WASHINGTON – Weeks before President Bush announced a plan to protect African babies from AIDS, top U.S. health officials were warned that research on the 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 the United States.
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.
The documents show 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.
Less than a month after 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.
U.S. standards failed
Because of the problems, NIH shut down the Uganda research for 15 months, from the spring of 2002 to the summer of 2003, to review the science and take corrective actions.
NIH officials said 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 U.S. standards.
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, said Dr. H. Clifford Lane, NIH’s No. 2 infectious disease official.
“It was unexpected, and what it means is nevirapine probably shouldn’t be a drug of first choice if other options are available,” Lane said.
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 that the underlying science was solid.
Widespread problems
Nevirapine is an antiretroviral drug marketed in the United States as Viramune that has been used since the 1990s to treat adult AIDS patients and is known to have potentially lethal effects such as 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 U.S.-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.
“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 Corp. 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 nevirapine. But they conceded it was incumbent on a U.S. research project to fully and quickly disclose them.
NIH officials reviewed the bad news in early March 2002.
But Tramont, the AIDS research chief, and other top NIH officials repeatedly dismissed the concerns as preliminary or overblown, and sought to salvage the flawed research’s underlying conclusions rather than start over.
“There is presently no evidence that the study’s scientific results are invalid,” said a report Tramont sent to his staff less than two weeks after getting the March 2002 Westat audit.
Action and inaction
In January 2002, Boehringer sent NIH an early copy of its report. But the drug maker, fearing publicity about the report might destroy its chance to get the FDA approval of the drug for domestic use, asked NIH to destroy it before FDA regulators could learn about it.
“Sensitive information. Asked for it to be destroyed when audit is upon us,” NIH official Mary Anne Luzar wrote on the cover page of Boehringer’s report.
Boehringer says it never requested the document be destroyed, saying “our actions throughout the study evaluation were proactive and forthcoming.”
NIH at first sought to postpone the FDA review of nevirapine, then top NIH and FDA officials arranged for the drug maker to pull its U.S. application rather than risk a public rejection.
Unaware of the internal NIH concerns, Bush announced in June 2002 a $500 million effort to fight the spread of AIDS in Africa and the Caribbean. The plan’s centerpiece was nevirapine.
Two years later, after hundreds of thousands of doses of nevirapine have been distributed to African mothers and children, the FDA has recommended NIH stop using the drug with certain patients. It also has demanded stronger warnings to doctors and patients about possible side effects.
African doctors said they weren’t aware of the full extent of NIH’s concerns but feel comfortable – at least until better options emerge – administering it in single doses to AIDS-sickened mothers who have few other choices to protect newborns.
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