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FDA Reporting Program Is Key to Safety Information

Donna Young

Reports submitted to MedWatch, FDA’s safety information and adverse-event-reporting program, by health care providers and consumers have spurred some of the safety alerts, product-labeling changes, and product removals made by the federal agency. The real-life experiences revealed in these reports, said Norman S. Marks, MedWatch’s medical director since 2000, has helped the government and manufacturers identify problems that were unknown before the products entered the U.S. market.

marksIn April 2000, for example, FDA approved the marketing of linezolid, or Zyvox, the first drug in a new class of antiinfective agents to treat infections associated with vancomycin-resistant Enterococcus faecium, including cases with bloodstream infection. Within months of the drug’s market debut, Marks said, MedWatch received about a dozen reports of myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia, in patients receiving linezolid.

Because of the seriousness of the adverse effects, he said, FDA required the drug’s manufacturer, Pharmacia Corporation, to add a warning to linezolid’s labeling.

Reports made to MedWatch about problems with linezolid, Marks said, have led to safer use of the drug.

ESI Lederle voluntarily withdrew 20 lots of gentamicin sulfate injection in July 1999 after MedWatch received reports of pyrogenic-like reactions, such as fever, chills, or dyspnea, in patients injected with the drug. The manufacturer notified health care providers of the recall, and MedWatch posted the lot numbers, expiration dates, and other information about the product on the FDA Web site.

FDA investigators initially believed that the off-label use of once-daily gentamicin doses caused patients’ exposure to higher amounts of endotoxins than normally encountered with conventional dosing and was responsible for the reactions, according to Toni Piazza-Hepp, deputy director of FDA’s Division of Surveillance, Research and Communication Support.

But an FDA inspection of the foreign supplier of bulk gentamicin sulfate, according to a letter coauthored by Piazza-Hepp and published in the New England Journal of Medicine,1 uncovered inadequacies in the firm’s manufacturing practices that led to more overall impurities in the final product than allowed by the United States Pharmacopoeia standard.

The agency banned imports from the supplier in September 1999.

"The reporting of these adverse events by diligent health care professionals led to the identification, investigation, and of these products by the FDA," wrote agency officials.

Last year, Bayer Pharmaceutical Division voluntarily withdrew cerivastatin, or Baycol, from the market due to reports made to MedWatch of fatal rhabdomyolysis associated with use of the drug.

And this year, a black-box warning was added to the labeling of Bristol-Myers Squibb’s nefazodone hydrochloride product, Serzone, after MedWatch received reports of rare cases of liver failure leading to transplant or death in patients.

FDA does not require a certain number of reported problems before determining that a warning must be added to a product’s labeling or the product must be removed from the market, Marks said. Rather, decisions are made on a case-by-case basis.

The agency requires manufacturers to report problems with drug products and medical devices. Health care professionals and consumers, Marks noted, should report problems with drug products, biologicals, medical devices, and dietary supplements to the MedWatch program.

MedWatch sends data to FDA’s Division of Drug Risk Evaluation, he said, where information is entered into the agency’s Adverse Event Reporting System to be sorted, tracked, and analyzed by drug safety evaluators.

The MedWatch reporting form, Marks said, includes an area for health care professionals and consumers to acknowledge if a reported problem was also submitted to a manufacturer or distributor. This information helps the evaluators identify duplicate reports.

The MedWatch program was established in 1993 to simplify the reporting of adverse events to FDA, Marks said. In 1998, the agency initiated online reporting for health care professionals and consumers from its Web site at Of the 23,208 reports submitted to MedWatch last year, 26% were made via the Internet, according to FDA’s Office of Drug Safety 2001 annual report.

Pharmacists made 9703 reports (PDF) to MedWatch last year—the most of any professional group.

This greater amount of reporting occurs because pharmacists are more accessible to the public than other health care providers and are better able to identify adverse drug events, said pharmacist David Konigstein, a commander with the Public Health Service and senior health promotion officer for MedWatch.

"Pharmacists are out there and are exposed to a lot of patients who may, when they are changing from one drug product to another, in casual conversation relate to a pharmacist ... a problem they had with a drug," he said. "Too often a physician will just change the prescription and not report that the patient had an adverse event."

According to FDA, 71% of the reports made to MedWatch last year involved problems with drug products. Nearly 3% of the reports were made about problems with dietary supplements and other special nutritional products.

Before the evolution of the Internet, Marks said, health care providers had difficulty getting current information about drug products’ labeling changes regarding new warnings about drug interactions, dosage adjustments, and possible adverse effects. Many health care professionals had only a printed version of AHFS Drug Information or Physicians’ Desk Reference to keep them updated about labeling changes.

"I was lucky if I had a current version" of those drug information guides, said Marks, who practiced as a urologist for many years in Indiana and Illinois before joining FDA in 1998. "But now, health care professionals are under greater pressure to be more efficient, and pharmacists are expected to keep current and yet do more work in a shorter time," he said.

To help spread the word about safety-related changes to products’ labeling, MedWatch established an e-mail notification program in 1998. Health care professionals and consumers can register with the program by signing up at the MedWatch Web site.

Subscribers receive alerts about drug product and medical device recalls, labeling changes, and other advisories, Marks said.

As of late October, Konigstein said, MedWatch had about 26,500 subscribers to the e-mail notification service. Subscribers’ names and e-mail addresses, he added, are not shared with any other organization.

Health care professionals and consumers may also use the MedWatch Web site to submit general questions, which Konigstein answers by e-mail.

  1. Fanning MM, Wassel R, Piazza-Hepp T. Pyrogenic reactions to gentamicin therapy. N Engl J Med. 2000; 343:1658-9. Letter.