MCC Decision to Deregister Nevirapine for
Mother-to-Child Transmission Prevention is Disturbing and
Confusing
31 July 2003
The Medicines Control Council
(MCC) is one of the most important institutions in public health. Its only task
is to ensure the safety, efficacy and quality of medicines in the public
interest. An independent and fearless MCC is essential to the health care
system. In 1996, the MCC registered nevirapine, an anti-retroviral for the daily
treatment of HIV/AIDS. This registration was done in accordance with its
statutory mandate. In April 2001, the MCC also registered nevirapine to reduce
mother-to-child HIV transmission.
Regrettably, the MCC has played
political games with the registration of nevirapine for mother-to-child-HIV
transmission since November 1999. Unfortunately, the MCC's questioning of
science appears to coincide with the conversion of President Mbeki and
Minister Tshabalala-Msimang to HIV denialist science. Despite their
protestations, the MCC cannot deny the enormous political pressure brought to
play on it during the registration process and in the MTCT court
case.
Now, the MCC has rejected the Ugandan HIVNET 012 study on the
prevention of mother-to-child HIV transmission. It has stated that it will
deregister nevirapine for single-dose mother-to-child transmission prevention
(MTCTP) in 90 days unless the patent-holder supplies it with new
data.
Many thousands of pregnant women and communities have already been
confused by the forays of the MCC into the politics of medicines and
anti-retrovirals. HIV/AIDS denialists misuse the MCC's authority to cause
further confusion and harm in our communities. The MCC has not provided the
public with any new scientific information to support it's inexplicable
position. The recent work of the MCC to register generic ARVs including
nevirapine is being undermined by its fork-tongued approach.
Nurses and
doctors in public hospitals and clinics around South Africa have expressed
dismay at this decision because it undermines the sustainability of the public
sector MTCTP programme. This programme has the potential when it is fully rolled
out to prevent approximately 30,000 babies from contracting HIV every
year.
Nevirapine is not the only drug that can be used to reduce
mother-to-child HIV transmission. AZT and other anti-retrovirals can be used as
individual drugs or in combination for this purpose. Since its inception TAC has
campaigned for the use of AZT. This is slightly more expensive and complex that
nevirapine. But, it is also more effective.
The TAC has for a long time
called for hospitals and clinics, where capacity exists, to begin using more
effective regimens than short-course nevirapine, but the reality is that many
facilities will not be in a position to upgrade their programmes to better
regimens for months or even years to come. It is these facilities whose MTCTP
programmes will be endangered if the MCC carries out its threat.
The
MCC's position contradicts a press statement by the World Health Organisation
(WHO) released in July 2003 (see below) which states that short-course
nevirapine for MTCTP should be part of the minimum standard of care for
HIV-positive women and their children. Nevirapine can be used and is used in the
United States, contrary to a popularly upheld belief frequently propagated by
AIDS denialists. Short-course nevirapine is recommended by the US Public Health
Service Task Force for MTCTP among HIV-positive women in labour who have had no
prior therapy. It is also included on the WHO essential medicines list for both
treatment and prevention purposes.
The TAC rejects this confusing and
seemingly unjustified decision by the MCC without a clear public explanation of
its reasons or motives. If there is evidence that it has acted
either incompetently or under political influence, there will be a dangerous
loss in confidence by the public, but especially health care workers, in South
Africa's medicines registration system. All the publicly available data on
short-course nevirapine used for mother-to-child transmission prevention
indicates that it is safe and effective. If the MCC has information to the
contrary, it must make this available because of the public interest in this
issue. In the meanwhile the TAC will seek legal opinion from its lawyers on how
to proceed on this matter.
Evidence for the Efficacy of Short-Course Nevirapine
In a radio
interview on Cape Talk (30 July 2003, 21:00-22:15 - transcript will be made
available next week) the MCC chairperson, Professor Peter Eagles, stated
unequivocally that that the MCC's decision is based on its concerns over the
efficacy of short-course Nevirapine and not its safety. The MCC is aware of the
following evidence that supports the efficacy of short-course
Nevirapine:
a. The HIVNET 012 trail conducted in Uganda found that
short-course nevirapine reduced transmission by nearly half.
b. The
South African Intrapartum Nevirapine Trail (SAINT) has confirmed that
short-course nevirapine (albeit with two doses to the mother, instead of one as
used in Uganda) is effective.
c. A number of trials have been (or
still are being) conducted using short-course nevirapine added to other MTCTP
regimens. These trials have demonstrated added efficacy due to the addition of
short-course nevirapine to other standard regimens. One of these studies
combined short-course AZT with short-course nevirapine and found that AZT plus
nevirapine reduced transmission by about 50% over AZT alone. The Western Cape
Department of Health has indicated that it intends to switch to this
regimen.
d. A study conducted at a hospital in South Africa that
has been submitted for publication examined 300 babies on a short-course
nevirapine mtctp programme (women were encouraged to use formula milk as well).
The study found a transmission rate of just under 9% at three months. This is
much lower than the typically seen 25 to 35% transmission rates in the
absence of MTCTP. This study confirms the operational effectiveness of
short-course nevirapine. (Researchers have requested confidentiality until the
study is published, but the MCC is aware of their findings.)
e. A
nevirapine MTCTP programme in Lusaka, Zambia found a transmission rate at 6
weeks of slightly over 11%. This study also confirms the operational
effectiveness of short-course nevirapine.
f. An unpublished study
from a hospital in Uganda implementing short-course nevirapine found a
transmission rate of about 12%. Before the programme this hospital recorded a
rate at 6 weeks of 20%.
The above demonstrates unequivocally that the
available evidence indicates that short-course nevirapine is effective for
MTCTP.
The MCC's Concerns
HIVNET 012
In the above-mentioned radio interview, Professor Eagles
stated that the MCC is unsatisfied with the conduct of the HIVNET 012 trial in
Uganda and therefore no longer considers this evidence of the efficacy of
short-course nevirapine. The facts however are as follows:
a.
The MCC registered short-course nevirapine for MTCTP without expressing
any concerns about the documentation from the HIVNET 012 trial in
2001.
b. The US based Food and Drug Administration (FDA), which is
the MCC's equivalent body in the US, returned an application for registration
for short-course MTCTP to the patent-holder because the HIVNET 012 trial's
documentation was not kept (nor ever intended to be kept) at the standards
required by the FDA. The FDA arguably has the most arduous documentation
requirements of any medicine regulatory authority in the world. The MCC does not
have the same documentation requirements and registers many medicines that the
FDA does not. This is a rational attitude in a country like South Africa which
has a less litiguous environment than the US and significantly worse health
issues. Nevertheless, the MCC has a justified reputation for requiring
high-standard documentation. Surely, we must assume that the MCC was satisfied
with the documentation supplied to it regarding the HIVNET 012 trial before it
registered short-course nevirapine for MTCTP.
c. The National
Institutes of Health who conducted the HIVNET 012 trial, commissioned an
independent audit of the trial to address concerns raised about the
documentation and conduct of the trial. This audit found that although there
were some irregularities in the documentation (which is common in many trials),
nothing they found cast doubt on the findings of the safety and efficacy of
nevirapine. The criticisms of the audit related to standards of patient consent
and unreported adverse events unrelated to nevirapine (such as malaria and
one child being born with an extra digit). Professor Eagles stated that it is on
the basis of this audit's findings that the MCC has made its decision not to
consider HIVNET 012 as evidence of the efficacy of short-course
nevirapine. Yet, the MCC's decision contradicts the finding of the audit.
If anything the audit has added to the confidence we can have in the HIVNET 012
trial.
d. In the radio interview, Professor Eagles first used the
FDA's decision not to register short-course nevirapine to justify the MCC's
decision. It was then pointed out to him that the MCC registers many medicines
that the FDA does not register. He denied this. But when specific examples of
such medicines were pointed out to him, he began arguing that the MCC is an
independent body that does not take its cue from the FDA. Surely Professor
Eagles cannot have it both ways unless rational argument is to be suspended. As
it happens, we concur with his view that the MCC most certainly should be an
independent body and that although it should consider FDA opinion, it should not
base decisions primarily on FDA concerns about documentation
requirements.
SAINT
The MCC has also cast doubt in the past on the findings of
SAINT (see the affidavit by Jonathan Levin of the MCC in the MTCTP court case on
the TAC website). It argued that SAINT was setup to demonstrate the superiority
of nevirapine over short-course AZT/Lamivudine. The trial failed to establish
this and since it was not set up as an equivalence trial, its findings on the
efficacy of short-course nevirapine cannot be inferred.
This is an unduly
picky argument which fails to consider that the slightly better efficacy of the
AZT/Lamivudine arm was not considered statistically significant, but more
importantly that the nevirapine results (12.3%) were far better than placebo
results from other trials (such as PETRA) and data on transmission rates where
no intervention has taken place. Even in Levin's affidavit (and when he
gave testimony at a parliamentary hearing on this issue) he acknowledges that
short-course nevirapine is effective. His argument is merely that it is not as
effective as found in the HIVNET 012 trial.
TAC members learnt from
scientists and lawyers that the MCC should take into account all available
evidence and that it is not obliged to consider only the findings of trials in
isolation from each other. It should also consider operational experience and
comparisons of results between trials. Frequently the MCC makes decisions doing
just this and frequently the MCC is alerted to flaws in trials, but yet accepts
their overall results on the balance of evidence. Clearly, given the available
evidence, it is not doing so here. It actually seems to be doing the opposite:
trying to find ways to cast doubt on the findings of essentially well-conducted
scientific trials.
Professor Eagles's Contradictions
In the Cape Talk interview,
Professor Eagles denied that the WHO had issued a statement directly supporting
short-course nevirapine, but the WHO statement (see below) was read out to him
over the air. Professor Eagles contradiction regarding the FDA has already been
pointed out. Furthermore the following package insert was read out to Professor
Eagles from a registered flu relief medicine package insert:
"Vitamin C
(ascorbic acid) has been claimed to be an essential factor in building up the
patients resistance to infections as well as speeding their recovery
rate."
It is clear then that the MCC allows package inserts to indicate
claims where there is some evidence, even if that evidence is not overwhelming.
We argue that the available evidence that short-course nevirapine is effective
is overwhelming. If the MCC has some doubts over nevirapine's efficacy, surely
it must allow manufacturers of the medicine to state that the balance of
evidence demonstrates that nevirapine is effective for the purposes of
mother-to-child transmission prevention. Professor Eagles offered no adequate
response to this argument.
We will make the transcript of this interview
available once we have obtained the tapes from Cape Talk.
MCC Must Re-establish Public and Health-Care Worker Confidence
The
MCC's decision has caused a crisis of confidence in its competence and
independence. It can however take steps to rectify this. Either it must produce
convincing evidence that most of the data supporting the effectiveness of
short-course nevirapine is significantly flawed or it must retract its decision
to deregister short-course nevirapine for MTCTP in 90 days unless the
patent-holder produces more evidence of the medicine's effectiveness. The TAC
would welcome either of these two routes. Furthermore, we believe that the
irrational views on HIV purveyed by the Minister of Health, has demonstrated the
need for a review of the current legislation whereby the Registrar of
Medicines is appointed (and can be removed) by the Minister of
Health.
Short-course nevirapine is by no means the best way to conduct
MTCTP, but it has offered hope to hundreds of thousands of mothers, nurses and
doctors. It would be scandolous if this hope is eroded by unscientific,
politically influenced decisions.
[END OF TAC STATEMENT]
World Health Organisation Statement
Nevirapine for the Prevention of Mother to Child Transmission of
HIV
WHO reconfirms its support for the use of nevirapine to prevent
mother-to-child transmission of HIV.
July 2003
The
Division of AIDS, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda has recently released the final report
(dated March 2003) from the reassessment of the trial procedures and results in
the HIVNET 012 trial conducted in Uganda1. This trial, the first to demonstrate
the safety and efficacy of nevirapine to prevent mother-to-child transmission
(MTCT) of HIV, was started in Uganda in 1997 and the results were published in
19992. A single dose of nevirapine given at onset of labour plus a single dose
to the newborn within 72 h of birth reduced the risk of HIV transmission down to
13%, almost 2-fold lower than a short course of zidovudine started during
labour. Concerns about the trial were raised in March 2002 when claims emerged
that certain serious adverse events had not been properly reported. The Division
issued a statement with the final report that concludes: "In summary, the
re-monitoring of the study determined that nevirapine, 200mg orally given to the
mother at delivery and 2mg/kg given to the neonate within 72 hours, is safe and
effective. However, the conduct of the study lacked the necessary documentation
to support a request to the FDA to consider this study as a stand alone pivotal
trial." Nevirapine has been registered in the USA, countries of the European
Union and numerous other countries for the treatment of AIDS (in combination
with other antiretroviral agents), and is also registered for MTCT prevention in
many countries worldwide. Nevirapine is recommended by the US Public Health
Service Task Force for MTCT prevention among women in labour who have had no
prior therapy3 and is included for both treatment and MTCT prevention purposes
in the WHO Model List of Essential Medicines, which is updated on a regular
basis.
In October 2000, WHO in partnership with UNAIDS, UNICEF and UNFPA,
convened a technical consultation to review all available evidence on the safety
and effectiveness of short-course antiretroviral drug-based interventions to
reduce the risk of MTCT4. The consultation concluded that all regimens which had
been shown to be safe and effective in controlled clinical trials could be used
in MTCT-prevention programmes. These regimens included zidovudine alone or in
combination with lamivudine, as well as nevirapine.
Since the consultation,
further research conducted in South Africa has demonstrated the safety and
efficacy of nevirapine as well as the zidovudine and lamivudine
combination5.
Scaling-up MTCT-prevention programmes in resource-limited
settings to reach more HIV-positive mothers and prevent any further infants
being infected with HIV is a major challenge, to which many governments,
non-governmental organizations, international aid agencies and WHO are
committed. While nevirapine is only one of several regimens which has been shown
to be safe and effective, the low cost and simplicity of use of the regimen
makes it particularly attractive.
Recommendations
WHO continues to support
the use of nevirapine in MTCT-prevention programmes. WHO agrees with the
National Institutes of Health report and the accompanying statement, which
emphasize that there is no evidence that the scientific data from the HIVNET012
study demonstrating the safety and efficacy of nevirapine are invalid. Each
year, about 800,000 infants become infected with HIV, mainly through
mother-to-child transmission. WHO and its partner United Nations agencies
recommend that MTCT prevention using antiretroviral regimens such as nevirapine
should be included in the minimum standard package of care for HIV-positive
women and their children. WHO is not aware of any information that should lead
to a change in this recommendation.
References
1. www.niaid.nih.gov/daids/Prevention.htm
2. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J,
Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L,
Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. Intrapartum and neonatal
single-dose nevirapine compared with zidovudine for prevention of
mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised
trial. Lancet 1999;354:795-802.
3. Public Health Service Task Force.
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected women
for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in
the United States, June 16, 2003. (http://AIDSinfo.nih.gov)
4. www.who.int/reproductive-health/rtis/MTCT_consultation.en.html
5.
Moodley D, Moodly J, Coodavia H, Gray G, McIntyre J, Hofmyer J, Nikodem C, Hall
D, Gigliotti M, Robinson P, Boshoff L, Sullivan JL, for the South African
Intrapartum Nevirapine Trial (SAINT) Investigators. A multicenter randomized
controlled trial of nevirapine versus a combination of zidovudine and lamivudine
to reduce intrapartum and early postpartum mother-to-child transmission of human
immunodeficiency virus type 1. Journal of Infectious Diseases
2003;187:725-735.
Contact
For further information please
contact:
Dr Tim Farley
Department of Reproductive Health and Research
E-mail: FarleyT@who.int
or
Dr Isabelle de
Zoysa
Department of HIV/AIDS
E-mail: DeZoysaI@who.int
[END OF WHO
STATEMENT]
[END OF NEWSLETTER]