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7/21/2003

Counterfeit Drugs Arise From Various Sources

Cheryl A. Thompson

Fourteen percent of questionable pharmaceuticals analyzed during a federal investigation of incoming packages at two international mail branches contained no identifiable active ingredient, a Bureau of Customs and Border Protection official told a congressional subcommittee in June.

The investigation, part of "Operation Safeguard," also found that large parcels of fake pharmaceuticals had been split among separate shipments labeled for the same addressee, said Elizabeth Durant, executive director of Trade Compliance and Facilitation at the bureau.

"There is a possibility that stateside pharmaceutical distributors could be using these products as a source of supply," Durant said. Once in this country's drug supply chain, she said, the counterfeits might end up in pharmacies.

Durant testified June 24 before the subcommittee on oversight and investigations, part of the House Committee on Energy and Commerce. The subcommittee had invited Durant and five other federal or state government employees to speak about the increasing number of imported, counterfeit, and unapproved pharmaceuticals entering the United States.

The ASHP House of Delegates, at its annual session in June, approved a professional policy statement on the integrity of drug products in the U.S. supply chain. This statement authorizes ASHP to encourage FDA to take the necessary steps to ensure that all drug products entering the country undergo thorough inspection and testing for evidence of adulteration or misbranding and that patients do not receive improperly labeled and packaged, deteriorated, outdated, counterfeit, or drug products lacking FDA-approved labeling. The statement also authorizes ASHP to encourage the agency to develop and implement regulations that would restrict or prohibit licensed drug wholesalers, repackagers, and manufacturers from purchasing medications from unlicensed entities and require accurate documentation at any given point in the distribution chain of the original source of drugs and the chain of custody from the manufacturer to the pharmacy.

Three years ago, the committee had questioned FDA's associate commissioner for regulatory affairs about the agency's efforts to keep counterfeit bulk drugs, such as gentamicin sulfate from unapproved sources in China, from entering the United States. The regulatory affairs head acknowledged under fire that FDA needed to improve its efforts.

John Taylor, current head of FDA's regulatory affairs group, told the subcommittee that the agency had opened 73 cases regarding counterfeit drugs since October 1996, yielding 44 arrests and 27 convictions.

But the agency, he said, has noted "a gradual, but troubling" increase in the production of counterfeit finished dosage forms.

"Much of this activity," he said, "has targeted high-volume, high-cost drugs where counterfeiters attempt to obtain the highest return possible in a short time period. . . . The latest several counterfeits have appeared in the wholesale market and received wider distribution than has been the case historically."

A Florida grand jury examining the safety of prescription medications in the state determined that "an alarming percentage" of the pharmaceuticals flowing through wholesalers had been illegally acquired by various means, including illegal importation from other countries. The grand jury concluded that forcing wholesalers to provide a drug product's pedigree—a document tracing all sales of the product, starting with the manufacturer—with each transaction would greatly decrease the chance of patients receiving counterfeit medications. Governor Jeb Bush signed a law to that effect on June 13.

Florida's Prescription Drug Protection Act, part of which goes into effect this year, raises the standard of business conduct for wholesalers, creates new felony crimes penalizing anyone who tries to obtain or sell pharmaceuticals without their pedigree, increases the seriousness of other felonies relevant to drug diversion, requires wholesalers to authenticate prior transactions on the pedigree papers, and increases the regulatory authority of the state health department.

Cesar Arias, a 16-year supervisor of drug inspectors for the Florida Department of Health, told the House subcommittee that drug counterfeiting has increased over the past two years.

Arias said his office works on cases as part of a state task force that, in the past 18 months, has identified 11 "cells" responsible for the diversion in Florida of about $250 million a year in pharmaceuticals.

Diversion, he said, occurred through thefts of cargo, burglaries, smuggling of foreign-made drug products, and resale of specially priced medications originally sold to specialty physicians for use in their office.

"In each instance in which counterfeits or diverted drugs have made their way into the mainstream distribution system, it has been through a dishonest wholesaler," Arias told the subcommittee. "Once the drugs enter the system, they can end up in any pharmacy in the nation. That is why there is no patient in the nation that can know with 100% certainty that the drugs they are getting are what they are purported to be or, if they are, that they have not been in the trunk of someone's car or sitting in a hot warehouse or a crack house in South Florida."

The April 2002 discovery of counterfeit epoetin alfa in the nation's drug supply resulted from a Florida undercover agent's purchase of 100 boxes of the product, Arias said. At the time of the purchase, investigators "had no clue, even after examining the boxes," that the product was counterfeit, he said. On scrutiny of the pedigree, however, the group knew something was wrong and submitted some of the boxes to the manufacturer and FDA for analysis.

Arias said as many as 110,000 vials of Epogen 2,000 units had been relabeled to Epogen or Procrit 40,000 units. The original package insert remained in each carton, he said, but the criminals had carefully removed each vial's label and replaced it with one indicating the vial contained 40,000 units of the protein that simulates production of red blood cells.

Robert Penezic, assistant statewide prosecutor in Florida and one of the advisers to the grand jury, told the House subcommittee that investigators found 800 boxes of the counterfeit Procrit at a large Texas wholesaler, which did not know it had bought the criminals' vials, and still other boxes in Kentucky. Less than 10% of the counterfeit Procrit was recovered by investigators, he said, and a profit of about $46 million might have been made by the criminals in the supply chain.

Amgen manufactures and sells epoetin alfa under the brand name Epogen and also produces the biological for Ortho Biotech Products, which sells it as Procrit.

In another case, Arias said, one of the men who pled guilty explained that he purchased vial stoppers and crimps on the Internet and used crude machinery to rinse out vials with tap water and make his counterfeit injectable product.

Arias also described the recent seizure in Florida of counterfeit Lipitor and Celebrex. He said he knew that FDA had alerted the public about counterfeits of the lipid-lowering product but had not heard that the agency had publicized the discovery of fakes of the nonsteroidal antiinflammatory drug.

Lipitor and Celebrex are products of Pfizer.

The Pharmaceutical Research and Manufacturers of America (PhRMA) on May 1 started a voluntary program in which participating companies and their subsidiaries agree to notify FDA within five business days of deciding that a product has likely been counterfeited (see June 1 AJHP News). A similar program was announced by the Healthcare Distribution Management Association, representing pharmaceutical distributors, one day before the House subcommittee hearing.

On June 11, PhRMA announced that it had adopted a five-point program to combat the counterfeiting of prescription drugs. In addition to encouraging member companies to participate in the voluntary-reporting program with FDA, PhRMA said it (1) urges FDA to implement the regulations requiring wholesalers to provide customers with a product's pedigree, (2) wants FDA, the Drug Enforcement Administration, and the Bureau of Customs and Border Protection to convene a summit with the industry and public to identify what can be done to "curb" the flow of counterfeit medications, (3) invites the entire health care community to join PhRMA in opposing legislative proposals that would ease the entry of counterfeit drug products, and (4) is forming a task force to determine the additional steps that the industry and government can take to stop the distribution of counterfeits.

Part of FDA's difficulty in stopping counterfeits from entering the country is rooted in inadequate funding. On questioning by a subcommittee member, Taylor explained that the Homeland Security Act directed and funded FDA to use a risk-based approach to assessing threats to the food supply but not the pharmaceutical supply.

Durant said the customs bureau intended to conduct a blitz of operations this summer at four international mail branches. One goal, she said, is to determine whether the volume of counterfeit pharmaceuticals being imported is stable at about 14%.