Label Issues Are Delaying Generic Drugs

Friday, January 3, 2003New York TimesBy Melody Peterson

When the patent on Rebetol, a drug used to treat hepatitis C, expired in June, patients hoped that they would be able to buy a generic form of the medicine to help lower the $20,000 cost of treatment.

They are still waiting.

The company that wants to sell a lower-price generic version of Rebetol says that government approval is being held up by a technicality that is proving to be quicksand for many generic medicines a dispute about the drug’s label.

The manufacturer, Three Rivers Pharmaceuticals, filed an application with the Food and Drug Administration 17 months ago to make ribavirin, the generic name for Rebetol, which Schering-Plough sells for about $10 a capsule. While Three Rivers will not say how much it plans to charge, patient advocates say they expect ribavirin to sell for about half that price.

Paul F. Fagan, general counsel at Three Rivers, said that regulators have told the company that the delay stems from one sentence on the drug’s label.

The label that the F.D.A. is focused on is not the one on the outside of the bottle or jar, but rather pages of information that physicians rely on. The label includes detailed instructions on how the medicine should be used, as well as information on its adverse side effects and results from clinical trials.

Under federal law, labels on generic drugs must be nearly identical to those of the brand name product they replicate. Regulators appear to fear that Schering could sue the government, Mr. Fagan said, if they let Three Rivers copy the sentence, which refers readers to the label of another Schering product, Peg-Intron, that is prescribed in combination with ribavirin.

Patient advocates say the high cost of Rebetol is causing many people with hepatitis C to go untreated. More than four million Americans are infected with hepatitis C, and many of them are H.I.V.-positive.

“Rebetol is $10 a capsule for a drug that we believe costs 10 cents to make,” said Brian D. Klein, the co-founder of the Hepatitis C Action and Advocacy Coalition.

An F.D.A. spokeswoman said the agency did not comment on pending applications.

The government’s approval of ribavirin would not immediately allow the sale of the lower-cost drug because of litigation between Three Rivers and Schering-Plough. But the lack of F.D.A. approval is slowing the litigation, Mr. Fagan said.

Experts say that the experience of Three Rivers is not unique.

Steven Lieberman, a patent lawyer at Rothwell, Figg, Ernst & Manbeck in Washington, said that drug companies are increasingly trying to block lower-cost competition by taking advantage of federal laws requiring generic and brand name drugs to have the same labeling.

The labeling issues have become a minefield for the F.D.A., said Mr. Lieberman, who represents the makers of both generic and brand name drugs. Regulators know, he said, “whatever move they make, they are likely to be sued by one side or the other.”

In one case last year, Bristol-Myers Squibb argued that federal laws prohibited the F.D.A. from approving a generic form of its diabetes drug Glucophage because of a recent addition to the medicine’s label about its use by children. The move by Bristol-Myers outraged members of Congress, who passed a law that included language aimed at closing that loophole. But drug companies continue to find other ways to use their labels to forestall competition.

William O’Donnell, a spokesman for Schering-Plough, said that the company “rejects any implication” that it had tried to manipulate the drug’s label to keep generic companies out of the market.

“Labeling for all products is the result of extensive consultation between the F.D.A. and the sponsoring company,” Mr. O’Donnell said. “There is nothing in the labeling of Rebetol that the F.D.A. does not believe should be there for the safe and effective use of this product.”

Schering-Plough also defended Rebetol’s price. “Products typically are not priced at the cost to make them,” Robert J. Consalvo, another company spokesman, said. “They’re priced at the value they bring to the patient.”

Executives of Three Rivers say the delay is especially frustrating because the F.D.A. recently approved a second brand name version of ribavirin Copegus, sold by Roche in just six months.

“The brands get through quickly,” Mr. Fagan said, “and the generics seem to languish.”

The government approves brand name drugs in about 14 months, while generic drug approvals take roughly 18 months, according to F.D.A. statistics.

Recently, the Bush administration has tried to find ways to hasten generic drug approvals.

Gary Buehler, director of the F.D.A.’s Office of Generic Drugs, said the agency approved 384 generic drug applications last year, up from 307 in 2001. “We are getting more generic drugs into the hands of the American public,” he said.

President Bush has also proposed a rule aimed at limiting the ability of drug companies to delay generic manufacturers by filing secondary patents on their products.

In the litigation between Schering-Plough and Three Rivers, Schering is arguing that Rebetol is still protected by one or more patents. Schering has at least eight patents protecting Rebetol many of them added in the last two years.

When such litigation is continuing, the F.D.A. grants the generic manufacturer tentative approval until the court case is settled.

Mr. Consalvo said that Schering-Plough is only trying to protect intellectual property that it rightfully owns.

Mr. Fagan of Three Rivers contends that the absence of tentative approval of generic ribavirin is stalling the litigation. He said that when Schering has asked for more time on certain issues, its lawyers have told the judge there is no need to hurry since Three Rivers has so far failed to get F.D.A. approval.

Left untreated, hepatitis C can cause cirrhosis, liver failure and liver cancer. The virus causes an estimated 8,000 to 10,000 deaths each year in the United States.

The current recommended treatment for patients with hepatitis C is ribavirin combined with peginterferon alfa, which Schering sells as Peg-Intron.

Recently, the F.D.A. approved Pegasys, Roche’s peginterferon product, as well as Copegus, its version of ribavirin.

Most patients must take the two drugs for 48 weeks. Depending on the dosage, Rebetol can cost an uninsured patient as much as $20,000. The patient would pay another $10,000 for peginterferon.

Ribavirin is relatively inexpensive to manufacture. A pharmacy in Pittsburgh is selling it to hundreds of patients for $1.50 a capsule. That pharmacy, Fisher’s SPS, is owned by many of the same people backing Three Rivers, which is based in Cranberry Township, Pa.

Doctors and patient advocates say that many patients especially the uninsured and underinsured are going untreated because of the high cost of Rebetol and Peg-Intron.

Patricia T. Gardner, a 46-year-old mother who says she believes she contracted the virus from gall bladder surgery, said she recently lost the insurance that had paid for most of her medicine. Ms. Gardner, who lives in Louisville, Ky., said she was suffering from severe cirrhosis and was not sure how she would pay for a year’s worth of treatment.

“Shame on them all,” she said, “for making treatment impossible for those of us who have already lost everything we have to this disease.”

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