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The Nelfinivir Files

From Associated Press - AIDS Research Chief Rewrote Safety Report

Resources provided by Associated Press

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Warning from Nevirapine prescribing information

NIAID year 2000 strategic plan lauds Nevirapine

Associated Press

AP Exclusive

AIDS Research Chief Rewrote Safety Report,
Ordered Clinic Opened Over Objections


By JOHN SOLOMON
Associated Press Writer

WASHINGTON (AP) - The government's chief of AIDS research rewrote a safety report on a U.S.-funded drug study to change its conclusions and delete negative information. Later, he ordered the research resumed over the objections of his staff, documents show.

Dr. Edmund Tramont, chief of the National Institutes of Health's AIDS Division, took responsibility for both decisions. He cited his four decades of medical experience and argued that Africans in the midst of an AIDS crisis deserved some leniency in meeting U.S. safety standards, according to interviews and documents obtained by The Associated Press.

Dr. Edmund Tramont
Dr. Edmund Tramont - Chief of the
US National Institutes
of Health AIDS Division

Tramont's staff, including his top deputy, had urged more scrutiny of the Uganda research site to ensure it overcame record-keeping problems, violations of federal patient safety safeguards and other issues that forced a 15-month halt to the research into using nevirapine to prevent African babies from getting AIDS from their mothers.

AP reported Monday that NIH knew about the problems in early 2002 but did not tell the White House before President Bush launched a plan that summer to spread nevirapine throughout Africa. Now, officials have new concerns the drug may cause long-term resistance in patients who received it, foreclosing future treatment options.

"I am not convinced that the site is indeed prepared to become active," Dr. Jonathan Fishbein, an expert NIH hired to improve the agency's research practices, wrote Tramont in July 2003.

Fishbein contended he should be given time to review Uganda's capabilities and safety monitoring before letting the site reopen, or NIH would risk being "toothless" in its new efforts to clean up sloppy research practices. He added that professional safety monitors hired by NIH had reservations about the site.

Nevirapine

Tramont dismissed the safety monitors' concerns, saying he didn't believe they fully understood AIDS.

"I am convinced that this site is ready to resume given the limitations of doing research in any resource-poor, underdeveloped country," Tramont wrote July 8, 2003, in response to Fishbein.

"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 evidence by the fact that their lab is now certified," he wrote.

NIH officials acknowledge Tramont rewrote the report and overruled his staff on the reopening, but said he did so because he was more experienced and had an "honest difference of opinion" with his safety experts. They noted he had no financial interest in nevirapine and that the troubled study began well before he joined NIH in 2001.

Those 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," said Dr. H. Clifford Lane, the NIH's No. 2 infectious disease specialist and one of Tramont's bosses.

"But at the end of the day the final responsibility lies with the head of the team and it is his job to put that together the way he sees it," Lane said.

Lane said an internal NIH review concluded Tramont had not engaged in scientific misconduct. Separately, the National Academy of Sciences continues to investigate whether the Uganda research was valid.

NIH believes it helped save hundreds of thousands of African babies by allowing nevirapine to be used in single doses to block the AIDS virus, Lane said. But he acknowledged the research was imperfect, and NIH now believes nevirapine should no longer be a first choice for newborn protection - if other options exist - because of the newly discovered problems about resistance.

Babies

Tramont wrote in 2003 e-mails that he reopened the clinics because he didn't want NIH "perceived as bureaucratic but rather thoughtful and reasonable" and that it was important to encourage Africans' fight against AIDS "especially when the president is about to visit them."

Bush visited the continent a few days after Tramont ordered the clinics reopened.

Tramont's actions, however, drew a blunt reply from his top deputy.

"I think we are cutting off our noses to spite our face here," AIDS Division Deputy Director Jonathan Kagan wrote. "...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."

Tramont prevailed and the research resumed. A few days later, Tramont sent a note to his staff ordering the end of an 18-month-long debate inside NIH over whether the science from the Uganda trials was valid and safe. That debate began in early 20002 when two audits divulged widespread problems with the research.

The Uganda trial "has been reviewed, re-monitored, 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 a July 13, 2003 e-mail instructing his staff that future issues about the drug be handled directly by his office.

Five months earlier, Tramont surprised one of his own medical officers who had written a report summarizing safety concerns uncovered during a second review of the Uganda trial.

Dr. Betsy Smith's report, finished in January 2003, said the Uganda trial suffered from "incomplete or inadequate safety reporting" and that records on patients were "of poor quality and below expected standards of clinical research."

She strongly urged NIH not to make sweeping conclusions about nevirapine based on the Uganda research. "Safety conclusions from this trial should be very conservative," she wrote.

Behind the scenes, Tramont asked to see Smith's report before it was submitted to medical authorities, including the Food and Drug Administration. "I need to see the primary data - too much riding on this report," Tramont wrote Jan. 23, 2003.

A few weeks later, the safety report was published and sent to FDA without Smith's concerns and with a new conclusion.

The study "has demonstrated the safety of single dose nevirapine for the prevention of maternal to child transmission," Tramont's version concluded. "Although discrepancies were found in the database and some unreported AEs (adverse reactions) were discovered ... these were not clinically important in determining the safety profile."

In disbelief, Tramont's staff began inquiring how Smith's report got changed. An answer came back from the top.

"I wrote it," Tramont responded.


*** Article ends***

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Nevirapine


Resources provided by Associated press:

Selected documents AP obtained in the investigation of nevirapine's use in Uganda (all are in PDF format).These documents have been uploaded to the Virus Myth Australia site for "safe-keeping".

A note by Dr. Edmund Tramont to his subordinates, noting his concern that safety monitors critical of the Uganda trial might not understand AIDS and that some leniency should be given to a black-run clinic in Africa in the midst of an AIDS epidemic.

An excerpt from an E-mail from Dr. Tramont noting the importance of encouraging the fight against AIDS "especially when the president is about to visit them."

A response to Tramont's letter by his top deputy, AIDS Division Deputy Director Jonathan Kagan, who warns against being "motivated by political gains."

By 2003, Tramont sought to put to rest debate about the practices and results of the Uganda trial. He told staff that any further review "would be beyond reason."

A report by Dr. Betsy Smith reaffirmed most of the safety concerns of the first two audits. She made a sweeping condemnation of the Uganda trial, noting "incomplete or inadequate safety reporting" and patient records "of poor quality and below expected standards of clinical research."

The same report as re-written by Dr. Tramont; this report removes Smith's concerns and arrives at a different conclusion.

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More Nevirapine Resources:

Google search for media reports on the Nevirapine Scandal

Viramune associated with high rate of severe rash


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Warning from Viramune Product/Prescribing Information:

Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and
cholestatic hepatitis, hepatic necrosis and hepatic failure, has been reported in patients
treated with VIRAMUNE. In some cases, patients presented with non-specific prodromal
signs or symptoms of hepatitis and progressed to hepatic failure. These events are often
associated with rash. Women, and patients with higher CD4 counts, are at increased risk
of these hepatic events. Women with CD4 counts >250 cells/mm3, including pregnant
women receiving chronic treatment for HIV infection, are at considerably higher risk of
these events. Patients with signs or symptoms of hepatitis must discontinue VIRAMUNE
and seek medical evaluation immediately. (See WARNINGS)

Severe, life-threatening skin reactions, including fatal cases, have occurred in patients
treated with VIRAMUNE. These have included cases of Stevens-Johnson syndrome, toxic
epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional
findings, and organ dysfunction. Patients developing signs or symptoms of severe skin
reactions or hypersensitivity reactions must discontinue VIRAMUNE and seek medical
evaluation immediately. (See WARNINGS)

It is essential that patients be monitored intensively during the first 18 weeks of therapy
with VIRAMUNE to detect potentially life-threatening hepatotoxicity or skin reactions. The
greatest risk of severe rash or hepatic events (often associated with rash) occurs in the
first 6 weeks of therapy. However, the risk of any hepatic event, with or without rash,
continues past this period and monitoring should continue at frequent intervals. In some
cases, hepatic injury has progressed despite discontinuation of treatment. VIRAMUNE
should not be restarted following severe hepatic, skin or hypersensitivity reactions. In
addition, the 14-day lead-in period with VIRAMUNE 200 mg daily dosing must be strictly
followed. (See WARNINGS)


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Nevirapine - Lauded by the US National Institute of Allergies
and Infectious Diseases as early as 2000


Nevirapine lauded by NIAID


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