Durham, N.C., has studied the wording and organization of information in black boxes and found them wanting.

Determining what information should be in a black box or on a warning letter is only part of the task, she said. "There's a whole body of research on what kind of sentences people can understand more easily than others." Dr. Day would like to see such research used to shape the information on package inserts and physician warning letters.

"When you think of physicians and all they have to do ... it's huge," she said. "So if you can make the experience of looking at the label quicker and easier, they are going to do it more often. The same applies with the health care professionals letter and the black-box warnings on the label."

The FDA has made efforts to electronically attract the attention of physicians and others via its MedWatch program. The program serves as a repository for physicians' voluntary reports of serious adverse drug reactions among patients and for pharmaceutical companies' mandatory reports of such reactions. Through a system of e-mail alerts, the program also notifies physicians and others about newly revealed drug problems.

So far, MedWatch has about 47,000 subscribers. The FDA would like to have many thousands more signed up.

The agency also published new guidance documents last month designed to help the pharmaceutical industry improve the way it assesses and monitors drug risk.

Meanwhile, members of the Senate Health, Education, Labor and Pensions Committee pledged to take action on the drug safety issue after holding hearings in early March. Committee Chair Sen. Michael Enzi, (R, Wyo.), said new tools are needed to help test drug toxicity before they even get to trial stage.

Committee member Sen. Edward Kennedy, (D, Mass.), said Congress needs to give the FDA the authority to relabel drugs on the market when clear safety concerns arise, instead of following the current system in which the agency has to negotiate with the drug's manufacturer to develop the new label language. "All prescription drugs carry some risks," he said, "and we're clearly not doing enough to minimize them."