Inconsistent Adherence to Black Box Warnings: A Newsmaker Interview With Anita Wagner, PharmD, DPH

Laurie Barclay, MD

November 18, 2005

Nov. 18, 2005 — Editor's Note: Physicians often fail to comply with Food and Drug Administration (FDA) black box warnings for drugs, especially with regard to laboratory monitoring, according to the results of a large survey reported online in the Nov. 18 issue of Pharmacoepidemiology and Drug Safety.

The Investigators in this retrospective study analyzed automated claims data from 929,958 enrollees in 10 geographically separated U.S. health plans. Specifically, they looked at use of 216 black box warning drugs and drug groups. From Jan. 1, 1999, through June 30, 2001, 42% of enrollees received at least one drug carrying a black box warning. In nearly half of all cases where the black box warning included recommendations for baseline laboratory monitoring, these recommendations were not followed. There were few instances of prescribing during pregnancy of drugs absolutely contraindicated in pregnancy, and almost no coprescribing of contraindicated drugs with the two QT-interval-prolonging black box warning drugs evaluated.

Physician compliance with recommendations listed in black box warnings was highly variable, ranging from 0.3% to 49.6%, which suggests a need for better methods to ensure the safe use of drugs carrying serious risks. To learn more about the implications of these findings, Medscape's Laurie Barclay interviewed lead author Anita Wagner, PharmD, DPH, assistant professor in the Department of Ambulatory Care and Prevention at Harvard Medical School and Harvard Pilgrim Health Care in Boston, Massachusetts. Dr. Wagner is also codirector of the Pharmaceutical Policy Research Fellowship, Drug Policy Research Group.


Medscape: What was the impetus behind performing this study?

Dr. Wagner: We are interested in improving medication use by patients and prescribers. Appropriate medication use requires that information about risks associated with drugs is effectively communicated to prescribers and patients. Risk communication through drug labeling is one of the FDA's primary approaches to risk management. A black box warning is the strongest labeling requirement the FDA has, intended to alert prescribers to the high risks associated with a drug.

We conducted the first large study of the prevalence of use of black box warning drugs. Our objectives were to find out which drugs carry a black box warning, how frequently they are used, and, for some of them, how consistent use is with the recommendations in the black box warning.

Medscape: What were the main findings of this study?

Dr. Wagner: We found that there are many black box warning drugs and groups of drugs that carry a black box warning (over 200); that they are used frequently (more than 40% of patients in ambulatory care receive black box warning medications); and that consistency of use with the black box warning recommendation varies widely among the drugs and types of black box warning. The wide use of black box warnings makes it very hard for prescribers to know what is important and what is really important.

Medscape: How serious a threat to public health is physicians' failure to observe black
box warnings?

Dr. Wagner: This is a very important question and should be a focus of future research. Our study cannot answer this question because we did not look at the effects of adhering or not adhering to the recommendations of a black box warning. Our study shows wide use of black box warning drugs and that prescribing compliance with the warnings varies, and thus suggests a potential for harm.

Medscape: Why do you believe some categories of warnings, such as performing pregnancy tests before starting potentially teratogenic drugs, are most often ignored?

Dr. Wagner: Generally, black box warnings recommending laboratory testing had the lowest adherence rates in our study. This may be due to a number of factors. For example, physicians may know about a women's potential to get pregnant, and when that is not an issue, decide not to order a baseline pregnancy test. Many drugs carry black box warnings that recommend liver function tests. There is debate about how useful liver function tests are to prevent drug-induced liver failure, and physicians' decisions not to monitor liver function may be based on the lack of evidence for their usefulness.

Medscape: What can be done to improve physician adherence to black box warnings?

Dr. Wagner: We need several things to improve the effectiveness of black box warnings: be clear about the magnitude of risk that justifies a black box warning and the evidence that underlies a black box warning monitoring recommendation; communicate black box warning content clearly to both clinicians and patients; and create systems, such as alerts in electronic medical records when a high-risk drug is prescribed, that support clinicians and patients in adhering to recommended practice.

Medscape: What type of additional research is needed?

Dr. Wagner: Achieving these goals will require new information about risks of drugs; the way drugs are used in everyday practice; effective methods of influencing clinicians' prescribing, which consider the time pressures and other demands put on clinicians and use information technology; and systems to improve patient-prescriber interaction and quality of care. [We will also need] ways to ensure that patients understand how to use their drugs as safely as possible, and an evaluation strategy to assess whether new risk communication efforts are effective.

Medscape: Is there anything you would like to add?

Dr. Wagner: Our study adds to evidence of other studies showing that black box warnings do not work well as risk communication tools. In fact, perhaps in response to limited adherence to black box warnings, the FDA and manufacturers increasingly implement strengthened risk management programs for certain drugs. An example is the iPLEDGE program for isotretinoin that requires wholesalers, pharmacies, prescribers, and patients to assume specific responsibilities designed to minimize pregnancy exposures. Prescribers must obtain and enter into the iPLEDGE system negative pregnancy test results for women of childbearing potential before prescribing isotretinoin, and only a current negative pregnancy test result authorizes a pharmacist to dispense the drug.

Disclosures: The Agency for Healthcare Research and Quality supported this study through a grant to the HMO Research Network Center for Education and Research on Therapeutics. Dr. Wagner reports no disclosures, financial or otherwise.

Pharmacoepidemiol Drug Safety. 2005;14:1-18

Reviewed by Gary D. Vogin, MD

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