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 thousands of severe reactions including deaths, government documents show.
The 2002 warnings about the drug, nevirapine (search), 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 premiere 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 C. Tramont, reported March 14, 2002, to his boss, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
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.
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 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.
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.
Africa accounts for more than two-thirds of the world's AIDS cases, with 27 million infected, and the United States sought to help slow the disease's spread across the continent.
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 U.S. 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.
One lesson 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, 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," 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, 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 Bush's $500 million plan in 2002 to send nevirapine to Africa. 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," spokesman Trent Duffy said.
Nevirapine is an antiretroviral drug (search) marketed in the United States as Viramune (search) 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 U.S.-funded research in Uganda.
Boehringer Ingelheim (search), 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 and 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 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 the single dose of nevirapine. But they conceded it was incumbent on a U.S. research project to fully and quickly disclose them.
Officials said the problems began when NIH converted the research from determining the drug's usefulness to supporting FDA approval for the drug. Paperwork in Uganda wasn't kept to the FDA standards, they said.
"We may not have reported exhaustively, but we reported all serious side effects," said Professor Francis Mmiro, a lead doctor in the Uganda study. "What you may call a serious side effect in the U.S. is not a serious side effect in Kampala."
NIH officials reviewed the bad news in early March 2002.
Meeting minutes, written in shorthand, raised broad concerns: Half the babies in the study were also enrolled in a vitamin A study that could have affected the outcome, and medical staff running the trials didn't follow procedures for divulging serious adverse events (SAEs).
"No mtg minutes, no training doc(umentation), site used their own criteria for grading SAEs. No lab normal values & serious underreporting of SAEs," the minutes stated.
The minutes quote an NIH official who visited Uganda as saying, "The site staff doesn't know what they don't know."
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.
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."
Lane said the request to destroy the report was inappropriate and NIH never complied. But he conceded his agency inappropriately kept the audit from FDA for weeks, saying, "It shouldn't have happened that way."
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 that might scare African countries looking for U.S. guidance on the drug.
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.
"This major commitment of my government to prevent mother-to-child HIV transmission is the first of this scale by any government, anywhere," Bush said in a Rose Garden announcement. The White House hoped the initiative would reach up to 1 million women a year and cut mother-to-child transmission of HIV by up to 40 percent.
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 lethal liver damage and rashes in patients who take nevirapine for longer periods of time.
African health officials are having second thoughts. South African officials in July recommended ending the single-use treatment because of the new concerns about drug resistance.
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.
"It's not ideal, but it works," said Dr. Ashraf Coovadia of Coronation Mother and Child Hospital in Johannesburg, South Africa. Without it, "many, many more babies would be born with HIV."
Boehringer Ingelheim said it has donated enough doses to treat more than 411,000 mothers and infants in Africa, and self disclosed the problems it found with the Uganda research. But it says it has research from other locations, like Thailand and South Africa, showing single dose usage at birth is safe and effective.
"The bottom line is there were these procedural issues, such as the speed of reporting adverse events, and the like. But the important scientific data was intact, and found to be valid," said Dr. Patrick Robinson, a top Boehringer AIDS specialist.
Still, the German-owned company no longer is seeking FDA permission to use nevirapine for protecting U.S. infants because better treatments have emerged, he said.