Making Sense of Drug Safety

Have you ever tried to read the official FDA-approved labeling for a drug? It's tough going even for physicians who are trying to find something in a hurry, and almost impossible for non-experts. Although there is a standard format for the subheadings, it has no rhyme or reason, and there is a lack of consistency in fonts and spacing. Both common sense and focus groups tell us that critical information such as the drug's uses, warnings and dosage should be up front, but instead it's buried in the middle of the labeling—and in impenetrable small print.<?xml:namespace prefix = o ns = “urn:schemas-microsoft-com:office:office” />


Consider, for example, the antibiotic Cipro, whose labeling in the Physicians' Desk Reference runs to five full, large pages of tiny print. The first paragraph of the first section, “Description,” contains this gem: “Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-t-fluoro-1, 4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance. . .” Just the info you need at your finger tips! And the second section, “Pharmacology,” is equally unhelpful, discussing absorption, distribution within the body, metabolism, excretion and so on.


It's not until the third page of the labeling that we finally get to critical information, “Indications and Usage.” After that follows a series of discrete sections whose contents overlap significantly (and problematically): “Contraindications,” “Warnings,” “Precautions,” and “Adverse Reactions.” (Even FDA officials cannot explain what goes where.) Later still, we get to “Dosage and Administration.”


Although final product labeling results from weeks or even months of discussions between a drug's manufacturer and the FDA (which has absolute discretion over the style and substance of labels), this incomprehensible, unwieldy format prevents efficient communication of essential information about the drug. If it had been up to drug companies, they would likely have adopted a standardized and more workable format decades ago; it appears that at last the FDA has gotten the message.


During a recent advisory committee meeting, FDA officials outlined proposed new labeling, which is expected to be published soon. Information will be organized logically and in order of importance: boxed warnings (the most forceful caution that FDA can require), what the drug is used for, and then the dosage and administration. Any major changes in the label will also be prominently featured, and the old sections on contraindications, warnings, precautions and adverse reactions (that is, side-effects) will be consolidated. There will also be, we are told, “more clarity in the adverse reaction section.”


The FDA also intends to introduce DailyMed, “an electronic repository of . . . the most current labeling, vetted, approved, the gold standard of drug information.” I am looking forward to it; the Physician's Desk Reference on my office bookshelf is the 2004 edition, which means that the data were compiled at least two years ago.


These initiatives will be a marked improvement over the current, antiquated system of drug labeling. However, all of the FDA's innovations are not so inspired. Much criticized lately for supposed deficiencies in the surveillance and reporting on the safety of drugs, the agency is implementing a wrong-headed scheme for releasing data on drugs' adverse reactions. In May, the FDA announced its new Drug Watch program, which will make “emerging safety information” publicly available. According to the FDA, this program “is intended to identify drugs for which FDA is actively evaluating early safety signals. The Drug Watch is not intended to be a list of drugs that are particularly risky or dangerous for use; listing of a drug on Drug Watch should not be construed as a statement by FDA that the drug is dangerous or that it is inappropriate for use. Rather, inclusion on the Drug Watch signifies that FDA is attempting to assess the meaning and potential consequences of emerging safety information.”


FDA further “clarifies” in the same document that Drug Watch is intended “to share emerging safety information before we have fully determined its significance or taken final regulatory action so that patients and healthcare professionals will have the most current information concerning the potential risks and benefits of a marketed drug product upon which to make individual treatment choices.”


However, it is difficult to fathom how physicians and other health-care providers—let alone members of the public—can make good use of such preliminary data, which will be available on the agency's website. There is a difference between indiscriminate data and useful information, and Drug Watch seems destined to provide far more of the former than the latter. Moreover, given the current fervor at FDA for ensuring drug safety, and the difficulty of proving a negative, one wonders how a “suspect” drug could ever clear its name and get off the Drug Watch list.


As FDA Deputy Commissioner Scott Gottlieb has said, “Information that could influence clinical medical practice needs to be made available more quickly, and more widely, after it has gone through a deliberative scientific process that firms up its meaning and the magnitude and the veracity of its conclusions [italics added].”


DailyMed, which will provide up-to-the-minute labeling information, meets these criteria, while Drug Watch fails miserably.


Surely, it would be better to rely on what FDA considers to be information that is “vetted, approved, gold standard” than on what Dr. Gottlieb himself has dismissed as data “still un-scrubbed by scientific rigor.”


My advice to FDA: Take two aspirin, get a good night's sleep, and perform a Drug Watch-ectomy in the morning.