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Recipe Trouble: Production Problems At Generic-Drug Firm Lead to Serious Claims

February 2, 1995

On Jan. 13, 1994, a day after his lungs collapsed, Jeffory Flower died in his mother’s arms. He was nine years old.

In the prior year, Jeffory, who had cerebral palsy and asthma, had been admitted to the hospital 12 times for pneumonia, says his mother, Michelle Hommerbocker. Soon after returning home each time, she says, his condition worsened.

Although she was baffled then, Ms. Hommerbocker eventually concluded that his asthma medicine played a role. When Jeffory was in the hospital, she says, he was given a brand-name inhalant, and his pneumonia abated. But at home in Oroville, Calif., where he inhaled a less-costly generic version of it mandated by his parents’ health plan, she says, the pneumonia always returned.

Many other patients thrived on the brand-name drug, Proventil, and degenerated on the generic version, Albuterol, according to plaintiffs in suits against Albuterol’s maker. The company, Copley Pharmaceutical Inc., of Canton, Mass., recalled the drug in January 1994 after finding bacterial contamination in it. The suits, most of them consolidated in federal court in Cheyenne, Wyo., allege that about 100 people died from Albuterol use.

Copley says that Albuterol contamination had nothing to do with Jeffory’s final bout of pneumonia and that there is no proof anyone has ever died from the drug. It says contamination affected only four lots that left the factory, 118,000 vials in all, and the bacteria involved were relatively benign. But Copley told the court last week that the number of adverse-reaction reports may exceed 10,000.

Food and Drug Administration records and Copley documents, some of them obtained from plaintiffs’ lawyers, show that questions about the company’s ability to make Albuterol bacteria-free began before it reached the market and continued throughout the 20 months it was sold. The FDA-approved recipe called for three ingredients to kill bacteria. But Copley now concedes it never used two of the three and never told the FDA it wasn’t doing so.

Some ex-employees say Copley also deviated from the FDA-approved recipe for making a generic version of an antihistamine. Copley recalled that drug last September, citing coating problems on the time-release pills.

Recipe trouble is a bane in the $10 billion generic-drug industry. Managed care and other attacks on health costs are increasing the use of generics, which are supposed to be therapeutically equivalent to brand-name drugs. In approving their manufacture, the FDA certifies this is so.

But in a number of cases in recent years, generics companies have had difficulty making the knockoffs they say they can, even though they had given the FDA test results showing the drugs worked. In some cases, this is because a drug sample has been made in small batches for lab testing, but the recipe proved inadequate when scaled up to full production, says Peter Rheinstein, an FDA official who used to head its generic-drugs division. And in a few cases, the drug tested for approval has been a phony version of the patented drug, or lab results have been fudged. The FDA doesn’t require clinical trials for generic drugs.

Companies discovering that their approved recipes didn’t work have been known to resort to unauthorized revisions. Last month, an executive of Halsey Drug Co. in Brooklyn, N.Y., was sentenced to 18 months in prison for conspiring to add unapproved ingredients to generic drugs for irregular heartbeats, meningitis and hyperthyroidism. This month, some executives of Mutual Pharmaceutical Co., in Philadelphia, are expected to be tried in federal court in Baltimore on charges of concealing deviations from an approved formula for a heart drug. And some officials from Alra Laboratories Inc., Gurnee, Ill., await trial in federal court in Chicago on charges of falsifying data in approval applications for a pediatric antibiotic and other generic drugs.

As for Copley, a federal grand jury in Boston is investigating whether it may have concealed drug-production problems and recipe deviations from the FDA. (It denies doing so.) An assistant U.S. attorney in Baltimore, Gary Jordan, says at least three other generic-drug companies are under similar grand-jury inquiry.

``The inability to make equivalent copies of brand-name drugs is the great unresolved problem in the industry today, and people are going to get hurt unless something is done,″ says Leroy Schwartz, a physician who is former head of New Jersey’s Drug Utilization Review Council.

The FDA says it doesn’t keep aggregate records of the reasons for drug recalls. But a review of 229 of the more serious recalls in FDA weekly reports since 1992 shows that about two-thirds related to formulation defects in generic drugs, which account for only about 40 percent of unit sales.

The generics industry, of course, has come under scrutiny before. In a number of cases in the late 1980s, officials of generic-drug companies were found to have bribed FDA officials. Some of the malefactors went out of business, and the industry started to regain its reputation. The FDA led a ``massive cleanup″ of the industry, says an FDA official, Douglas Sporn, but he adds that ``anytime you have a big industry and there’s a lot of money to be made, you can’t be sure everyone’s going to play by the rules.″

In October 1993, when 51 percent of Copley was bought by Hoechst AG of Germany, analysts praised Copley for its good record with the FDA. But issues concerning the soundness of Albuterol were already brewing. After Copley applied in 1989 to make this generic version of Proventil (a Schering-Plough Corp. asthma drug made under license from Glaxo), Schering objected. It went to court challenging the FDA definition of bioequivalency. The issue is on appeal.


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