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[e-drug] U.S.'s Misguided and Bad-Faith Attack on WHO 3-by-5

E-drug: U.S.'s Misguided and Bad-Faith Attack on WHO 3-by-5
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[Cross-posted from Ip-health. Thanks. Long message! HH]


U.S.'s Misguided and Bad-Faith Attack on the WHO's 3-by-5 Plan
Brook K. Baker, Northeastern University School of Law and Health
GAP

December 18, 2003

As the U.S. government plods slowly towards expanded funding for
its largely bilateral global AIDS initiative (President's Emergency
Plan for AIDS Relief) and as it sends successive waves of
teary-eyed politicians on fact-finding tours to AIDS orphanages in
Africa, it has been working hard behind the scenes to undercut
multilateral AIDS initiatives including the Global Fund to Fight AIDS,
TB, and Malaria and the WHO 3-by-5 plan (three million people on
antiretroviral therapy by the end of 2005). The U.S. systematic
under-funding of the Global Fund and its persistent suppression of
donor and recipient expectations has been well documented. The
"highlight" of the Administration's campaign for the planned failure
of the Global Fund is its scale-back of annual donations to the
Global Fund, now set at only $200 million annually for the next five
years. That will keep the Fund's executive structure going while
Richard Feachem (Executive Director) and Tommy Thompson
(Chairperson of the Board and U.S. Secretary of Health and
Human Services) supervise the gradual dissipation of all forward
motion on a unique plan to provide a coordinated global response
to the worst pandemics of modern time.

Having succeeded in engineering a downward slope in grant
applications at the Global Fund, the U.S. has recently turned its
attention on the WHO and its ambitious plan to provide
antiretroviral therapy to 3 million people living with AIDS by the end
of 2005, roughly one-third of those in need of AIDS medication to
prevent their premature deaths within the following two years.
Jealous of the WHO's leadership role, desirous of unilateral credit,
and eager to tout the gentle flip side of its brutal War on Terror, the
Bush Administration has embarked on a subtle disinformation
campaign, coordinated with its business ally, Big Pharma, to try to
undermine the role of low cost, standard quality generic medicines
in the battle against AIDS and to discredit efforts to rapidly increase
capacity to deliver antiretroviral therapy by relying less on medical
experts and more on community-based health workers.

In mounting its attack on the WHO's historic enterprise, the U.S.
has wrapped itself in the mantle of medical ethics and questioned
key components of the WHO plan including: (1) "overly simplistic"
recommendations for simplified and standardized front-line
combination therapies, including fixed-dose combination
medicines; (2) reliance on the WHO's pre-qualification program to
identify presumptively safe and efficacious AIDS medicines,
particularly Cipla's Triomune; (3) advocacy for free treatment rather
than co-payments; and (4) reliance on a new corps of community
health workers for much of the direct care delivery. In essence the
U.S. government is saying that it has a unique vision for a
platinum-standard program of AIDS treatment and that anything
less is third-rate and violates medical ethics. Coincidentally, the
U.S. bemoans that African countries have minimal capacity to
deliver such high quality care and thus the U.S. is justified in its
go-slow approach to appropriations and planning.

There is a deep and abiding irony in the U.S.'s hypocritical attack
on the ethics of the WHO's 3-by-5 plan whereby it seeks to ride the
high horse of exaggerated concern for highest quality treatment.
This is the same government that has inspired and enforced
structural adjustment policies at the World Bank and the
International Monetary Fund and in its own bilateral programs that
have decimated the already weak, but theretofore improving public
health systems of sub-Saharan Africa during much of the 1980's
and 90's. This is the same government that dramatically reduced
development spending in Africa and the rest of the world at the end
of the Cold War because it no longer needed to prop up corrupt
post-colonial allies in the struggle against the Soviet Union. This is
the same government that has pursued neo-liberal economic
policies and unfair trade policies that have undermined rural
economies and prompted much of the migration that fuels the
spread of HIV/AIDS. And, most significantly, this is the same
government that sat on the sidelines and flat-funded international
funding for AIDS during the 1990's as the pandemic exploded
exponentially on an unprepared continent.

Moral exhortations from a recently converted perpetrator are
always a bit hard to swallow, but the hypocrisy of the U.S. position
is not just that it denies its past but that it is using the discourse of
medical ethics to mask its underlying pursuit of pharmaceutical
interests. There is an extraordinary match between the talking
points pursued by Administration spokespersons at the WHO and
the well-worn talking point of PhRMA and other industry
mouthpieces. Big Pharma has consistently slandered the quality of
"pirated" generic products to preserve the illusion of the superiority
of their patent-protected and monopoly-priced medicines. It has
tried to impose higher-than-necessary regulatory standards on
drug registration authorities in developing countries through
harmonization schemes and otherwise.  And, it has relentlessly
pursued heightened intellectual property protections in multilateral,
regional, and bilateral trade agreements - protections that would
limit compulsory license and parallel importation rights, extend
patent terms, deny access to clinical trial data, and undermine
exportation of generic medicines to countries that can't make them
on their own.

Certainly it is appropriate for health officials and experts to question
the WHO's 3-by-5 plan in good faith. Though the U.S. attacks are
undoubtedly advanced in bad faith, it makes sense to review the
merits of the expressed concerns, always weighing in the
background the reality of 8000 deaths a day.

Fixed-dose combinations

There are two central and interrelated benefits that arise from the
use of FDCs in the administration of Highly Active Antiretroviral
Therapy (HAART) in developing countries. The first is a lower
overall pill count that predictably increases adherence to treatment
regimes. The second is that FDCs have been shown to increase
compliance because patients can take all their required medicines
on a regular and fixed schedule rather than having to cope with a
more complicated schedule of multiple pills on differing time
schedules. The impact of reduced pill count and of simplified
dosing schedules is to decrease the incidence of resistance of the
AIDS virus to ARV treatment.

The World Health Organization has emphasized the importance of
developing innovative strategies for enhancing adherence to
antiretroviral therapy because it is a life-long therapy.[1] It is widely
accepted, including by surveys by pharmaceutical manufacturers,
that a main obstacle to patient compliance with HAART is too many
pills and complicated dosing schedules. [2] Thus, the WHO has
recommended that medical providers utilize strategies to increase
adherence to treatment regimes that "include minimizing pill counts
and dosage frequencies by preferentially using combination pills on
a once-daily or twice-daily basis."[3] According to the WHO,
"[w]hen available, fixed-dose combinations are advantageous with
respect to the simplification of regimens and consequent improved
adherence."[4]

In addition to referencing the benefits of fixed-dose combinations
produced by major pharmaceutical manufacturers,[5] the WHO
acknowledges that fixed-dose formulations have been produced by
generic manufacturers, "which [formulations] may facilitate
simplified regimens, decrease cost and promote adherence if they
can be legally used and their quality and bioequivalence has been
demonstrated."[6]

The theoretical importance of FDCs has been confirmed by recent
research on twice-daily regimens. "[R]ecent work on simplification
of HAART regimens, reported at the latest Glasgow conference on
HIV treatment, could have a major impact on compliance-related
treatment failure in both resource-rich and resource-poor countries.
- It is well documented that adherence rises as the complexity of a
HAART regimen declines, a point emphasized by a recent
comparison of the fixed-dose combination of zidovudine and and
3TC (Combivir) with the 2 drugs given separately."[7] Of course,
the long-term goal is to reach a goal of a once-daily regimen that
"provides patients with a regimen that can fit more easily into their
established routines, thereby increasing treatment adherence."[8]

Medical experts have emphasized that patient compliance is
dependent on a reduced pill burden and simplified dosing
schedules, but fixed-dose combinations have other advantages in
terms of ensuring that patients take triple as opposed to mono or
dual therapy. Triple therapy is essential to counteract HIV's
extraordinary mutation rate, which leads to an accelerated
incidence of drug-resistance in mono or dual therapy regimes.[9]
Providing HAART through three-drug FDCs reduces the possibility
that patients will be treated with a substandard number of drugs,
which is still unfortunately common in African countries.[10]

Administering HAART through fixed-dose combination pills might
also reduce, though not eliminate, the risk that the patient would
split therapies with others. Although there has been little research
on pill splitting in resource poor settings, especially since there has
so little ARV therapy provided, there is reason to believe that
patients are sometimes coerced to share pills or do so out of
concern for others, especially within family settings.[11] This is one
reason why treatment providers have begun to encourage
voluntary counseling and testing with both partners and why
mother-to-child-prevention-plus programs[12] extend ARV therapy
to an entire family group, since HIV infection is likely to be
intra-familial.

The clinical benefit of increased adherence resulting from the use
of fixed-dose combinations is the decreased incidence of
resistance of the AIDS virus to individual medicines and to entire
classes of medicines. According to the WHO, adherence to
HAART must be at a very high level to achieve lasting viral
suppression because of the rapid replication and mutation rates of
HIV.[13] The advantage of triple-therapy is that it attacks HIV in
three ways at the same time, meaning that a mutation that is
resistant to one medicine is unlikely to be simultaneously resistant
to the other two.

Why the U.S. Picks on Cipla's Triomune

Cipla of India has twice ruptured the complacency of Big Pharma
with respect to its patent monopolies on AIDS medicines, first on
February 7, 2001, when it announced a price heard round the world
- a standard package of ARVs for as little as $350/year to NGOs
and $600/year to governments in Africa[14] and a second time on
August 7, 2001, when it announced the formulation of a new
three-in-one antiretroviral tablet, Triomune, combining stavudine,
lamivudine, and nevirapine.[15] The public announcement of these
breakthrough emphasized the cost and therapeutic advantages of
the new fixed-dose combination medicine, only slightly more than a
$1 a day - a fifth or sixth of the cost of the then cheapest treatment
with brand-name drugs that extra pills and more complex dosing
schedules. Since Cipla's historic announcement, other Indian
companies have begun to produce fixed-dose combination
ARVs,[16] as have companies in Thailand,[17] and China,[18] and
prices of these treatments have continued to decreased over
time.[19] This fall, a new benchmark price has been established by
four generic producers, three Indian and one South African - less
than $140 per year for WHO preferred fixed-dose combination
medicines. [20] Accordingly, standard quality FDC generics are
now available for a penny on the dollar of what the major
pharmaceutical companies charge in rich markets.

Given the therapeutic importance of FDCs, it is important to
understand why so few proprietary pharmaceutical manufacturers
have produced combination ARVs and, more to the point, why
none of them have done so with a competitor's product. In this
context, it is important to remember that HIV medicines are
individually patented and that patent-holders have a perverse
economic interest in avoiding the creation of FDCs and in delaying
product improvements.[21] Let's take the Cipla example. Britain's
GlaxoSmithKline holds the patent for lamivudine, Germany's
Boehringer Igelheim the patent on nevirapine and the US's
Bristol-Myers Squibb the patent on stavudine. Nothing in principle
prohibits these three companies from entering into voluntary
cross-licensing agreements to produce a three-in-one fixed-dose
ARV tablet, especially since this combination is both efficacious
and inexpensive; indeed, the WHO recommends it as a first-line
combination for resource poor settings.[22] However, in practice,
the proprietary manufacturers have not wanted to dilute individual
brand recognition, nor have they wanted to indirectly promote the
products of a competitor. Although GlaxoSmithKline will combine its
own HIV products, e.g. Combivir (AZT+3TC) and Trizivir
(AZT+3TC+ABC), neither it nor its competitors have yet combined
ARVs with other manufacturers. As a consequence, in countries
where generics are excluded because of patent status, doctors and
patients are left with the unwieldy task of prescribing and taking
multiple tablets, multiple times a day, and then monitoring
compliance with overly complicated treatment regimes.

The logic of single-medicine pills makes sense in the twisted world
of global pharmaceuticals, where maximizing profit, maintaining
competitive advantage, and promoting brand recognition prevail,
but it does not make sense in the actual lives of AIDS patients in
developing countries where simpler regimes are crucially important
to survival. FDC medicines can be distributed more easily and
reliably; they can ease patient compliance; and they can reduce
risks of resale of drugs by desperately poor patients who might
otherwise be tempted to resell part of their treatment regime in the
hope that one out of three medicines might be enough. One
three-in-one pill twice a day will also be easier for health aids to
monitor if directly observed therapy is instituted on a broad scale.

There are rumors that major drug companies recognize the
comparative therapeutic advantages of Cipla's FDC Triomune (and
Ranbaxy's and Aspen's as well) and that two companies,
GlaxoSmithKline and Bristol Myers Squibb are engaged in
discussions about exclusive cross-licensing agreements to
produce fixed-dose combinations of their joint products.  This
exclusive deal would not increase competition, but the combined
product would undoubtedly offer therapeutic advantages. In
addition to this still unrealized option, drug companies are urging
the WHO to endorse blister packs containing products from several
patent holders (with a.m. and p.m. doses), arguing that this solution
offers greater treatment flexibilities. Again, this kind of packaging
does offer some therapeutic advantages, but it does not reverse
the even great therapeutic value of low-cost, generic FDCs.

WHO Pre-Qualification Project

The U.S. delegation and Big Pharma could not mount a credible all
out assault on the concept of fixed-dose combination medicines
and on the idea of Cipla's Triomune, so instead they are attacking
the WHO Pre-Qualification Project, at least to the extent that it
"improperly" pre-qualified Triomune. By punishing Cipla and subtly
undermining WHO pre-qualification standards, the
U.S./Big-Pharma team continue to hype the superior quality of
proprietary, patented drugs and to freeze its most loathed generic
competitor out of the rapidly expanding global market for ARVs.

Because poor quality medicines can have serious health
consequence, all treatment advocates and program designers
must be concerned that there are exacting quality standards during
both the production and distribution process. If medicines do not
contain the correct active ingredients in correct quantities, if
medicines contain harmful substances, or if quality and efficacy
deteriorate because of improper handling or expiration, patients will
be exposed to substandard or even dangerous therapies that can
lead to treatment failure, drug resistance, and even death. The
issue of drug quality is particularly important in AIDS therapy
because the therapeutic range of most ARVs is quite narrow and
because on the life-threatening consequences of non-therapeutic
dosing.

The WHO has just released a study documenting the growing
problem of substandard and counterfeit medicines estimating that
up to 25% of medicines consumed in poor countries are deficient
and that the deficiencies are particularly problematic for
high-markup products treating HIV/AIDS, tuberculosis, and
malaria.[23] "Trade in substandard and counterfeit medicines is
most prevalent in countries with weak drug regulation control and
enforcement, scarcity and/or erratic supply of basic medicines,
unregulated markets and unaffordable prices," according to the
WHO press release. To redress these recurrent problems, the
WHO recommended legislative reform to strengthen enforcement
powers in drug regulatory authorities, strategies to reduce
corruption and criminal activity, and international cooperation.

Because of the importance of product safety and efficacy and
because the documented risks of substandard and counterfeit
medicines, pharmaceutical products procured with multilateral and
bilateral resources in pursuit of the 3-by-5 goal should certainly be
authorized by the relevant national drug regulatory authority
(NDRA) in the country in which they will be used. However, in
addition, they should be separately evaluated for safety, quality,
and efficacy, if the relevant NDRA does not have the capacity to
enforce appropriate standards. In this respect, the WHO
Pre-Qualification Project can play an important role in identifying
AIDS medicines which are bio-equivalent to standard products and
which are produced according to Good Manufacturing
Processes.[24] Of course, an alternative route to quality assurance
is to require registration by a stringent NDRA, one that is a member
of the Pharmaceutical Inspection Convention/Scheme and/or the
International Conference of Harmonisation.[25]

The essence of the U.S. attack on Triomune's pre-qualification at
the WHO is that the WHO pre-qualification project cut too many
corners and, more subtly, that registration should instead, if
possible, be based on registration at a strict NDRA, like the FDA. In
particular, the U.S. is "concerned" that the pre-qualification project
has just pre-qualified Cipla's generic fixed-dose combination ARVs
despite the lack of underlying evidence on bio-availability and
despite clinical trials comparing the efficacy and safety of
fixed-dose combinations versus treatment regimes that using
proprietary products. The U.S. presumably cites the risk that
co-formulation of medicines can affect potency and rates of
absorption of individual components (bio-availability) and that care
must be exercised to combine drugs that are complementary in
action and, have similar half-lives, and present non-cumulative side
effects. Fortunately, this is a technological problem that can often
be solved if detected early in the production process.[26]

In an ideal world, drug companies would have cross-licensed their
medicines to each other (rather than merely protect their patent
kingdoms), conducted relevant clinical trials, and thereby produced
fully satisfactory evidence on the superiority of fixed-dose
combinations, particularly when one takes into account patient
compliance. There would be Pharmacopoeia monographs and
standards available by which to evaluated generic equivalents.
However, in the imperfect world we live in, the WHO was left to a
slightly less optimal alternative - it had to establish pharmacokentic
bio-equivalence of generic fixed-dose combinations against
evidence derived from the individual products,[27] a procedure that
had previously been allowed even in the U.S. with respect to
GlaxoSmithKline's combo drug Trizivir. This kind of pragmatic
flexibility, while still pursuing high standards, is the correct response
to an AIDS pandemic where the world doesn't have an extra five
years to conduct double-blind clinical studies of the most promising,
pro-adherence product.

The U.S. makes it sound like the WHO pre-qualification project
used a big rubber stamp in a back office to approve Triomune, but,
of course, the truth is far different. Where pre-existing evidence of a
comparable product is lacking, the WHO appoints experts who
perform a rigorous and comprehensive evaluation of products to
confirm compliance with international standards. In this regard,
investigators perform dossier evaluations and conduct site
inspections of manufacturing facilities. Dossiers are evaluated for
compliance with WHO recommendations and guidelines regarding
the assessment of multi-source products.[28] Assessment teams
included three specialists on quality issues and two on
bio-availability/bio-equivalence. In addition, inspections are
performed for individual products at individual manufacturing sites
to assess compliance with Good Manufacturing Practices as
recommended by the World Health Organization.[29] The team of
inspectors includes a leader inspector from countries that are
members of the Pharmaceutical Inspection Co-operation Scheme,
a WHO expert from its Quality Assurance and Safety: Medicines
team, and an inspector for the local NDRA. Only after this rigorous
process did the WHO pre-qualify multiple generic ARVs including
fixed-dose combinations.[30]

Free treatment vs. user fees and cost recovery

One would have thought that the neo-liberal ideology of
cost-recovery and user fees, brought to an art form by the World
Bank and the IMF, would have been sufficiently discredited that no
one would seriously propose that poor people living with HIV/AIDS
would have choose drugs over food, shelter, and schooling.
Evidence that co-payments had reduced use of family planning
and SDI clinics prompted Congress to adopt legislation ordering
the Executive to oppose user fees for health and schooling at the
World Bank and IMF. The wisdom of that ban was confirmed by a
recent study showing that financial constraints, including though not
limited to the out-of-pocket cost of antiretrovirals, have been
reported as the most significant barrier to antiretroviral adherence
in patients living with HIV/AIDS in Botswana prior to the introduction
of free treatment.[31] Even with the costs of medicines going down
to $140 a year, the costs of treatment are likely to be overwhelming
for the vast majority of patients in sub-Saharan Africa who earn
less than $2 a day. What portion of their meager salary should
destitute Africans pay to source life-saving medicines- What child
should they keep home from school, which daily meals should they
skip-

The WHO has undoubtedly selected the correct standard in urging
that antiretroviral therapy be offered free as part of a rich package
of public health services in developing countries. Where medical
aid schemes cover the costs of treatment and drug purchases,
certainly some cost recovery will occur. But what you don't want to
do, in the middle of an escalating pandemic, is impose fees that
deter treatment for a life-long condition. Hopefully, some sound
minds in Washington will realize the absurdity of imposing failed
user fees and co-payments on poor people in developing
countries.

Community health workers

The last U.S. attack on the WHO 3-by-5 plan involves a critique of
excessive reliance sub-physician health workers and on
40,000-60,000 new community health workers, workers to be
recruited, trained, and deployed as part of the WHO's 3-by-5 plan.
Presumably, the U.S., blinded by the culture of increasing medical
specialization and the medicalization of all public health initiatives,
thinks that it is better to wait for a decade of intensive medical
training for physicians before you start to dose the AIDS pandemic.
As much as it is desirable to have more HIV/AIDS specialists in
developing countries, wishing won't make it happen - it won't
necessarily prompt long-term commitments by First World health
specialists (though many are heroically offering their services) and
it certainly won't magically improve primary, secondary, tertiary,
and medical education in Africa to train 50 times the number of
doctors that there are now.

Instead of waiting on strategies to retain existing physicians and
nurses who are being recruited to Northern health sectors in record
numbers and to recruit a greatly expanded corps of highly trained
AIDS physicians, the WHO has adopted a two-part strategy for
using non-physician health care workers. Key decisions concerning
when to start therapy, whether to substitute drugs because of
adverse side effect, whether to switch regimens because of
treatment failure and drug resistance, and when to stop therapy will
be made nurse practitioners or physician's assistants working
under the supervision of doctors; harder cases will be referred to
physicians in district hospitals. Reliance on non-physician
resources even for these important decisions will be aids by WHO's
adoption of standardized and simplified treatment regimes and by
wholesale training of existing health sector workers.

As the frontline eyes and ears of the program and as culturally
competent community health practitioners the WHO advocates
"urgently training tens of thousands of community health workers to
support the delivery and monitoring of HIV/AIDS treatment. An
intensive training programme would enable these health workers to
evaluate and monitor patients, and make sure they receive and are
taking their medicines."[32] The value of community health workers
is that they can aid community mobilization, initiate treatment
preparedness, accelerate prevention efforts through VCT and
otherwise, and help ensure adherence to medical regimens.

Conclusion

Although it is important to respond to each of the U.S. attacks
against the WHO 3-by-5 plan on the merits, it is equally important
to understand the politics behind this attack. In essence, at the
behest of it pharmaceutical masters, the U.S. is arguing that
brand-name, patent medicines preferentially be used to fight global
AIDS. At the alter of neo-liberal orthodoxy, it insists that user-fees
should be imposed, that poor consumers will appreciate what they
are forced to pay for, even though study after study has shown that
user fees, on the ground, impede rather than enhance access to
treatment. And, at the behest of conservative elements of the
medical establishment, it argues that scale-up should be scaled
back - that it is better to go slow than to practice less than ideal
care, even though ideal care is decades away. The WHO 3-by-5
plan will certainly need to be fine-tuned and improved over time.
Excessive compromises on quality should not be made at the alter
of expediency and operational deficiencies should be quickly
corrected. But the WHO has launched an initiative where few have
dared tread below - it is replacing rhetoric and hallow, platitudinous
expressions of concern with a pragmatic and bold plan for action.
Rather than stand by and watch millions die needlessly every year,
the WHO has overcome its own historical lethargy and is finally
beginning to meet its mandate as a global public health institution.
We can not let the U.S. succeed in undermining this new
commitment with its nit-picking and bad faith concerns.

____________________________________
[1] World Health Organization, Scaling Up Antiretroviral Therapy in
Resource-Limited Settings: Guidelines for a Public Health
Approach, 16 (June 2002) [WHO Scaling Up]; World Health
Organization, Adherence for Long-Term Therapies: Evidence for
Action, 95-106 (2003) [WHO Adherence for Long-Term Therapies]
(noting that the large number of medications, complicated dosing
requirement, and sub-optimal tolerability make adherence difficult).
[2] See, e.g., HIV-Positive Patients Find Medications Hard to Take,
GlaxoSmithKline Survey Finds, Kaiser Daily HIV/AIDS Report
(March 19, 2001)
http://www.kaisernetwork.org/daily_reports/print_report.cfm-
DR_ID=3495&dr_cat=1 ; Protease Inhibitors: Drug Companies
Seek Treatments to Reduce Pill Intake, Kaiser Daily Reports
(February 3, 2000) (reporting a small study by Bristol-Myers Squibb
and multiple quotes from medical experts about the desirability of
reducing the pill burden)
http://www.kaisernetwork.org/aids/2000/02/kh000203.3.htm.
[3] WHO Scaling Up at 16. The WHO notes that, "[a] number of
fixed-dose combination products containing two or three ARV
drugs, current on the market, can be used twice a day." Id. "There
is evidence that simplified regimens that require fewer pills and
lower dose frequencies improve adherence." WHO Adherence for
Long-Term Therapies at 97. See, Panel on Clinical Practices for
Treatment of HIV, Guidelines for the use of antiretroviral agents in
HIV-infected adults and adolescents (NIH 2002) (recommending, if
possible, to reduce dose frequency and number of pills).
[4] WHO Scaling Up at 31.
[5] WHO Scaling Up at 31, including GlaxoSmithKline's Combivir
and Trizivir (now a disfavored combination).
[6] WHO Scaling Up at 31 (referring presumably to fixed-dose
combinations like Trimune from Cipla Ltd.).
[7] Jeffrey Laurence, M.D., Simplifying HIV Therapeutics, and the
Global Treatment of AIDS, AIDS Read 13(1): 5-6 (2003)(citing J.
Jordan, T. Delea, B. Sherrill, et al., Impact of fixed-dose
combination zidovudine/lamivudines on adherence to antiretroviral
therapy: a retrospective claims-based cohort study, in: Program
and abstracts of the 6th International Congress on Drug therapy in
HIV Infection; November 17-21, 2002; Glasgow, U.K., Abstract
P97) (accessed July 1, 2003
www.medscape.com/viewarticle/449706_print).
[8] Richard B. Pollard, M.D., Management Trends: Can HIV
Infection Be Treated Successfully With a Once-Daily Regimen-,
AIDS read 12(11): 489-500 (2002) (accessed July 1, 2003
www.medscape.com/viewarticle/444894_print). "HAART typically
involves a complex intermingling of medications, dosing schedules,
and side effects that often place a heavy burden on patients.
Once-daily doxsing is the least confusing schedule and is the one
preferred by patients, as is a regimen with fewer pills that can be
taken without dietary restrictions. Although drug research has not
quite met all of these conditions, achievement of this objective is
coming closer. - The potential advantages of once-daily dosing
include better under standing of the regimen by the patient and,
hence, increased adherence." Id.
[9] Scaling Up at 24.
[10] Scaling Up at 29 (noting that "it is recognized that many
HIV-infected individuals in the developing world are being treated
with dual [nucleoside analogue reverse transcriptase inhibitor]
combinations because potent three-drug and four-drug
combinations are not affordable").
[11] Julian Meldrum, Success and failure in HIV treatment:
contrasting lessons from South Africa, AIDSMAP (August 25,
2003) http://www.aidsmap.com/news/newsdisplay2.asp-
newsId=2264.
[12] "The MTCT-Plus Initiative is a new HIV/AIDS treatment
program coordinated by the Mailman School of Public Health at
Columbia University in response t the UN Secretary General's Call
to Action. The MTCT-Plus Initiative will support the provision of
HIV-specific care, including access to a number of standardized
antiretroviral option when clinically indicated, to HIV-infected
women and children identified in pMTCT programs, and to their
HIV-infected family members as appropriate. The MTCT-Plus
Initiative aims to decrease morbility and mortality, further reduce
mother-to-child transmission of HIV, lessen orphanage, promote
VCT, and strengthen local health care capacity. It is hoped that this
Initiative can provide an important first step towards greater access
to HIV care in resource-limited settings."
http://www.mtctplus.org/index.html.
[13] WHO Adherence for Long-Term Therapies at 96.
[14] Donald G. McNeil Jr., Indian Company Offers to Supply AIDS
Drugs at Low Cost in Africa, New York Times, Feb. 7,
2001<http://www.nytimes.com/2001/02/07/health/07AIDS.html>.
[15] Cipla Releases Three-in-One Drug Combination of Stavudine,
Lamivudine and Nevirapine, Kaisernetwork.org: daily reports
(August 7, 2001).
[16] See MSF Untangling the web at 13.
[17] Thai Government to Sell AIDS Drug Combination Pill for Less
Than $1 Per Day, Kaisernetwork.org: daily reports (March 25,
2002).
[18] Chinese Pharmaceutical Firm Begins Distribution of Generic
Antiretroviral Drugs, Kaisernetwork.org: daily reports (January 30,
2003).
[19] MSF Untangling the web.
[20] Mark Schoofs, Clinton Program Would Help Poor Nations Get
AIDS Drugs, Wall Street Journal (October 23, 2003).
[21] In the search for simpler treatment regimes, it is also important
to emphasize the goal of developing once-a-day, time-released
pills and medicine formulations that reduce the side effects of
ARVs, such as nausea. Once again, the perverse financial
interests of patent-holders often stand in the way of early
introduction of truly effective treatment protocols. Why- Because
patent-holders like to hold reformulations of their already patented
medicines in reserve so that they can extend their patents through
a process called evergreening. For example, Bristol Myers Squibbs
waited until 2000 to file a patent application on a once a day
enteric-coated ddI, the third generation of this drug. ddI is the
second oldest AIDS drug and one developed at public expense to
the degree that the U.S. Department of Health and Human
Services holds the first patent. Why did Bristol-Myers wait over ten
years to announce an enteric-coating- Did it lack such "technology"
in 1990- Of course not, it delayed an improved formulation so that it
could "evergreen" and extend its pricing monopoly with a "new"
patent on this minor but important reformulation.
[22] WHO Scaling Up at 30, Table 3.
[23] WHO, Substandard and counterfeit medicines, Fact Sheet no.
275 (Nov. 2003).
[24] WHO pre-qualification should not replace the requirement of
in-country registration, but it should help fill a capacity gap in
low-income countries that have difficulty independently assessing
quality of medicines and manufacturers' adherence to Good
Manufacturing Practice. See
<http://www.who.int/medicines/organization/gsm/activities/pilotproc/
pilotprocmain.shtml>. 
[25] The ICH brings together the regulatory authorities from the
United States, the European Union and Japan. See
<http://www.ich.org>.  The IPC/S is comprised of Australia, Austria,
Belgium, Canada, Czech Republic, Denmark, Finland, France,
Germany, Greece, Hungary, Iceland, Ireland, Italy, Liechtenstein,
Malaysia, Netherlands, Norway, Portugal, Romania, Singapore,
Slovak Republic, Spain, Sweden, Switzerland, United Kingdom.
See <http://www.picscheme.org/overview/picsauth.htm>.
[26] Email from Richard Laing to Pharm-policy list, Aug 13, 2001,
http://lists.essential.org/pipermail/pharm-policy/2001-August/00135
6.html.
[27] "Triomune, produced pharmacokinetics similar to those
produced by the 3 drugs when they were given individually." 
Jeffrey Laurence, M.D., Simplifying HIV Therapeutics, and the
Global Treatment of AIDS, AIDS Read 13(1): 5-6 (2003)(citing J. A.
Gogtay, V. Manek, V. G. Nayak, et al., A pharmacokenetic
evaluation of lamivudine, stavudine, and nevirapine given as a
fixed dose combination pill versus the same drugs given separately
in health  human  volunteers,  in:  Program and abstracts of the 6th
International Congress on Drug therapy in HIV Infection; November
17-21, 2002; Glasgow, U.K., Abstract PL8.4).
[28] WHO, Marketing Authorization of Pharmaceutical Products
with Special Reference  to Multisource (Generic) Products:  A
Manual for a Drug Regulatory Authority, (WHO/DMP/RGS/98.5)
and Bio-equivalence Data (Annex 9, WHO Technical Report Series
No. 863). In some instances the evaluators used ICH guidelines to
complement WHO guidelines.
[29] WHO, Quality Assurance of Pharmaceuticals. A Compendium
of Guidelines and  Related  Materials, Volume 2, Good
Manufacturing Practices and Inspections.
[30] See WHO Procurement, Quality and Sourcing Project: Access
to HIV/AIDS Drugs and Diagnostics of Acceptable Quality:
Manufacturers and Suppliers whose HIV-Related Medicines have
been Found Acceptable in Principle for Procurement by UN
Agencies (Eleventh edition, December 1, 2003).
[31] Weiser S et al. Barriers to antiretroviral adherence for patients
living with HIV infection and AIDS in Botswana. J Acquir Immune
Defic Syndr, 34:281-288, 2003.
[32] WHO, World Health Organization and UNAIDS Unveil Plan to
get 3 million AIDS   Patients   on  Treatment  by  2005  (Dec.  1, 
2003)
<http://www.who.int/mediacentre/releases/2003/pr89/en/print.html>

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