NIH Officials Warned in 2002 of Risks Associated With Nevirapine Use in Pregnant Women But Did Not Inform White House

Although NIH officials were warned that a Ugandan clinical trial using the antiretroviral drug nevirapine was "flawed" months before President Bush announced an initiative to reduce mother-to-child HIV transmission in Africa and the Caribbean, they did not inform the White House of the risks associated with the drug's use in pregnant women, the AP/Boston Globe reports. According to documents obtained by the Associated Press, poor record keeping might have underreported severe reactions to the drug, including deaths, the AP/Globe reports. In March 2002, NIH received data from a Ugandan study that prompted the agency to suspend the trial for more than a year and warn Uganda's government of the risks associated with nevirapine, according to the AP/Globe. However, NIH officials did not inform the Bush administration of the drug's risks as it "scrambled to keep its specialists' concerns from scuttling the use of nevirapine in Africa as a less-expensive solution," according to NIH documents, the AP/Globe reports. The documents show that Dr. Edmund Tramont, director of the National Institute of Allergy and Infectious Diseases Division of AIDS, and other NIH officials regarded the problems with the trial as "overblown" and did not immediately report safety concerns about the drug to FDA, according to the AP/Globe. However, the data did prompt Boehringer Ingelheim -- the drug's manufacturer -- to withdraw its FDA application to market the drug in the United States for the prevention of vertical HIV transmission (Solomon, AP/Boston Globe, 12/14). At the time, researchers attributed the problems with the study to its design, which they said was intended to be a public health project and was not intended to meet the requirements necessary of an FDA submission (Kaiser Daily HIV/AIDS Report, 3/25/02).

Ugandan Study
NIH in 1997 began studying the use of nevirapine in single doses among HIV-positive pregnant women in Uganda to determine the drug's ability to prevent vertical HIV transmission. The initial results showed that the drug prevented HIV transmission to newborns in as many as 50% of births. However, by early 2002, medical safety specialists and an auditor with NIH as well as Boehringer all cited "widespread problems" with the research in Uganda -- including a failure to receive participants' consent about changes in the study, administration of incorrect doses, and delays and underreporting of "fatal and life-threatening" reactions to the drug, according to the AP/Globe. Because of the reported problems, NIH suspended the research for 15 months from spring 2002 to summer 2003 in order to "review the science and take corrective actions," according to the AP/Globe. Investigators found that the research was "riddled" with poor record keeping and could not be sure from records which participants received nevirapine, the AP/Globe reports. Therefore, researchers had to use blood samples to confirm the doses used in the study, according to the documents obtained by the Associated Press. In addition, NIH's Office for Human Research Protections in 2002 informed Ugandan authorities that the research "may have represented a failure to minimize risk to the subjects." Westat, a professional medical auditing firm hired by NIH to review the Ugandan study, reported that there were 14 deaths not accounted for in the study database as of early 2002 and that the study's top two researchers had admitted to "thousands" of adverse reactions to the drug that were not disclosed, the AP/Globe reports. "It appeared likely, in fact, that many adverse events and perhaps a significant number of serious adverse events for both mother and infants may not have been collected and reported in a timely manner," Westat reported in March 2002. According to NIH meeting minutes taken after the agency received the information from the investigation, half of the infants in the Ugandan study also were enrolled in a vitamin A study that could have affected the outcome of the nevirapine study. Medical staff managing the nevirapine study also did not follow procedures for reporting serious adverse side effects, according to the documents, the AP/Globe reports.

NIH, Boehringer Reaction
Despite problems with the study, Tramont and other officials tried to "salvage the flawed research's underlying conclusions rather than start over," the AP/Globe reports. "There is presently no evidence that the study's scientific results are invalid," Tramont said in a report he sent to his staff less than two weeks after receiving the Westat analysis. In January 2002, Boehringer sent to NIH an early copy of a report on the Ugandan study that identified at least one "critical compliance issue" that might have compromised the integrity of the study and more than 48 issues the report called "serious" and "major," according to the AP/Globe. However, because Boehringer "fear[ed] publicity about the report might destroy its chance" for FDA approval of nevirapine in the United States to prevent mother-to-child HIV transmission, the company asked NIH to destroy the report before it was discovered by FDA regulators, the AP/Globe reports. "Sensitive information. Asked for it to be destroyed when audit is upon us," NIH official Mary Anne Luzar wrote on the cover page of the Boehringer report. However, Boehringer officials said they never asked for the report to be destroyed and that "our actions throughout the study evaluation were proactive and forthcoming." Dr. Clifford Lane, a clinical director at NIAID, said that Boehringer's request was "inappropriate" and that the agency "never complied," according to the AP/Globe. Lane also said that NIH "inappropriately kept the audit from FDA for weeks" and that "it shouldn't have happened that way," the AP/Globe reports. While NIH initially attempted to postpone the FDA review of nevirapine, officials from FDA and NIH eventually "arranged" for Boehringer to withdraw its application "rather than risk a public rejection that might scare African countries looking for U.S. guidance on the drug," according to the AP/Globe.

White House Initiative
In June 2002, Bush announced a three-year, $500 million initiative to reduce mother-to-child HIV transmission in Africa and the Caribbean with nevirapine as the plan's "centerpiece," the AP/Globe reports (AP/Boston Globe, 12/14). The initiative aimed to provide treatment to one million HIV-positive pregnant women annually to reduce vertical HIV transmission by 40% in target countries within five years or less (Kaiser Daily HIV/AIDS Report, 6/19/02). However, the administration did not know about NIH's concerns over the drug because the agency -- although aware in spring 2002 of the impending White House announcement -- chose not to tell presidential aides about the problems with the study. According to Lane, NIH officials were "confident, even before reviewing the Uganda research, that the underlying science was solid," the AP/Globe reports. Now two years later, FDA has recommended that NIH stop using the drug with certain patients after "hundreds of thousands" of doses of nevirapine have been distributed to pregnant women and children in Africa, according to the AP/Globe.

NIH Review
NIH officials have reviewed the Ugandan study and other research and "remain confident" that nevirapine can be used safely in single doses by African women and children to prevent vertical HIV transmission, the AP/Globe reports. However, officials also have "acknowledged their Uganda research failed to meet required U.S. standards," the AP/Globe reports. NIH recently asked the National Academy of Sciences to investigate the study and has spent millions of dollars over the past two years "improving its safety monitoring and record keeping," according to the AP/Globe. "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," Lane said. He added that a closer review of the Ugandan study indicated that even single doses of nevirapine can create "instant" drug resistance and that patients might not be able to use nevirapine or similar drugs in its class when their health deteriorates, the AP/Globe reports. "It was unexpected, and what it means is nevirapine probably shouldn't be a drug of first choice if other options are available," he said.

Reaction
Senate Finance Committee Chair Chuck Grassley (R-Iowa) has asked the Department of Justice to investigate NIH conduct on the issue, saying in a letter released Monday that he was compelled to do so by the "serious nature of these allegations and the grave implications if the allegations have merit." FDA also has asked for stronger warnings to doctors and patients about possible liver damage and rashes in people who take the drug for long periods of time (AP/Boston Globe, 12/14). "The FDA and NIH are clearly letting the American public -- and the world at large -- down with regard to their so-called roles as regulatory bodies overseeing the safety and efficacy of our drug supply," AIDS Healthcare Foundation President Michael Weinstein said, adding, "We also have grave concerns about the possibility that people in resource-poor countries around the world may be participating in studies and research treatments that the drug companies might not undertake here in the U.S. and that should cease" (AHF release, 12/13). Although Boehringer said it has research from locations such as Thailand and South Africa indicating that a single dose of nevirapine is safe in infants at birth, the company is no longer seeking FDA approval because "better treatments have emerged," according to Dr. Patrick Robinson, a Boehringer AIDS specialist, the AP/Globe reports (AP/Boston Globe, 12/14).