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[e-drug] US FDA approves South African generic ARV

E-DRUG: US FDA approves South African generic ARV
[Andy Gray of DRUGINFO made a good compilation of news around the FDA approval 
of a South African generic ARV. Crossposted with thanks. WB]

Hi all

There were many breathless statements made yesterday about the Aspen
announcement (see below). That it's the first company to get approval
for an FDC or co-blistered presentation under the new FDA process is
significant. Other firms will certainly follow. As highlighted in the
press releases, the major implication is that the approved Aspen product
can now to paid for with PEPFAR monies. Recipient countries may well
have additional regulatory requirements, but some have little control
over medicines. The current PEPFAR recipient countries are: Botswana,
Cote d' Ivoire, Ethiopia, Guyana, Haiti, Kenya, Mozambique, Namibia,
Nigeria, Rwanda, South Africa, Tanzania, Uganda and Zambia (see
http://www.globalhealth.gov/PEPFAR_factsheet_022304.shtml). Aspen's
voluntary license conditions will also affect which countries may
receive the approved co-blistered product - at present, my understanding
is that export is limited to sub-Saharan Africa, thus ruling out Guyana
and Haiti. This could provide an interesting test case for the
"paragraph 6" process, although the existence of patent protection in
such countries is unlikely. A compulsory license issued here for export
would perhaps be necessary, unless the voluntary license conditions
could be eased. Information about the exact conditions of such licenses
is not always easily accessible.

Much was made of the possible impact on prices. Economies of scale may,
in time, allow such cuts. Much though depends on whether or not the
Clinton Foundation "deal" with Aspen and the Indian generic companies is
ever put into effect. The local tender process has not been concluded

The FDA guidance document on such products is at
http://www.fda.gov/oc/initiatives/hiv/hivguidance.html. This stemmed
from the FDC meeting held in Gaberone, for which the final document can
be found at http://www.globalhealth.gov/Final_FDC_index.shtml.
Critically, the FDA has listed combinations which they consider
"proven", and for which no further clinical studies are required: the
operative statement is "To encourage development of FDCs and co-packaged
products, FDA has created a list of examples of regimens and regimen
components (Attachment B) for which the clinical safety and efficacy of
concomitant use have been evaluated and described in product labels or
peer reviewed literature.  FDA expects that developing FDCs or
co-packaged products for combinations on this list could be accomplished
without conducting new clinical efficacy and safety studies and that
FDCs consisting of combinations on the attached list will satisfy the
principles underpinning 21 CFR 300.50 with regard to their safe and
effective use in combination". This is extremely important, as the FDCs
or co-blisters are not strictly speaking "generic" versions of existing
medicines. The list will develop over time, and the prerequisites for
new combinations are clearly spelled out - Approved individual
components; Two-drug nucleoside analogue components (to be used with a
protease inhibitors or NNRTI); Three-drug regimens, consisting of two
NRTIs and a protease inhibitor or NNRTI; Once or twice daily dosing 
Triple regimen (or two-drug component) studied for at least 48 weeks in
trials evaluating changes in HIV-RNA and CD4 cells; Comparison of the
regimen to appropriate controls; Acceptable risk-benefit profile,
particularly for treatment-naive patients; Recommended as preferred or
alternate regimens for initiating antiretroviral therapy". The exitsing
list is already extensive, including seven 2-drug combinations (to be
used with a third) and sixteen 3-drug combinations.

World first from Aspen Pharmacare  2005-01-25  

JSE Securities Exchange listed Aspen Pharmacare, Africa's largest
pharmaceutical manufacturer, is the world's first generics producer to
receive approval (tentative approval*) by the US Food and Drug
Administration (FDA) for the manufacture of selected generic
antiretrovirals (ARVs) containing Lamivudine/ Zidovudine and Nevirapine
for the treatment of HIV/Aids. This treatment is the world's most
widely used triple cocktail antiretroviral regimen and it has met the
FDA's quality, safety and efficacy standards and will be available for
potential procurement under the President's Emergency Plan for AIDS
Relief (PEPFAR) and for use in South Africa and other PEPFAR nations.

Stephen Saad, Aspen Pharmacare Group Chief Executive said "this is a
landmark announcement from the FDA and is a historic moment in the South
African pharmaceutical industry. Aspen is the world's first
pharmaceutical manufacturer to be granted generic ARV approval by the
FDA for these three important antiretrovirals. Aspen's combination
treatment is comprised of Lamivudine/Zidovudine and Nevirapine
co-packaged tablets in conventional adult dosages. This world first
recognizes South Africa and Aspen's scientific and technical
capabilities, its manufacturing, quality and GMP compliances and its
strong management team. This development represents a significant window
of opportunity for Aspen in that it now has access to PEPFAR's US$15
billion funds to manufacture generic ARVs for specified developing
countries. An additional advantage is that at present there are no
generic pharmaceutical manufacturers globally other than Aspen that have
voluntary licences for the patents of the generic ARVs, have obtained
FDA acceptance of a facility as a source of approved generic ARVs and
have FDA approval of their generic ARVs." 

"Aspen has remained committed to finding a meaningful solution to the
HIV/Aids blight for years. This announcement enables Aspen to
manufacture cost effective generic ARVs for society's poorest, most
vulnerable and most desperate and who have been afflicted by the biggest
medical scourge we have seen in recent times. It is with pride that
Aspen, a South African company, is at the forefront of the battle
against HIV/Aids," said Saad.

In 2004 the US government announced the establishment of the PEPFAR
initiative. This initiative also made provision for manufacturers to
obtain an expedited FDA review and approval of their products, whilst
ensuring that the products are safe, effective and meet the stringent
quality standards of US FDA. 

Aspen applied to the FDA for an expedited review and Aspen's Oral
Solid Dosage (OSD) facility subsequently underwent a rigorous audit. The
FDA's approval of Lamivudine/Zidovudine and Nevirapine underscores
Aspen's ability to compete on a global scale with the world's
leading pharmaceutical manufacturers.

Aspen pioneered the formulation and development of generic ARVs under
voluntary licences from the originators. Aspen's ARV basket is
comprised of Aspen Stavudine, Aspen Didanosine, Aspen Nevirapine, Aspen
Lamivudine (Tablets and Solution), Aspen Zidovudine (Tablets and
Solution) and Aspen Lamzid (combination Lamivudine/Zidovudine). The
generic ARV tablets and capsules are to be manufactured at the OSD

Dr Humphrey Zokufa, Chief Director Pharmaceutical Planning and Strategy
Department of Health said, "this world first speaks volumes for the
scientific, technical, medicine regulatory and manufacturing standards
in our country and reinforces the decisive response that Aspen as a
local South African manufacturer has taken in arresting this destructive

The results of the South African government's first ARV tender are
still awaited, however Aspen is well positioned to be a major player in
the supply of cost effective generic ARVs, both in South Africa and
export markets. 

* Tentative approval is granted in cases where there are still patents
or marketing exclusivity in effect in the U.S.

Stephen Saad
Aspen Pharmacare Group Chief Executive
25 January 2005
FDA News
January 25, 2005
 Media Inquiries: 301-827-6242
Consumer Inquiries: 888-INFO-FDA
FDA Grants Tentative Approval to Generic AIDS Drug Regimen for
Potential Purchase Under the President's Emergency Plan for AIDS Relief
The Food and Drug Administration (FDA) today announced the tentative
approval of a co-packaged antiretroviral drug regimen manufactured by
Aspen Pharmacare of South Africa for the treatment of HIV-1 infection in
adults. The agency's tentative approval means that although existing
patents and/or exclusivity prevent U.S. marketing of Aspen's product, it
meets FDA's quality, safety and efficacy standards for U.S. marketing.
This action makes this product available for potential procurement by
President Bush's Emergency Plan for AIDS Relief. 

Today's action is the first tentative approval of an HIV drug regimen
manufactured by a non-U.S.-based generic pharmaceutical company. Once
Aspen 's marketing application was complete on January 13, 2005, FDA
completed its review within two weeks. 

"Today's action honors the commitment of the Department of Health and
Human Services and Secretary Thompson to the President's Emergency Plan
for AIDS Relief," said Dr. Lester M. Crawford, Acting FDA Commissioner.
"The goal of the emergency plan is to make safe, effective and
affordable quality drugs available quickly for patients with HIV/AIDS."

"Through an expedited review process, FDA has worked diligently to
approve a product with great public health significance. Our
contributions to the goals of the emergency plan are an integral part of
that effort," added Dr. Crawford. 

The Emergency Plan for AIDS Relief, which President Bush first
announced in his 2003 State of the Union Address, is currently providing
$15 billion to fight the HIV/AIDS pandemic over five years, with a
special focus on 15 of the hardest hit countries. It targets three
specific areas related to HIV/AIDS: 

Prevention of HIV transmission; 
Treatment of AIDS and associated conditions; 
Care, including palliative care for HIV infected-individuals, and care
for orphans and vulnerable children. 

The tentatively approved regimen consists of co-packaged
lamivudine/zidovudine fixed dose combination tablets and nevirapine
tablets. Lamivudine/zidovudine fixed dose combination tablets are a
version of the already approved Combivir tablets manufactured by
GlaxoSmithKline, and nevirapine tablets are a version of Viramune
tablets manufactured by Boehringer-Ingelheim. The new co-packaged
product consists of two tablets (lamivudine/zidovudine and nevirapine)
each to be taken twice daily, after the initial two-week initiation
phase of this nevirapine regimen. 

More information on HIV and AIDS is available online at FDA's website:

Andy Gray MSc(Pharm) FPS
* Senior Lecturer
Dept of Therapeutics and Medicines Management
* Study Pharmacist
Centre for the AIDS Programme of Research 
in South Africa (CAPRISA)
Nelson R Mandela School of Medicine
University of KwaZulu-Natal
PBag 7 Congella 4013
South Africa
Tel: +27-31-2604334/4298 Fax: +27-31-2604338
email: graya1@ukzn.ac.za or andy@gray.za.net
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