FDA Targets Unapproved Drugs

[February 15, 2007, AJHP News]

Donna Young

ROCKVILLE, MD, 29 January 2007—FDA has been aware for decades that thousands of drug products are sold on the U.S. market with unapproved labeling, yet the agency has taken only discretionary enforcement against certain companies.

Regulators estimate that about 2% of all U.S. prescriptions are for drugs with unapproved labeling.

Last June, the agency announced that it planned to get tougher on firms that sell products with unapproved labeling and issued a final guidance document, Marketed Unapproved Drugs—Compliance Policy Guide.

The guidance document does not affect compounding pharmacies, according to FDA officials.

The document, regulators contend, sets forth a prioritized approach that helps drug makers come into the approval process, while giving the agency the ability to force unsafe medications with unapproved labeling off the market.

"We're taking this responsibility quite seriously, and not approaching it in a draconian or punitive way, but intending to . . . facilitate a cooperative way," FDA Commissioner Andrew von Eschenbach told representatives from several pharmaceutical firms at an educational session about the drug approval process on January 9 in Rockville, Maryland.

"There is a way forward" for products with unapproved labeling to receive approval, he said, adding that FDA's new approach is "flexible, but firm."

Some in attendance at the January workshop said that their companies had never submitted an approval application to FDA, even though their firms had medications on the U.S. market. Others at the meeting were angry that regulators had allowed drugs with unapproved labeling to compete on the market with their firms' medications with legitimately approved labeling.

The agency held the educational workshop, von Eschenbach said, to avoid working through the approval process "on a piecemeal basis, with company-by-company, drug-by-drug."

Tackling the problem of unapproved drugs, said Steven K. Galson, director of FDA's Center for Drug Evaluation and Research, is an "integral" and "important" part of the agency's mission.

Drugs with unapproved labeling, he said, "may not meet the standards of safety, efficacy, quality, and labeling."

"Americans expect their drug products to be approved by the FDA," Galson said. "They don't want drug products from the dinosaur age of drug regulation. They want products that meet modern standards of safety, efficacy, and manufacturing."

Many drugs with unapproved labeling are older products that were developed and marketed before successive changes to the federal Food, Drug, and Cosmetic Act, regulators said.

Many products with unapproved labeling may be included in widely used pharmaceutical reference materials, such as the Physicians' Desk Reference, and are sometimes advertised in medical journals, said Deborah M. Autor, director of FDA's Office of Compliance.

Health care providers cannot assume the drugs they may prescribe have been found by FDA to be safe and effective, she said.

Practitioners cannot rely on a product's National Drug Code (NDC)—the unique 10-digit, three-segment number that identifies the manufacturer, product, and package size—to identify drugs with unapproved labeling, Autor noted.

Currently, FDA assigns the labeler code—the first of the NDC's three segments. Drug companies provide the other two segments: the product code and the package code.

The agency has not previously distinguished drugs with approved labeling from those with unapproved labeling when issuing NDC numbers.

However, in an August 29, 2006, proposal, FDA said it wants to assign all three NDC segments to have more control over the numbers to ensure that each is unique and that the numbers are not inappropriately used.

The change in the regulation, said John W. Gardner, director of FDA's Division of Compliance, Risk Management, and Surveillance, will help regulators more easily recognize drugs with unapproved labeling and force them off the market.

The agency hopes to have a final rule about its NDC proposal by the end of the year, he said.

On June 8, 2006—the same day FDA issued its guidance document on unapproved drugs—regulators warned makers of products with unapproved labeling containing the antihistamine carbinoxamine that they had three months to stop manufacturing the drugs.

Officials said they were aware of about 120 products containing carbinoxamine that were marketed in the United States without FDA-approved labeling. Many of those products are marketed to treat cough and cold symptoms—unapproved indications.

Some of the illegal carbinoxamine products were labeled for use in children under age 2 years.

On October 5, 2006, FDA announced that it had negotiated a consent decree of permanent injunction with Syntho Pharmaceuticals and Intermax Pharmaceuticals of Farmingdale, New York, that blocked the firms from manufacturing and selling cough and cold tablets and products used to treat migraine headaches and urinary tract infections that contain labeling not approved by the agency.

On December 12, 2006, regulators told drug firms marketing products containing quinine with labeling not approved by FDA that they had 60 days to stop making those products.

Mutual Pharmaceutical Company's Qualaquin is the only quinine product approved by FDA for marketing in the United States. The agency granted marketing approval for that drug in August 2005 to treat falciparum malaria.

About 99.5% of quinine use is for off-label conditions, primarily for leg cramps, according to FDA.

Quinine is also prescribed for the treatment or prevention of restless legs syndrome, babesiosis—a parasitic infection—and certain myotonic disorders.

Officials in December explicitly warned against the use of quinine for leg cramp conditions.

GlaxoSmithKline's ropinirole, or Requip, is the only medication on the U.S. market approved as a treatment for restless legs syndrome.

Last year the agency also sent warning letters to four drug makers that were manufacturing and selling products on the U.S. market that contain unapproved labeling: Neil Laboratories, East Windsor, New Jersey; Concord Laboratories, Fairfield, New Jersey; Scientific Laboratories, Columbia, Maryland; and Sheffield Laboratories, New London, Connecticut.

FDA intends to "accelerate" its enforcement actions this year against firms that are selling drugs with unapproved labeling, Galson said. Officials declined to identify any manufacturers or the types of drugs that are the targets of those enforcement actions.