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http://www.nytimes.com/2002/07/19/business/19JOHN.html

Drug Factory of Johnson & Johnson Under Inquiry

By ANDREW POLLACK

he government is conducting a criminal investigation into a Johnson & Johnson factory that makes an anemia drug that has been linked to a spate of serious illnesses in Europe and Canada, according to court documents and people close to the situation.

The factory, in Puerto Rico, manufactures Eprex, a drug that is used to increase the levels of red blood cells in people who are undergoing kidney dialysis or suffering from anemia caused by chemotherapy.

Health authorities in Europe and North America have become increasingly concerned over the last few months about a mysterious rise in the number of Eprex users who have developed pure red cell aplasia, a condition in which the body can lose its ability to produce red blood cells, leaving the patient dependent on blood transfusions to survive.

The investigation, by the Food and Drug Administration and the Justice Department, is tied to a whistle-blower lawsuit filed against Johnson & Johnson by Hector Arce, a former employee at the factory. Mr. Arce, who was fired in March 1999, contends he was pressed to falsify data to cover up manufacturing lapses and then was suspended a few days before an expected interview with F.D.A. inspectors.

Johnson & Johnson denies the accusations. It said Mr. Arce was a boiler operator not directly involved in the manufacture of Eprex and that he was fired for numerous violations of company procedures and for dishonesty.

"We investigated the allegations, and we found no support for them," said Carol Goodrich, a spokeswoman for Johnson & Johnson. "Even if they were true, they would not have affected the product integrity."

But Ms. Goodrich said the company was "aware of an investigation by the F.D.A. presumably related to the lawsuit." She said the company did not know the precise nature of the investigation but intended to cooperate. The F.D.A. did not comment.

Over the last few months, Jaime Pieras Jr., the judge presiding over the lawsuit in United States District Court in Puerto Rico, has twice ordered the government to file reports under seal "regarding the status of its criminal investigation." And Juan H. Saavedra Castro, a lawyer for Mr. Arce, said, "The case has been stayed pending this criminal investigation"

It is unclear whether the government suspects that manufacturing violations are responsible for the illnesses suffered by Eprex patients. A person close to the situation said, however, that the government became active only this spring as concern about the illnesses grew. A year earlier, the government had declined to intervene in the lawsuit.

Johnson & Johnson said it did not know what is causing the aplasia. But the company and health authorities have speculated it might have to do with manufacturing. Even slight changes in manufacturing conditions can affect products like Eprex, which are made in living cells, scientists say.

A reason for this speculation is that while there have been 141 suspected cases of red cell aplasia in Eprex users, only a handful of cases have appeared in people using the equivalent drug in the United States. That drug, sold by Johnson & Johnson as Procrit and by Amgen as Epogen, is made by Amgen.

Moreover, cases involving Eprex began to rise sharply starting about 1999, with only three cases reported from 1988 to 1998. Johnson & Johnson made some manufacturing changes at the Puerto Rico plant in 1997 and in 1998 stopped using human blood protein as a stabilizer in the vials. But the packaging of the vials is done in Europe, not in Puerto Rico.

Despite the rise, the cases are still rare even in Eprex users. Johnson & Johnson estimates the occurrence at 1.14 cases for every 10,000 patient-years of use. It said almost all had occurred in patients with kidney failure who injected the drug under their skin, rather than taking it intravenously, which is the way most of it is given in the United States.

Eprex is a brand name for erythropoietin or EPO, a human protein that stimulates the production of red blood cells. The drug, developed by Amgen and licensed to Johnson & Johnson, is produced by splicing the human EPO gene into animal cells. More than three million people worldwide have used EPO; combined sales for Johnson & Johnson and Amgen exceed $5 billion, making it the best-selling product produced by genetic engineering and one of the biggest-selling drugs in the world.

But the EPO produced in the genetically engineered animal cells is subtly different from the natural protein and it appears that in the patients with aplasia, the drug is being recognized as a foreign protein. The patient's body makes antibodies to the EPO and those antibodies also attack the patient's own EPO. That leaves the body unable to replenish its red blood cells, which carry oxygen to the body's tissues.

Patients experience severe sudden anemia with a feeling of fatigue and shortness of breath, meaning that the drug has produced a more severe version of the disease it was supposed to cure. There has been at least one death in such patients. Some patients improve if they stop taking the drug or take other drugs to suppress their immune systems.

Manufacturing of drugs is strictly regulated, and the F.D.A. has recently cracked down on companies like Eli Lilly and Schering-Plough, keeping drugs off the market until factory violations are fixed.

In his lawsuit, filed in March 2000, Mr. Arce, who had worked at the plant since 1989, said that to avoid problems for the company with the F.D.A. he was pressed to fill out forms regarding the operating of the boiler for other employees who had failed to do so. The suit says there are more than 100 examples of such falsified forms.

In another instance, Mr. Arce said, he wrote in a logbook of an incident in which an alarm had gone off indicating that the carbon dioxide and the acidity of the fermentation process were outside specifications. Mr. Arce's supervisor reprimanded him and ripped the page from the logbook, the suit says.

In other cases the factory continued operating when the conductivity of the water or the humidity in the factory were outside required parameters, and Mr. Arce was told to falsify the records to cover this up, he said. He is asking for an unspecified amount of money that his lawyer said could be millions of dollars.

In its response to the complaint, Johnson & Johnson said Mr. Arce had been fired for numerous violations and had been previously suspended for sleeping during working hours. It also said he lied about reasons for absences, changed and deposited certain checks of a co-worker into his own account and falsely claimed his residence was damaged by a hurricane to receive financial aid from the company.

The problems with Eprex could help Amgen, which is selling a new version of EPO called Aranesp in competition with Johnson & Johnson. Previously, the two companies had split the market, though the relationship had been a stormy one.

On Monday, Amgen tried to distance its products from the problems of Eprex. The F.D.A. said in May that there had been four cases of aplasia in people that used Amgen's Epogen. Johnson & Johnson said this week it thought there were eight cases among users of Epogen and Procrit combined.
 

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