Firm Pulls Application for AIDS Drug Use in U.S.

By Shankar Vedantam

A Johns Hopkins University trial of an AIDS medicine in Uganda suffered from procedural flaws, researchers and regulators announced yesterday, prompting the drug’s manufacturer to withdraw its application to have the medicine approved for a particular use in the United States.

The flaws do not mean that the drug, nevirapine, is unsafe or ineffective, and American safety regulators said they had no evidence that countries using the medicine should stop. The Hopkins trial found that inexpensive treatment with nevirapine could reduce the transmission of AIDS from mothers to their newborn babies.

On Wednesday, the medicine’s maker, Boehringer Ingelheim Pharmaceuticals Inc., withdrew its application to the Food and Drug Administration to have nevirapine approved in America for the prevention of mother-child HIV transmission. The drug is already approved here for the treatment of AIDS in children and adults.

Officials at Hopkins and the National Institute of Allergy and Infectious Diseases, the federal government body that funded the research and oversaw the project, said the problems identified in the trial were mostly about paperwork. They said the study had been designed as a public health project and not with the stringent requirements of an FDA submission in mind.

But two senior FDA officials said the problems were more than mere paperwork. The officials declined to be specific.

Referring to the importance of documentation, an official who asked not to be identified said : "In a clinical trial that extends over months or years, documentation of what happened with patients, what was given to patients, is obviously extremely important in understanding whether the results of the trial accurately depict what is going on."

Nor would the withdrawal of the company’s application end the FDA’s interest in the trial, the official said. The Hopkins researchers were obliged to follow American procedures and rules, and the FDA has now flagged the trial for "additional attention."

"We need to be confident and have people outside the U.S. be confident about those trials and those results," the official said. "Having a study done under [FDA supervision] is a brand name of quality. We want to make sure that is maintained."

On Thursday in South Africa, the health minister cited the FDA’s concerns and interpreted them to be questions about the medicine’s safety. The FDA official said yesterday that such fears were unwarranted and that he was optimistic the agency’s evaluation would confirm the original findings.

Hopkins spokesman Gary Stephenson said the problems in the trial were not "life-threatening or health-threatening."

Two areas of dispute with the FDA, he said, were over the issue of getting informed consent from some patients and deciding which side effects were caused by the medicine.

"When people were being screened, they orally consented to a blood draw rather than a signed formal consent," he said. "In other cases, the FDA’s interpretation or definition of adverse events were different than the study protocol."

"In Uganda, you have got all kinds of sicknesses and ailments that are not related to the study," he said. "The FDA would want those reported, where we documented things relevant to the study."

Examples, he said, were malaria, fever, diarrhea and certain ear infections.

John La Montagne, deputy director of the National Institute of Allergy and Infectious Diseases, added that the Hopkins team had created an alternative — and better — system of tracking patients than was used at Uganda hospitals. He said that the FDA wanted the original hospital data and that it was taking scientists time to correlate the "shadow" charts with hospital records.

"The issue is completeness of the record," he said. "I have not heard about any concerns of long-term safety with this medication."

The study was conducted between 1997 and 1999 and observed the effects of nevirapine treatment on 645 mother-child pairs, Stephenson said. It found that giving the mother a dose of the medicine shortly before birth and another to the child shortly after birth could reduce transmission of the AIDS virus.

Boehringer Ingelheim’s global chief of HIV programs in the developing world, John Wecker, said the company had withdrawn its application because it believed that researchers would not be able to get the FDA all the necessary information on time.

"It is our intention to resubmit" the application once all the information is in place, he said.

Source : http://www.washingtonpost.com/wp-dyn/articles/A5310-2002Mar22.html