WASHINGTON – Weeks before President Bush announced a plan to protect African babies from AIDS, top American health officials were warned that research on the plan’s key drug was flawed and may have underreported severe reactions including deaths, government documents show.

The 2002 warnings about the drug, nevirapine, were serious enough to suspend testing for more than a year, let Uganda’s government know of the dangers, and prompt the drug’s maker to pull its request for permission to use the medicine to protect newborns in America.

But the National Institutes of Health, the government’s premier health research agency, chose not to inform the White House as it scrambled to keep its experts’ concerns from scuttling the use of nevirapine in Africa as a cheap solution, according to documents obtained by The Associated Press.

“Everyone recognized the enormity that this decision could have on the worldwide use of nevirapine to interrupt mother-baby transmission,” NIH’s AIDS research chief, Dr. Edmund Tramont, reported March 14, 2002, to his boss, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

The documents show that Dr. Tramont and other NIH officials dismissed the problems with the nevirapine research in Uganda as overblown and were slow to report safety concerns to the Food and Drug Administration.

NIH’s nevirapine research in Uganda was so riddled with sloppy record keeping that NIH investigators couldn’t be sure from patient records which mothers got the drug. Instead, they had to use blood samples to confirm doses, the documents show.

Less than a month after Mr. Bush announced a $500 million plan to push nevirapine across Africa to slow the AIDS epidemic, the Health and Human Services Department sent a nine-page letter to Ugandan officials identifying violations of federal patient protection rules by NIH’s research. Africa accounts for more than two-thirds of the world’s AIDS cases, with 27 million infected.

The NIH research “may have represented a failure to minimize risk to the subjects,” the Office of Human Research Protections told Ugandan authorities in summer 2002.

Nevertheless, NIH officials told AP they remain confident after re-reviewing the Uganda study and other research that nevirapine can be used safely in single doses by African mothers and children to prevent HIV transmissions during birth. But they acknowledged their Uganda research failed to meet required American standards.

As a result, NIH recently asked the National Academy of Sciences to investigate its science in the case and has spent millions in the last two years improving its safety monitoring and record keeping.

“I would say there are many lessons that we have learned from this review that will help us do our clinical research, both domestically and internationally, much better,” said Dr. H. Clifford Lane, NIH’s no. 2 infectious disease official.

Senate Finance Committee Chairman Charles Grassley, a Republican of Iowa, has asked the Justice Department to investigate NIH’s conduct. In a letter released yesterday, Mr. Grassley said he was compelled to do so by “the serious nature of these allegations and the grave implications if the allegations have merit.”

One lesson already derived from a closer review of the Uganda research is that even single doses of nevirapine can create instant resistance, meaning patients may not be able to use the drug or others in its class again when their AIDS worsens, Dr. Lane said.

“It was unexpected, and what it means is nevirapine probably shouldn’t be a drug of first choice if other options are available,” Dr. Lane said.

Dr. Lane said NIH officials were aware in spring 2002 about the impending White House announcement on nevirapine but did not tell presidential aides of the problems because they were confident, even before reviewing the Uganda research, that the underlying science was solid.

The White House – though unaware of the NIH concerns – also remains confident in Mr. Bush’s $500 million 2002 plan to send nevirapine to Africa. Mr. Bush approved $2.9 billion for global AIDS fighting next year.

“The president’s mission is to try to stop the spread of AIDS in Africa and to come at it from a new angle, and that is what this is all about,” a spokesman, Trent Duffy said.

Nevirapine is an antiretroviral drug marketed in America as Viramune that has been used since the 1990s to treat adult AIDS patients and is known to have potentially lethal effects like liver damage and severe rashes when taken over time.

In 1997, NIH began studying in Uganda whether it could be given safely in single doses to stop mother-to-baby transmissions. That research showed it could reduce transmission in as many as half the births.

But by early 2002, an NIH auditor, the agency’s medical safety experts, and the drug’s maker all disclosed widespread problems about the American-funded research in Uganda.

Boehringer Ingelheim, the Connecticut-based company that makes nevirapine, told NIH it identified at least one “critical compliance issue” that compromised the integrity of the study and more than four dozen issues it described as “serious” and “major.”

Boehringer and NIH auditors cited concerns such as failing to get patients’ consent about changes in the experiment, administering wrong doses, delays, and underreporting of “fatal and life threatening” problems.

“It appeared likely, in fact, that many adverse events and perhaps a significant number of serious adverse events for both mother and infant may not have been collected or reported in a timely manner,” Westat Corporation reported in March 2002. Westat is a professional medical auditing firm hired by NIH to visit and audit the Uganda site.

Westat reported there were 14 deaths not reported in the study database as of early 2002, and that the top two researchers in Uganda acknowledged “thousands” of bad reactions that weren’t disclosed.

NIH said the subsequent review whittled that list down significantly, all deaths were eventually recorded; and the majority of bad reactions are believed to have been caused by the poor health of patients, not the single dose of nevirapine. But NIH conceded it was incumbent on a U.S. research project to fully and quickly disclose them.