[e-drug] Nevirapine /MTCT indication withdrawn in USA

[e-drug@usa.healthnet.org]

E-DRUG: Nevirapine /MTCT indication withdrawn in USA
-----------------------------------------------
[Boehringer Ingelheim last wednesday asked the FDA in USA to withdraw the
NDA status for the MTCT indication of nevirapine. This was immediately
picked up by the South African government, which asked the Medicines
Control Council to review the indication for MTCT in South Africa as well.
Please note that the SA government is involved in a court case with the
Treatment Action Campaign which has successfully asked the courts to
instruct the Dept of Health to provide nevirapine to HIV+ pregnant mothers
which have been appropriately counselled and tested. The SA government
position is at odds with WHO's advice of October 2000, in which it was
clearly stated that nevirapine was safe and effective, and that countries
could roll out nationwide.
Below the statements of WHO/UNAIDS and NIH about the USA nevirapine
developments. It appears there is no reason to change the position on
nevirapine for MTCT.
It would however be helpful to know what the administrative irregularities
were in the Uganda trial.
Finally a write-up from the Washington Post. Copied as fair use. WB]

WHO AND UNAIDS CONTINUE TO SUPPORT USE OF NEVIRAPINE FOR PREVENTION OF
MOTHER-TO-CHILD HIV TRANSMISSION

Geneva, 22 March 2002 - The statement released today by the United States
National Institutes of Health (NIH), concerning some reporting and
documentation irregularities in clinical trial HIVNET012, does not warrant
any change in the recommendations issued following a WHO technical
consultation on mother-to-child HIV transmission in October 2000.

This expert group, convened by WHO on behalf of UNICEF, UNFPA, and the
UNAIDS Secretariat, concluded that the safety and effectiveness of
antiretroviral regimens, including nevirapine, in preventing
mother-to-child HIV transmission has been clearly documented and that the
use of these regimens is thus warranted for preventing mother-to-child HIV
transmission. The simplest regimen requires a single dose of nevirapine to
the mother at delivery and a single dose to the newborn within 72 hours of
birth.

The NIH statement emphasized that, according to available information,
there has been no evidence the scientific data from the HIVNET012 study
demonstrating the safety and effectiveness of nevirapine is invalid.

Each year, more than 600 000 infants become infected with HIV, mainly
through mother-to-child transmission. WHO and the UNAIDS Secretariat
recommend that the prevention of mother-to-child transmission of HIV,
including antiretroviral regimens such as nevirapine, should be included in
the minimum standard package of care for HIV-positive women and their
children.  We are aware of no information that would cause the WHO and
UNAIDS to change its recommendations.

_____________________________________
For more information, please contact Bernhard Schwartlander, WHO, Geneva
(+41 79) 689 1332, Jon Lidén, WHO, Geneva (+41 79) 244 6006, Anne Winter,
UNAIDS, Geneva, (+41 22) 791 4577, Dominique de Santis, UNAIDS, Geneva,
(+41 22) 791 4509 or Andrew Shih, UNAIDS, New York, (+ 1 212) 584 5012.

------
NIH/NIAID statement

March 22, 2002

Review of HIVNET 012

(A Clinical Trial to Determine the Efficacy of Oral AZT and the
Efficacy of Oral Nevirapine for the Prevention of Vertical Transmission of
 HIV-1 Infection in Pregnant Ugandan Women and Their Neonates)

Since 1997, funding from the National Institute of Allergy and Infectious
Diseases (NIAID), National Institutes of Health (NIH), has supported a
trial known as HIVNET 012, conducted by co-investigators at Makerere
University in Kampala, Uganda, and the Johns Hopkins University in
Baltimore, Maryland.  The trial was designed to examine the effectiveness
of nevirapine (NVP) in blocking transmission of HIV from a mother to her
newborn baby by treating the mother and baby at the time of birth. NVP is
approved by the U.S. Food and Drug Administration (FDA) for the treatment
of HIV infection in adults and children.

Enrollment in HIVNET012 was completed in 1999. The results, published in
Lancet in 1999, concluded that NVP significantly reduced the risk of HIV
transmission from mother to child during the first week of life. Other
studies conducted in the United States and internationally were consistent
with the results from HIVNET 012. Based on the data from these studies, a
U.S. Public Health Service Task Force currently recommends NVP as an option
for prevention of mother-to-child transmission (MTCT) for women and their
newborns in the United States who have not received antiretroviral therapy
during pregnancy.

An examination of the data to support an extension of the indication for
the use of NVP to include prevention of MTCT was recently begun. Although
no evidence has been found that the conclusions of HIVNET 012 are invalid
or that any trial participants were placed at an increased risk of harm,
certain aspects of the collection of the primary data may not conform to
FDA regulatory requirements.  A comprehensive effort to access the primary
data has begun to determine the applicability of the data collection
processes to these regulatory requirements.

The reduction in perinatal transmission by the use of NVP, an accessible,
inexpensive regimen, represents a major public health advance in
resource-poor settings and NIAID believes there is no reason for programs
implementing this life-saving regimen to change their practices.

NIAID is committed to ensuring the highest standards of patient safety,
investigator conduct and accountability, and regulatory cooperation in all
clinical trials carried out in the United States and abroad.

NIAID is a component of the NIH.  NIAID supports basic and applied research
to prevent, diagnose, and treat infectious and immune-mediated illnesses,
including HIV/AIDS and other sexually transmitted diseases, illness from
potential agents of bioterrorism, tuberculosis, malaria, autoimmune
disorders, asthma and allergies.

###
Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892
Press Office: (301) 402-1663

---------

http://www.washingtonpost.com/wp-dyn/articles/A5310-2002Mar22.html
Firm Pulls Application for AIDS Drug Use in U.S.
By Shankar Vedantam
Washington Post Staff Writer
Saturday, March 23, 2002; Page A08

A Johns Hopkins University trial of an AIDS medicine in Uganda suffered
from procedural flaws, researchers and regulators announced yesterday,
prompting the drug's manufacturer to withdraw its application to have the
medicine approved for a particular use in the United States.

The flaws do not mean that the drug, nevirapine, is unsafe or ineffective,
and American safety regulators said they had no evidence that countries
using the medicine should stop. The Hopkins trial found that inexpensive
treatment with nevirapine could reduce the transmission of AIDS from
mothers to their newborn babies.

On Wednesday, the medicine's maker, Boehringer Ingelheim Pharmaceuticals
Inc., withdrew its application to the Food and Drug Administration to have
nevirapine approved in America for the prevention of mother-child HIV
transmission. The drug is already approved here for the treatment of AIDS
in children and adults.

Officials at Hopkins and the National Institute of Allergy and Infectious
Diseases, the federal government body that funded the research and oversaw
the project, said the problems identified in the trial were mostly about
paperwork. They said the study had been designed as a public health project
and not with the stringent requirements of an FDA submission in mind.

But two senior FDA officials said the problems were more than mere
paperwork. The officials declined to be specific.

Referring to the importance of documentation, an official who asked not to
be identified said: "In a clinical trial that extends over months or years,
documentation of what happened with patients, what was given to patients,
is obviously extremely important in understanding whether the results of
the trial accurately depict what is going on."

Nor would the withdrawal of the company's application end the FDA's
interest in the trial, the official said. The Hopkins researchers were
obliged to follow American procedures and rules, and the FDA has now
flagged the trial for "additional attention."

"We need to be confident and have people outside the U.S. be confident
about those trials and those results," the official said. "Having a study
done under [FDA supervision] is a brand name of quality. We want to make
sure that is maintained."

On Thursday in South Africa, the health minister cited the FDA's concerns
and interpreted them to be questions about the medicine's safety. The FDA
official said yesterday that such fears were unwarranted and that he was
optimistic the agency's evaluation would confirm the original findings.

Hopkins spokesman Gary Stephenson said the problems in the trial were not
"life-threatening or health-threatening."

Two areas of dispute with the FDA, he said, were over the issue of getting
informed consent from some patients and deciding which side effects were
caused by the medicine.

"When people were being screened, they orally consented to a blood draw
rather than a signed formal consent," he said. "In other cases, the FDA's
interpretation or definition of adverse events were different than the
study protocol."

"In Uganda, you have got all kinds of sicknesses and ailments that are not
related to the study," he said. "The FDA would want those reported, where
we documented things relevant to the study."

Examples, he said, were malaria, fever, diarrhea and certain ear
infections.

John La Montagne, deputy director of the National Institute of Allergy and
Infectious Diseases, added that the Hopkins team had created an
alternative -- and better -- system of tracking patients than was used at
Uganda hospitals. He said that the FDA wanted the original hospital data
and that it was taking scientists time to correlate the "shadow" charts
with hospital records.

"The issue is completeness of the record," he said. "I have not heard about
any concerns of long-term safety with this medication."

The study was conducted between 1997 and 1999 and observed the effects of
nevirapine treatment on 645 mother-child pairs, Stephenson said. It found
that giving the mother a dose of the medicine shortly before birth and
another to the child shortly after birth could reduce transmission of the
AIDS virus.

Boehringer Ingelheim's global chief of HIV programs in the developing
world, John Wecker, said the company had withdrawn its application because
it believed that researchers would not be able to get the FDA all the
necessary information on time.

"It is our intention to resubmit" the application once all the information
is in place, he said.



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