"President Bush’s recent trip to Africa has highlighted the need for
increased funding for development assistance and truly free trade, yet
development assistance to Africa remains stagnant, minus money for AIDS it
is actually decreasing."

WHAT GREAT NEWS.

AP: U.S. Officials Knew of AIDS Drug Risks

Mon Dec 13, 3:11 PM ET
   
 White House - AP

By JOHN SOLOMON, Associated Press Writer

WASHINGTON - Weeks before President Bush (news - web sites) announced a
plan to protect African babies from AIDS (news - web sites), top U.S.
health officials were warned that research on the key drug was flawed and
may have underreported thousands of severe reactions including deaths,
government documents show.

AP Photo

AP Photo

Slideshow: HIV/AIDS

     

The 2002 warnings about the drug, nevirapine, were serious enough to
suspend testing for more than a year, let Uganda's government know of the
dangers and prompt the drug's maker to pull its request for permission to
use the medicine to protect newborns in the United States.

But the National Institutes of Health (news - web sites), the
government's
premiere health research agency, chose not to inform the White House as
it
scrambled to keep its experts' concerns from scuttling the use of
nevirapine in Africa as a cheap solution, according to documents obtained
by The Associated Press.

"Everyone recognized the enormity that this decision could have on the
worldwide use of nevirapine to interrupt mother-baby transmission," NIH's
AIDS research chief, Dr. Edmund C. Tramont, reported March 14, 2002, to
his boss, Anthony Fauci, director of the National Institute of Allergy
and
Infectious Diseases (news - web sites).

The documents show Tramont and other NIH officials dismissed the problems
with the nevirapine research in Uganda as overblown and were slow to
report safety concerns to the Food and Drug Administration (news - web
sites).

NIH's nevirapine research in Uganda was so riddled with sloppy record
keeping that NIH investigators couldn't be sure from patient records
which
mothers got the drug. Instead, they had to use blood samples to confirm
doses, the documents show.

Less than a month after Bush announced a $500 million plan to push
nevirapine across Africa to slow the AIDS epidemic, the Health and Human
Services (news - web sites) Department sent a nine-page letter to Ugandan
officials identifying violations of federal patient protection rules by
NIH's research.

The NIH research "may have represented a failure to minimize risk to the
subjects," the Office of Human Research Protections told Ugandan
authorities in summer 2002.

Africa accounts for more than two-thirds of the world's AIDS cases, with
27 million infected, and the United States sought to help slow the
disease's spread across the continent.

Nevertheless, NIH officials told AP they remain confident after
re-reviewing the Uganda study and other research that nevirapine can be
used safely in single doses by African mothers and children to prevent
HIV
(news - web sites) transmissions during birth. But they acknowledged
their
Uganda research failed to meet required U.S. standards.

As a result, NIH recently asked the National Academy of Sciences (news -
web sites) to investigate its science in the case, and has spent millions
in the last two years improving its safety monitoring and record keeping.

"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," said Dr. H. Clifford Lane, NIH's No. 2
infectious disease official.

One lesson derived from a closer review of the Uganda research is that
even single doses of nevirapine can create instant resistance, meaning
patients may not be able to use the drug or others in its class again
when
their AIDS worsens, Lane said.

"It was unexpected, and what it means is nevirapine probably shouldn't be
a drug of first choice if other options are available," Lane said.

Lane said NIH officials were aware in spring 2002 about the impending
White House announcement on nevirapine but did not tell presidential
aides
of the problems because they were confident, even before reviewing the
Uganda research, that the underlying science was solid.

The White House — though unaware of the NIH concerns — also remains
confident in Bush's $500 million plan in 2002 to send nevirapine to
Africa. Bush approved $2.9 billion for global AIDS fighting next year.

"The president's mission is to try to stop the spread of AIDS in Africa
and to come at it from a new angle, and that is what this is all about,"
spokesman Trent Duffy said.

     

Nevirapine is an antiretroviral drug marketed in the United States as
Viramune that has been used since the 1990s to treat adult AIDS patients
and is known to have potentially lethal effects like liver damage and
severe rashes when taken over time.

In 1997, NIH began studying in Uganda whether it could be given safely in
single doses to stop mother-to-baby transmissions. That research showed
it
could reduce transmission in as many as half the births.

But by early 2002, an NIH auditor, the agency's medical safety experts
and
the drug's maker all disclosed widespread problems about the U.S.-funded
research in Uganda.

Boehringer Ingelheim, the Connecticut-based company that makes
nevirapine,
told NIH it identified at least one "critical compliance issue" that
compromised the integrity of the study and more than four dozen issues it
described as "serious" and "major."

Boehringer and NIH auditors cited concerns such as failing to get
patients' consent about changes in the experiment, administering wrong
doses and delays and underreporting of "fatal and life threatening"
problems.

"It appeared likely, in fact, that many adverse events and perhaps a
significant number of serious adverse events for both mother and infant
may not have been collected or reported in a timely manner," Westat Corp.
reported in March 2002. Westat is a professional medical auditing firm
hired by NIH to visit and audit the Uganda site.

Westat reported there were 14 deaths not reported in the study database
as
of early 2002 and that the top two researchers in Uganda acknowledged
"thousands" of bad reactions that weren't disclosed.

NIH said the subsequent review whittled that list down significantly, all
deaths were eventually recorded and the majority of bad reactions are
believed to have been caused by the poor health of patients, not the
single dose of nevirapine. But they conceded it was incumbent on a U.S.
research project to fully and quickly disclose them.

Officials said the problems began when NIH converted the research from
determining the drug's usefulness to supporting FDA (news - web sites)
approval for the drug. Paperwork in Uganda wasn't kept to the FDA
standards, they said.

"We may not have reported exhaustively, but we reported all serious side
effects," said Professor Francis Mmiro, a lead doctor in the Uganda
study.
"What you may call a serious side effect in the U.S. is not a serious
side
effect in Kampala."

NIH officials reviewed the bad news in early March 2002.

Meeting minutes, written in shorthand, raised broad concerns: Half the
babies in the study were also enrolled in a vitamin A study that could
have affected the outcome, and medical staff running the trials didn't
follow procedures for divulging serious adverse events (SAEs).

"No mtg minutes, no training doc(umentation), site used their own
criteria
for grading SAEs. No lab normal values & serious underreporting of SAEs,"
the minutes stated.

The minutes quote an NIH official who visited Uganda as saying, "The site
staff doesn't know what they don't know."

But Tramont, the AIDS research chief, and other top NIH officials
repeatedly dismissed the concerns as preliminary or overblown, and sought
to salvage the flawed research's underlying conclusions rather than start
over.

"There is presently no evidence that the study's scientific results are
invalid," said a report Tramont sent to his staff less than two weeks
after getting the March 2002 Westat audit.

In January 2002, Boehringer sent NIH an early copy of its report. But the
drug maker, fearing publicity about the report might destroy its chance
to
get the FDA approval of the drug for domestic use, asked NIH to destroy
it
before FDA regulators could learn about it.

"Sensitive information. Asked for it to be destroyed when audit is upon
us," NIH official Mary Anne Luzar wrote on the cover page of Boehringer's
report.

Boehringer says it never requested the document be destroyed, saying "our
actions throughout the study evaluation were proactive and forthcoming."

Lane said the request to destroy the report was inappropriate and NIH
never complied. But he conceded his agency inappropriately kept the audit
from FDA for weeks, saying, "It shouldn't have happened that way."

NIH at first sought to postpone the FDA review of nevirapine, then top
NIH
and FDA officials arranged for the drug maker to pull its U.S.
application
rather than risk a public rejection that might scare African countries
looking for U.S. guidance on the drug.

Unaware of the internal NIH concerns, Bush announced in June 2002 a $500
million effort to fight the spread of AIDS in Africa and the Caribbean.
The plan's centerpiece was nevirapine.

"This major commitment of my government to prevent mother-to-child HIV
transmission is the first of this scale by any government, anywhere,"
Bush
said in a Rose Garden announcement. The White House hoped the initiative
would reach up to 1 million women a year and cut mother-to-child
transmission of HIV by up to 40 percent.

Two years later, after hundreds of thousands of doses of nevirapine have
been distributed to African mothers and children, the FDA has recommended
NIH stop using the drug with certain patients. It also has demanded
stronger warnings to doctors and patients about possible lethal liver
damage and rashes in patients who take nevirapine for longer periods of
time.

African health officials are having second thoughts. South African
officials in July recommended ending the single-use treatment because of
the new concerns about drug resistance.

African doctors said they weren't aware of the full extent of NIH's
concerns but feel comfortable — at least until better options emerge —
administering it in single doses to AIDS-sickened mothers who have few
other choices to protect newborns.

"It's not ideal, but it works," said Dr. Ashraf Coovadia of Coronation
Mother and Child Hospital in Johannesburg, South Africa. Without it,
"many, many more babies would be born with HIV."

Boehringer Ingelheim said it has donated enough doses to treat more than
411,000 mothers and infants in Africa, and self disclosed the problems it
found with the Uganda research. But it says it has research from other
locations, like Thailand and South Africa, showing single dose usage at
birth is safe and effective.

"The bottom line is there were these procedural issues, such as the speed
of reporting adverse events, and the like. But the important scientific
data was intact, and found to be valid," said Dr. Patrick Robinson, a top
Boehringer AIDS specialist.

Still, the German-owned company no longer is seeking FDA permission to
use
nevirapine for protecting U.S. infants because better treatments have
emerged, he said.

___

AP reporter Alexandra Zavis in Johannesburg, South Africa, contributed to
this story.

On the Net:

Documents gathered by AP for this story are available at:
http://wid.ap.org/nevirapine1.html

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

Boehringer Ingelheim: http://www.boehringer-ingelheim.com

Mon Dec 13, 3:11 PM ET
   
 White House - AP

By JOHN SOLOMON, Associated Press Writer

WASHINGTON - Weeks before President Bush (news - web sites) announced a
plan to protect African babies from AIDS (news - web sites), top U.S.
health officials were warned that research on the key drug was flawed and
may have underreported thousands of severe reactions including deaths,
government documents show.

AP Photo

AP Photo

Slideshow: HIV/AIDS

     

The 2002 warnings about the drug, nevirapine, were serious enough to
suspend testing for more than a year, let Uganda's government know of the
dangers and prompt the drug's maker to pull its request for permission to
use the medicine to protect newborns in the United States.

But the National Institutes of Health (news - web sites), the
government's
premiere health research agency, chose not to inform the White House as
it
scrambled to keep its experts' concerns from scuttling the use of
nevirapine in Africa as a cheap solution, according to documents obtained
by The Associated Press.

"Everyone recognized the enormity that this decision could have on the
worldwide use of nevirapine to interrupt mother-baby transmission," NIH's
AIDS research chief, Dr. Edmund C. Tramont, reported March 14, 2002, to
his boss, Anthony Fauci, director of the National Institute of Allergy
and
Infectious Diseases (news - web sites).

The documents show Tramont and other NIH officials dismissed the problems
with the nevirapine research in Uganda as overblown and were slow to
report safety concerns to the Food and Drug Administration (news - web
sites).

NIH's nevirapine research in Uganda was so riddled with sloppy record
keeping that NIH investigators couldn't be sure from patient records
which
mothers got the drug. Instead, they had to use blood samples to confirm
doses, the documents show.

Less than a month after Bush announced a $500 million plan to push
nevirapine across Africa to slow the AIDS epidemic, the Health and Human
Services (news - web sites) Department sent a nine-page letter to Ugandan
officials identifying violations of federal patient protection rules by
NIH's research.

The NIH research "may have represented a failure to minimize risk to the
subjects," the Office of Human Research Protections told Ugandan
authorities in summer 2002.

Africa accounts for more than two-thirds of the world's AIDS cases, with
27 million infected, and the United States sought to help slow the
disease's spread across the continent.

Nevertheless, NIH officials told AP they remain confident after
re-reviewing the Uganda study and other research that nevirapine can be
used safely in single doses by African mothers and children to prevent
HIV
(news - web sites) transmissions during birth. But they acknowledged
their
Uganda research failed to meet required U.S. standards.

As a result, NIH recently asked the National Academy of Sciences (news -
web sites) to investigate its science in the case, and has spent millions
in the last two years improving its safety monitoring and record keeping.

"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," said Dr. H. Clifford Lane, NIH's No. 2
infectious disease official.

One lesson derived from a closer review of the Uganda research is that
even single doses of nevirapine can create instant resistance, meaning
patients may not be able to use the drug or others in its class again
when
their AIDS worsens, Lane said.

"It was unexpected, and what it means is nevirapine probably shouldn't be
a drug of first choice if other options are available," Lane said.

Lane said NIH officials were aware in spring 2002 about the impending
White House announcement on nevirapine but did not tell presidential
aides
of the problems because they were confident, even before reviewing the
Uganda research, that the underlying science was solid.

The White House — though unaware of the NIH concerns — also remains
confident in Bush's $500 million plan in 2002 to send nevirapine to
Africa. Bush approved $2.9 billion for global AIDS fighting next year.

"The president's mission is to try to stop the spread of AIDS in Africa
and to come at it from a new angle, and that is what this is all about,"
spokesman Trent Duffy said.

     

Nevirapine is an antiretroviral drug marketed in the United States as
Viramune that has been used since the 1990s to treat adult AIDS patients
and is known to have potentially lethal effects like liver damage and
severe rashes when taken over time.

In 1997, NIH began studying in Uganda whether it could be given safely in
single doses to stop mother-to-baby transmissions. That research showed
it
could reduce transmission in as many as half the births.

But by early 2002, an NIH auditor, the agency's medical safety experts
and
the drug's maker all disclosed widespread problems about the U.S.-funded
research in Uganda.

Boehringer Ingelheim, the Connecticut-based company that makes
nevirapine,
told NIH it identified at least one "critical compliance issue" that
compromised the integrity of the study and more than four dozen issues it
described as "serious" and "major."

Boehringer and NIH auditors cited concerns such as failing to get
patients' consent about changes in the experiment, administering wrong
doses and delays and underreporting of "fatal and life threatening"
problems.

"It appeared likely, in fact, that many adverse events and perhaps a
significant number of serious adverse events for both mother and infant
may not have been collected or reported in a timely manner," Westat Corp.
reported in March 2002. Westat is a professional medical auditing firm
hired by NIH to visit and audit the Uganda site.

Westat reported there were 14 deaths not reported in the study database
as
of early 2002 and that the top two researchers in Uganda acknowledged
"thousands" of bad reactions that weren't disclosed.

NIH said the subsequent review whittled that list down significantly, all
deaths were eventually recorded and the majority of bad reactions are
believed to have been caused by the poor health of patients, not the
single dose of nevirapine. But they conceded it was incumbent on a U.S.
research project to fully and quickly disclose them.

Officials said the problems began when NIH converted the research from
determining the drug's usefulness to supporting FDA (news - web sites)
approval for the drug. Paperwork in Uganda wasn't kept to the FDA
standards, they said.

"We may not have reported exhaustively, but we reported all serious side
effects," said Professor Francis Mmiro, a lead doctor in the Uganda
study.
"What you may call a serious side effect in the U.S. is not a serious
side
effect in Kampala."

NIH officials reviewed the bad news in early March 2002.

Meeting minutes, written in shorthand, raised broad concerns: Half the
babies in the study were also enrolled in a vitamin A study that could
have affected the outcome, and medical staff running the trials didn't
follow procedures for divulging serious adverse events (SAEs).

"No mtg minutes, no training doc(umentation), site used their own
criteria
for grading SAEs. No lab normal values & serious underreporting of SAEs,"
the minutes stated.

The minutes quote an NIH official who visited Uganda as saying, "The site
staff doesn't know what they don't know."

But Tramont, the AIDS research chief, and other top NIH officials
repeatedly dismissed the concerns as preliminary or overblown, and sought
to salvage the flawed research's underlying conclusions rather than start
over.

"There is presently no evidence that the study's scientific results are
invalid," said a report Tramont sent to his staff less than two weeks
after getting the March 2002 Westat audit.

In January 2002, Boehringer sent NIH an early copy of its report. But the
drug maker, fearing publicity about the report might destroy its chance
to
get the FDA approval of the drug for domestic use, asked NIH to destroy
it
before FDA regulators could learn about it.

"Sensitive information. Asked for it to be destroyed when audit is upon
us," NIH official Mary Anne Luzar wrote on the cover page of Boehringer's
report.

Boehringer says it never requested the document be destroyed, saying "our
actions throughout the study evaluation were proactive and forthcoming."

Lane said the request to destroy the report was inappropriate and NIH
never complied. But he conceded his agency inappropriately kept the audit
from FDA for weeks, saying, "It shouldn't have happened that way."

NIH at first sought to postpone the FDA review of nevirapine, then top
NIH
and FDA officials arranged for the drug maker to pull its U.S.
application
rather than risk a public rejection that might scare African countries
looking for U.S. guidance on the drug.

Unaware of the internal NIH concerns, Bush announced in June 2002 a $500
million effort to fight the spread of AIDS in Africa and the Caribbean.
The plan's centerpiece was nevirapine.

"This major commitment of my government to prevent mother-to-child HIV
transmission is the first of this scale by any government, anywhere,"
Bush
said in a Rose Garden announcement. The White House hoped the initiative
would reach up to 1 million women a year and cut mother-to-child
transmission of HIV by up to 40 percent.

Two years later, after hundreds of thousands of doses of nevirapine have
been distributed to African mothers and children, the FDA has recommended
NIH stop using the drug with certain patients. It also has demanded
stronger warnings to doctors and patients about possible lethal liver
damage and rashes in patients who take nevirapine for longer periods of
time.

African health officials are having second thoughts. South African
officials in July recommended ending the single-use treatment because of
the new concerns about drug resistance.

African doctors said they weren't aware of the full extent of NIH's
concerns but feel comfortable — at least until better options emerge —
administering it in single doses to AIDS-sickened mothers who have few
other choices to protect newborns.

"It's not ideal, but it works," said Dr. Ashraf Coovadia of Coronation
Mother and Child Hospital in Johannesburg, South Africa. Without it,
"many, many more babies would be born with HIV."

Boehringer Ingelheim said it has donated enough doses to treat more than
411,000 mothers and infants in Africa, and self disclosed the problems it
found with the Uganda research. But it says it has research from other
locations, like Thailand and South Africa, showing single dose usage at
birth is safe and effective.

"The bottom line is there were these procedural issues, such as the speed
of reporting adverse events, and the like. But the important scientific
data was intact, and found to be valid," said Dr. Patrick Robinson, a top
Boehringer AIDS specialist.

Still, the German-owned company no longer is seeking FDA permission to
use
nevirapine for protecting U.S. infants because better treatments have
emerged, he said.

___

AP reporter Alexandra Zavis in Johannesburg, South Africa, contributed to
this story.

On the Net:

Documents gathered by AP for this story are available at:
http://wid.ap.org/nevirapine1.html

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

Boehringer Ingelheim: http://www.boehringer-ingelheim.com