NIH AIDS Research Chief Rewrote Safety Report – AP

Wed, 15 Dec 2004

John Solomon of The Associated Press continues his documented expose of the inner workings of the AIDS Division of theNational Institutes of Health (NIH). At the same time that the Los Angeles Times and Congfressional hearings focused on major conflicts of interest at NIH, NIH’s AIDS Division was embroiled in a struggle between its chief and the medical research experts: "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.”

A January 2003 report by Dr. Betsy Smith said the Uganda trial of the AIDS drug, nevirapine, suffered from “incomplete or inadequate safety reporting” and records on patients were “of poor quality and below expected standards of clinical research.” But AP reports, that Dr. Edmund Tramont rewrote the expert report that was submitted to the FDA to make the experimental drug, nevirapine, appear safe and effective.

Questions arise about how reliable is the investigators’ published 2003 report in The Lancet claiming that nevirapine treatment reduced the transmission of HIV from mother to infant by 41%?

Within the last couple of years, we have witnessed a mounting body of evidence pointing to systemic corruption within the academic medical research community – including the FDA and NIH. A cascade of alarming evidence comes from highly credible sources – including company documents obtained through court procedures, eye witness reports by courageous whistleblowers in academia, government agencies, and the pharmaceutical industry.

The evidence demonstrates a deep divide between honorable physician/ scientists and a politicized leadership whose decisions always further the commercial interest of manufacturers of drugs, vaccines, and medical devices– often in complete disregard of life-threatening safety issues.

See: Flawed Device Places F.D.A. Under Scrutiny By BARRY MEIER THE NEW YORK TIMES December 15, 2004, p. A-1

The public is witnessing the unmasking of a fatally flawed system in which high ranking NIH officials have disregarded their (and the agency’s) professional and civic responsibility to the public, to practicing physicians, to the scientific community, and to taxpayers. The circle of trust has been broken – the system needs a complete overhaul. Industry’s influence must be eliminated from the evaluation / oversight process.

In the case of the AIDS Division of NIH, the cover-up of safety issues in the Uganda trial extended to deceiving the White House. Even the President of the US cannot rely on the integrity of scientific information from the nation’s premier medical research institution.

Contact: Vera Hassner Sharav
212-595-8974

http://www.dailybreeze.com/news/nationworld/articles/1146172.html
ASSOCIATED PRESS
AIDS Research Chief Rewrote Safety Report
By JOHN SOLOMON

WASHINGTON – The government’s chief AIDS researcher removed some negative safety conclusions from a subordinate’s report on a U.S.-funded drug experiment, then ordered the research to resume over objections from his staff, memos show.

As justification, Dr. Edmund Tramont, chief of the National Institutes of Health’s AIDS Division, cited his four decades of medical experience and argued that Africans with an AIDS crisis deserved some leniency in meeting U.S. safety standards, according to interviews and documents obtained by The Associated Press.

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. These problems had forced a 15-month halt to the research into using a single dose of 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 lone dose of nevirapine may cause long-term resistance to AIDS drugs in the hundreds of thousands of African patients who received it, foreclosing future treatment options.

In July 2003, Dr. Jonathan Fishbein, an expert NIH hired to improve agency research practices wrote Tramont: “I am not convinced that the (Ugandan) site is indeed prepared to become active.”

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.

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 evidenced 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 Tramont 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. Lane was designated by NIH to speak to AP on Tramont’s behalf.

“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 with resistance.

One of the nation’s premier AIDS charities said Tuesday it is concerned the controversy over the 2002 study problems will cause African countries to stop using the drug, and called on medical experts to find ways to get better new solutions into the Third World.

“Rather than focus on withdrawing nevirapine from those who urgently need it, the entire world should focus on how we can provide the funding for infrastructure improvements, training, and drug purchase costs so that more and more women will have access to the most effective drug regimens possible,” the Elizabeth Glaser Pediatric AIDS Foundations said in response to AP’s stories.

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 criticism 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.

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 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.

On the Net: Documents gathered by AP for this story are available at: http://wid.ap.org/documents/nevirapine2.html

Selected documents AP obtained in the investigation of nevirapine’s use in Uganda (all are in PDF format):

• 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.

National Institutes of Health: http://www.nih.gov

~~~~~~~~~

USA TODAY
AIDS drug worth the risk, federal health official says
From staff and wire reports

WASHINGTON – A National Institutes of Health official said Tuesday that an AIDS drug at the center of a controversial federal report has prevented thousands of infants from getting HIV.

The Associated Press, citing documents and interviews, said that a federal government AIDS research official rewrote a negative safety report on a U.S.-funded drug study in Uganda to cast the drug in a more positive light.

But Clifford Lane, acting deputy director of the National Institute of Allergy and Infectious Diseases (NIAID), said the drug, nevirapine, is so beneficial in preventing the spread of HIV to the infants of infected mothers that it has been deemed worth the risk.

The drug is made by Boeringer Ingelheim. A study involving 645 pregnant women in Kampala, Uganda, found that a one-time nevirapine treatment for the mother during labor and the infant after delivery reduced the risk of HIV transmission by 41%, researchers reported in the Sept. 13, 2003, issue of The Lancet, a British medical journal.

The study’s results were so favorable that an independent data and safety monitoring board stopped the study so all of the participating mothers and infants could receive the drug. Other studies also demonstrated the drug’s safety and effectiveness.

But problems surfaced when the manufacturer approached the U.S. Food and Drug Administration in 2002 to request that the drug be approved for widespread use to prevent mother-to-infant transmission of HIV. An FDA review of the data from the Uganda study disclosed multiple irregularities.

An internal report on the Uganda study by Betsy Smith of NIAID, finished in January 2003, said that the study suffered from “incomplete or inadequate safety reporting” and that records on patients were “of poor quality and below expected standards of clinical research,” according to the AP. She strongly urged NIH not to make sweeping conclusions about nevirapine based on the Uganda research.

Edmund Tramont, chief of NIH’s Division of AIDS, took responsibility for rewriting Smith’s report. It was published in early 2003 and sent to the FDA without Smith’s concerns included and with new, more favorable conclusions.

According to interviews and documents obtained by AP, Tramont cited his four decades of medical experience and said that Africans in the midst of an AIDS crisis deserved leniency in meeting U.S. safety standards.

The problems at the Uganda site led to a 15-month halt of research into using nevirapine to prevent African babies from getting AIDS from their mothers. Later, Tramont ordered the research resumed over the objections of his staff, AP said..

Jonathan Fishbein, an expert hired by NIH to improve the agency’s research practices, wrote Tramont in July 2003 that he should be given time to review Uganda’s capabilities and safety monitoring before letting the site reopen. He said NIH would risk being “toothless” in its new efforts to clean up sloppy research practices.

NIH knew about the problems in early 2002, before Smith’s report was finished, but did not tell the White House before President Bush launched a plan to distribute nevirapine throughout Africa, according to the documents.

Lane, one of Tramont’s bosses, said there was no reason to tell the White House about record-keeping irregularities, because the evidence demonstrated that the drug was safe and effective. He said allegations that Ugandan researchers had failed to report “thousands” of severe side effects were unfounded. “In the entire study, there were only two serious adverse events that were felt to be related to nevirapine, and those two were reported,” he said.

Fishbein has released thousands of documents to reporters and members of Congress. He has cast himself as a whistleblower, hired a lawyer and established a Web site that details his concerns about research safety at NIH.

He has also raised concerns that nevirapine may make the AIDS virus resistant to other drugs in its class. The issue so concerns scientists that it is routinely addressed at scientific meetings.

Contributing: Steve Sternberg

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a ‘fair use’ of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit.