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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).
Related articles:
Reference
Source 127
December 17, 2004
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