Cefaclor

A French pharmaceutical company has been fined $33 million for deliberately failing to disclose to Food and Drug Administration officials all of the locations where the antibiotic cefaclor was being manufactured. The monetary penalty is one of the largest ever imposed in a criminal pharmaceutical prosecution.

Paris-based Roussel Uclaf S.A. was ordered to pay the fine after pleading guilty on behalf of its Italian subsidiary company, Biochimica Opos S.p.A., to felony charges of conspiracy and introducing adulterated drugs into interstate commerce with the intent to defraud or mislead. Cefaclor, approved to treat various infections, was being marketed to American consumers, but was manufactured outside the United States at facilities not disclosed to the FDA. The purpose of the illegal scheme was to increase sales of cefaclor in the United States, according to FDA special agents.

U.S. District Judge Peter J. Messitte in Greenbelt, Md., handed down the fine in October 2001. The case represents the first time that a foreign corporation has been criminally punished for defrauding the FDA concerning an approved drug product manufactured outside the United States and marketed to the American public.

Roussel Uclaf manufactured and distributed various drug products in the United States. Biochimica Opos, an Italian subsidiary, developed, manufactured, promoted, and sold generic drug products, including cefaclor. Personnel from Roussel Uclaf had certain oversight responsibilities for the business activities of both companies.

According to the FDA's office of criminal investigations (OCI), the case began in May 1996, when the agency conducted a post-approval inspection of Biochimica Opos regarding production of cefaclor.

"Post-approval inspections are performed once a manufacturer is authorized to market a drug," says Kim Rice, an OCI assistant special agent in charge. "They allow the FDA to monitor and evaluate the integrity of the drug and the process used to produce it." Discrepancies in manufacturing procedures were found during the inspection, leading investigators to become suspicious about the production of cefaclor. For example, the inspection team noted inconsistencies in statements made to them about information they had requested.

Pharmaceutical manufacturers that legally export drugs to the United States are required to create and maintain production and control records for each batch of a drug product. These records include the identity of each active and inactive ingredient used, the location of the manufacturing facility, laboratory test results, a description of each step in the drug's manufacturing process, and the names of all persons performing and supervising each significant step in the drug's manufacture.

In this case, employees provided batch production records at the May 1996 inspection that misrepresented the production method for cefaclor, and falsely showed the manufacturing facilities involved in the production of the drug. In addition, some of the essential ingredients used to manufacture cefaclor were obtained from unapproved sources, and false records, including raw material log books, a double software application, and work orders, were kept to conceal the fraudulent activities.

In October 1996, after the inspection, Roussel Uclaf admitted to various violations in connection with the production of cefaclor at the Opos facility, including failure of the company to make the antibiotic according to the original drug application approved by the FDA. Roussel officials also admitted to similar violations in the manufacturing processes for two other approved antibiotics, clindamycin and minocycline. They confirmed that critical manufacturing steps were being secretly performed at other locations. Roussel then recalled the three drugs from pharmaceutical manufacturers in the United States, and withdrew each drug's approved marketing application. Opos also stopped shipping the drugs to the United States at this time.

In early 1997, the FDA inspected yet another Italian drug manufacturer suspected of being involved with Opos' violations. In fact, evidence proved that the Italian company was obtaining essential ingredients for making cefaclor from unapproved sources. Once more related events surfaced, the FDA's Center for Drug Evaluation and Research referred the case to the OCI's special prosecution staff.

"This case was a very difficult one to develop due to the fact that the illegal acts occurred outside the U.S.," says Rice. "Most of the documents of evidentiary value," he says, "were located in foreign countries." In addition, Rice adds that the documents were written primarily in French, Italian or German, and that some potential witnesses were foreign citizens "who may not have been subject to U.S. subpoena power."

OCI's investigation revealed that Roussel misled the FDA by not disclosing that unapproved facilities in Italy, France and Romania were involved in the manufacture of cefaclor. Rice says that foreign authorities helped OCI criminal investigators obtain documents and conduct interviews with many witnesses.

COPYRIGHT 2002 U.S. Government Printing Office
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