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NIH Official Altered Safety Report on Nevirapine Use in Pregnant Women

Dr Edmund Tramont, director of the National Institute of Allergy and Infectious Diseases Division of AIDS, rewrote a safety report on the use of the antiretroviral drug nevirapine in pregnant women in order to change its conclusions and remove negative information about the drug.

In March 2002, NIH received data from a Ugandan study testing whether nevirapine can reduce the risk of mother-to-child HIV transmission that prompted the agency to suspend the trial for more than a year and warn Uganda's government of the risks associated with the drug when used in pregnant women.

According to documents obtained by the Associated Press, poor record keeping might have caused an underreporting of severe reactions to the drug, including deaths. The documents also show that Tramont and other NIH officials regarded the problems with the trial as exaggerated and did not immediately report safety concerns about the drug to FDA.

Report Changes

By early 2002, medical safety specialists, an NIH auditor and the drug's manufacturer Boehringer Ingelheim all cited "widespread" problems with the nevirapine 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 Associated Press.

Because of the reported problems, NIH suspended the research for 15 months from spring 2002 to summer 2003 in order to review the trial and take corrective steps (Kaiser Daily HIV/AIDS Report, 12/14).

One report reviewing the Ugandan study -- which was conducted by Dr. Betsy Smith, a medical officer under Tramont -- in January 2003 said that the research had "incomplete or inadequate safety reporting" and that patient records were "of poor quality and below expected standards of clinical research," according to the AP/Globe.

Because of the reported problems, Smith "urged" NIH not to make "sweeping conclusions" about nevirapine based on the research in Uganda, the AP/Globe reports. "Safety conclusions from this trial should be very conservative," Smith wrote. However, Tramont asked to review Smith's report before it was submitted to authorities, including FDA. "I need to see the primary data -- too much riding on this report," Tramont wrote on Jan. 23, 2003. The report was published and sent to FDA a few weeks later with a new conclusion and without Smith's recommendations, according to the AP/Globe.

Tramont's version of the report concluded that the Ugandan study "has demonstrated the safety of single-dose nevirapine for the prevention of maternal-to-child transmission. Although discrepancies were found in the database and some unreported (adverse reactions) were discovered, ... these were not clinically important in determining the safety profile." According to the AP/Globe, Tramont said he had written the report after his staff began inquiring how Smith's report was changed.

Study Resumption

During the 15-month suspension of the Ugandan study, Dr. Jonathan Fishbein, a specialist hired by NIH to improve the agency's research practices, wrote in a message to Tramont that he was "not convinced that the [trial] site is indeed prepared to become active." Fishbein added that he should be allowed to review the site's capabilities and safety monitoring abilities before the study resumed or NIH would be "toothless" in its efforts to rectify the situation, according to the AP/Globe.

However, Tramont "dismissed" Fishbein's and other safety monitors' concerns, saying he believed they did not fully comprehend HIV/AIDS, according to the AP/Globe. "I want this restriction lifted ASAP because this site is now the best in Africa run by black Africans, and everyone has worked so hard to get it right as evidenced by the fact that their lab is now certified," Tramont wrote in response to Fishbein on July 8, 2003.

After the research resumed, Tramont sent a message to his staff "ordering the end of an 18-month-long debate" over the validity and safety of the Ugandan research, the AP/Globe reports. The trial "has been reviewed, remonitored, debated and scrutinized. To do any more would be beyond reason. It is time to put it behind us and move on," Tramont wrote in an e-mail dated July 13, 2003 (AP/Boston Globe, 12/15).

Fishbein recently released to journalists and members of Congress "thousands" of documents regarding the the nevirapine trial, and he is seeking whistleblower status, according to USA Today (Sternberg, USA Today, 12/15).

Tramont, NIH Reaction

According to the AP/Globe, Tramont has taken "responsibility" for the decisions to alter Smith's report and resume the Ugandan study, citing his "four decades of medical experience and argu[ing] that Africans in the midst of an AIDS crisis deserved some leniency in meeting U.S. safety standards."

Although NIH officials have acknowledged that Tramont rewrote the report and overruled his staff by resuming the trials, they said he did so because of his experience and an "honest difference of opinion" with safety specialists, the AP/Globe reports.

They added that Tramont had no financial interest in nevirapine and that the Ugandan study began "well before" he joined NIH in 2001, according to the AP/Globe.

Dr. Clifford Lane, acting deputy director of NIAID, said that staff members who raised objections "were part of a large team of which Dr. Tramont was the head, and it is important that the people involved in that team should express their opinion and there should be discussion." Lane added that an internal NIH review concluded that Tramont did not engage in scientific misconduct. The National Academy of Sciences also is reviewing the Ugandan study. NIH believes that it "helped save hundreds of thousands of African [infants] by allowing" single-dose nevirapine use, Lane said, according to the AP/Globe. However, after reopening the trial site, Tramont received "a blunt reply" from DAIDS Deputy Director Jonathan Kagan, the AP/Globe reports. "I think we are cutting off our noses to spite our face here," Kagan wrote to Tramont, adding, "We should not be motivated by political gains, and it's dangerous for you, of all people, to be diminishing the value of our monitors" (AP/Boston Globe, 12/15).

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Reference Source 127
December 17, 2004



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