FDA scrutinizes old meds that skipped approval

Washington -- It is a surprise to many of the nation's physicians -- and their patients -- that an estimated 2% of drugs never have been approved by the Food and Drug Administration.

This category of products, which could include thousands of drugs prescribed and sold in the United States, is now the focus of bolstered FDA enforcement activities and an element of the agency's drug safety efforts.

Specifically, the FDA has embarked on an initiative to require that all drugs, even those in use for 15 or 20 years, be backed by scientific evidence of safety and efficacy. The drugs under review are primarily cough and cold preparations with antihistamines, some narcotics and a few types of sedatives, including phenobarbital.

"Americans expect their products to be approved by the FDA," said Steven Galson, MD, MPH, director of the agency's Center for Drug Evaluation and Research. "They don't want products from the dinosaur age of drug regulation." He spoke at a Jan. 9 workshop for manufacturers and other stakeholders to provide information on how products could be brought into compliance.

Several reasons are given for why these drugs are on the market. In some cases, the medicines, which might contain unapproved active ingredients, are older and were in use before the passage of tougher laws, some enacted as early as the 1960s, that require evidence of efficacy as well as safety. In these instances, no company has sought FDA approval for these drugs under the modern system.

In other cases, after one company gains approval to sell a drug, other firms illegally follow suit with their versions without having undergone the FDA approval process.

With billions of prescriptions written each year, questions about what pharmaceuticals should be considered reliable treatments are troubling. "Most if not all physicians assume that the drugs on the market are FDA-approved," said AMA President-elect Ron Davis, MD.

While physicians welcome the agency's close watch over the nation's pharmaceuticals, Dr. Davis cautioned that some drugs long in use but without benefit of modern safety and effectiveness trials should not be hastily withdrawn, because no comparable substitutes may exist. "We would hope that the process could be undertaken in such a way as to avoid any interruption in the availability of important medications."

Currently, physicians likely find it difficult to know which drugs, especially among older or long-marketed products, have been tested in the well-designed trials needed to gain FDA approval. They are still advertised in medical journals or are included in the Physicians' Desk Reference along with their well-tested companions. Manufacturers pay to have their drugs listed in the PDR.

As of mid-January, no definitive list of unapproved pharmaceuticals had been compiled, although such a list is needed, Dr. Davis said.

Physicians trying to determine which drugs fall into this group should check among the FDA's listing of approved drugs for the names of manufacturers of a product or an active ingredient. If a manufacturer's name does not appear on that listing, the FDA advises following up with that company.

The agency already has begun its crackdown. In June 2006, unapproved products containing the antihistamine carbinoxamine were removed from the market because of dangers they could pose to children younger than age 2.

In addition, unapproved products containing quinine were withdrawn in December 2006. Approved options were available in both cases.

An expensive journey

Since pharmaceutical manufacturers must travel a long and costly road to comply, some smaller companies that market drugs falling into this "unapproved" category are crying foul at the millions of dollars necessary to undertake the FDA's New Drug Application process. They advocate for an abbreviated process for drugs long in use with safe track records and plan to discuss this option with the FDA.

"People in the industry for a long time might say, 'We've used the drug for 15 years. Physicians say it works. We don't have any safety issues with it. Why do we have to spend these huge amounts of money that will drive the consumer price up to prove what we essentially already know?' " said Davis Caskey, vice president of pharmaceutical operations at ECR Pharmaceuticals in Richmond, Va.

Trials for some of these drugs cost $7 million to $8 million, Caskey said, which could push the medication's cost up by five to six times its current price and, if sales fall off, drive small companies out of business. "So we are trying to work with the FDA to see if there is some other pathway."

Complicating matters is the fact that some claims for unapproved drugs already are being rejected by Medicare Part D plans, said Tom Clark, director of policy and advocacy for the American Society of Consultant Pharmacists. "One of the challenges we have is that there is no list of these drugs. We can't tell our members which drugs are excluded."

Dr. Galson warned those who attended the January workshop that the FDA is passing on information about unapproved drugs to the Centers for Medicare & Medicaid Services.

The FDA announced its stepped-up efforts to rein in the marketing of unapproved drugs last June when the issue gained the attention of Congress and the public.

A guide to the pharmaceutical industry on gaining approval of products was released then and was followed by the January workshop.

Describing the issue as "exceedingly important for public health," FDA Commissioner Andrew von Eschenbach, MD, pledged that the agency would work cooperatively and collaboratively with the companies.