By Paul Recer

AP 22 March 2002

Washington -- Problems which federal officials said were "potentially quite serious" prompted the withdrawal of an application for approval to allow pregnant women and newborn babies to take an existing AIDS drug.

Boehringer Ingelheim Pharmaceuticals Inc. of Ridgefield, Conn., announced Friday that it was withdrawing the application. It had asked the Food and Drug Administration to approve the drug nevirapine for preventing mother-to-child HIV transmission.

John Wecker of Boehringer said that the decision came after researchers at the National Institute of Allergy and Infectious Diseases audited a 1999 clinical trial conducted in Uganda for the NIAID by Johns Hopkins University researchers.

The audit raised questions about documents and records supporting the study results, Wecker said. They were published in the British journal Lancet.

"The NIH (National Institutes of Health conducted an audit and the FDA called the three parties together to discuss it," Wecker said. "We agreed to withdraw the application. Once the issues are resolved, we intend to resubmit."

The 1999 study concluded that nevirapine was more effective than another drug in preventing pregnant women from passing HIV infection to their babies during birth and nursing.

Wecker said the audit uncovered "no reason to suspect that there was a problem with the fundamental conclusions."

However, Jason Brodsky, an FDA spokesman, said there are problems with the study that "the agency believes are potentially quite serious."

Brodsky declined to identify the problems, but said the FDA is not recommending any change in the approved uses of nevirapine. The drug, marketed under the name Viramune, is approved in the U.S. to treat HIV in adults and in children over the age of two.

Nevirapine continues to be used in dozens of other countries by pregnant women and newborns.

Dr. John R. LaMontagne of the NIAID, the NIH agency that paid for the Uganda study, said that the problems mostly are in record keeping. He said there are differences in the way hospitals in Uganda keep records and the requirements of the FDA.

"There is no question about the validity of the Lancet study," LaMontagne said. "The problems are in the rather arcane requirements in record keeping."

He said the FDA "quite rightly has a rigorous standard" and that there were problems meeting this standard in a study conducted in Uganda.

The Hopkins researchers meticulously gathered data for the study using a system of "shadow records," which are separate copies of the records kept by the Ugandan hospital, LaMontagne said. The FDA requires that a drug application include the original records for the patients.

The FDA also requires that any "serious adverse event" experienced by a patient during a drug trial be reported in data submitted to the agency. Adverse events are illnesses or other health-related incidents that occur while a patient is on the test drug.

LaMontagne said there often were differences of opinion between the Hopkins researchers and the Uganda hospital staff of what constituted a "serious adverse event." He called it "professional differences of opinion."

"The FDA wants us to cross-match our patient charts against the hospital records," LaMontagne said. "The FDA is right in doing this. It is an important safeguard."

Dr. Peter Lurie of Public Citizen Health Research Group, a watchdog group that monitors federal health policies, said it is up to the researchers to maintain records that meet the strict FDA standards.

The FDA requires that data from drug trials, no matter where in the world the studies are conducted, must meet the same standard. Otherwise, they cannot be used to evaluate a drug for approved use in this country, Brodsky said.

The pharmaceutical company continues to donate nevirapine to programs in some 23 countries where the drug is used to help prevent mother-to-child HIV transmission, Wecker said.