WORKING COMPULSORY LICENSING
ACCORDING TO TRIPS
- THE ESSENTIAL DRUG CANDIDATES -
INTERNAL WORKING DOCUMENT FOR MSF
Pierre Chirac
Access to Essential Medicines
Médecins Sans Frontières
November, 25th 1999
Many thanks to Pascale Boulet, Ellen 't Hoen and Jean-Rigal; Daniel Berman, Bernard Pécoul,
Carmen Pérez-Casas. Special thanks to James Love for making precious information available
through the Internet.
CONTENT
Legal and political background ........................................................ page 3
List of patented drugs in the WHO's Essential Drug List .............. page 6
Complementary list of essential drugs according to MSF ............. page 7
Case studies
azithromycin ........................................................................................ page 8
ceftriaxone ........................................................................................... page 10
ciprofloxacin......................................................................................... page 12
didanosine ........................................................................................... page 14
fluconazole .......................................................................................... page 16
indinavir ............................................................................................... page 18
lamivudine ........................................................................................... page 20
nevirapine ............................................................................................ page 22
ofloxacin .............................................................................................. page 24
zidovudine ........................................................................................... page 25
Conclusion ......................................................................................... page 27
Bibliography....................................................................................... page 28
2
LEGAL AND POLITICAL BACKGROUND
- WTO
The Final Act of the GATT Uruguay Round, signed on April 15 th, 1994, gave birth to
the World Trade Organisation (WTO). This agreement ratifies the world-wide
implementation of a free-trade economy. Two types of provision within WTO seem
particularly important with regard to pharmaceutical policy, and particularly for the
accessibility (i.e. affordability) of drugs in developing countries: those that put an end
to protectionist measures, and those that define as mandatory the protection through
patents of new drugs and their respective manufacturing processes, i.e. the
Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS
Agreement). The latter is particularly important, as implementation of the TRIPS
agreement in national patent law is compulsory for all WTO members (by year 2000,
2005, or 2006 according to the level of development and the level of previous patent
rights in developing countries).
Many developing countries did not fully acknowledge patent rights in the area of
pharmaceutical products before TRIPS (Paris convention), as patent protection was
voluntary. Full implementation of the TRIPS agreement will have consequences for
access to essential medicines. Concerns about the effect of TRIPS on access to
drugs include the following issues (1):
 Increased patent protection will lead to higher drug prices, while the number of
patented drugs of importance from a public health point of view will increase in the
coming years;
 The access gap between developed and developing countries will increase. A key
question is should developing countries wait for years before they can have
access to pharmaceutical innovations?
 Enforcement of the WTO regulations will have an effect on local manufacturing
capacity and remove a source of generic innovative quality drugs on which the
poorer countries depend;
 There is no reason to believe that the Agreement will encourage technology
transfer and R&D in developing countries. Pharmaceutical companies in the
developed world have stated repeatedly that the reason for not conducting
research on tropical diseases is the lack of protection for innovations in some
developing countries, which would also explain their limited investments in the
countries concerned. However, it is unlikely that Western manufacturers will
devote much effort to non-solvent populations, with or without patents. All things
considered, it is to be feared that tropical research will not have a more promising
future, even if patents are widely enforced.
In conclusion, the enforcement of the WTO agreements with regard to the
pharmaceutical sector raises certain doubts and concerns. This is why an
international debate has been opened on how to minimise the potential drawbacks of
WTO agreements for access to drugs (i.e., affordability of new essential drugs).
The TRIPS Agreement is to some extent a balanced agreement. The potential
negative impact of patents on prices (linked to the abuse of the dominant position of
the patent holder) can be remedied under the TRIPS. Articles 7 and 8 of TRIPS
clearly mention that “the protection and enforcement of intellectual property rights
3
should contribute to the promotion of technological innovation and to the transfer and
dissemination of technology, to the mutual advantage of producers and users of
technological knowledge and in a manner conducive to social and economic welfare,
and to a balance of rights and obligations ” (Art. 7). “Members may, in formulating or
amending their laws and regulations, adopt measures necessary to protect public
health and nutrition, and to promote the public interest in sectors of vital importance
to their socio-economic and technological development, provided that such
measures are consistent with the provisions of this Agreement (Art. 8-1). ”
There are two main ways of trying to mitigate the consequences of the WTO
agreements: parallel imports and compulsory licences, two options that countries
could still include in their national legislation for possible use one day.
1. According to the legal principle of "exhaustion of rights,” the holder of a patent in
a country X cannot prevent this country from importing the drug from a country Z
where one of its subsidiary is producing and selling this drug at a lower price
(parallel importing).
2. The second way of minimising the negative effects of the WTO agreements is
compulsory licensing: the rights of a patent holder can be limited under certain
conditions defined by Article 31 of TRIPS. According to this article, WTO members
may “allow for other use of the subject matter of a patent without the authorisation
of the right holder, including use by the government or third parties authorised by
the government. ” There is no limitation on the grounds for utilising Article 31, but
conditions to be fulfilled include the provision that “prior to such use, the proposed
user has made efforts to obtain authorisation from the right holder on reasonable
commercial terms and conditions and that such efforts have not been successful
within a reasonable period of time.”
WTO Members seem to have some room to manoeuvre in interpreting Article 31 in
light of Articles 7 and 8. Indeed, Article 31 stipulates, for instance, that the
requirement of preliminary efforts to obtain authorisation from the right holder before
the granting a compulsory licence “may be waived by a Member in the case of a
national emergency or other circumstances of extreme urgency or in cases of public
non-commercial use.”
- WHO
In May 1999, the 52d World Health Assembly in Geneva adopted Resolution
WHA52.19 on the Revised Drug Strategy (RDS). This resolution gives WHO the goahead to expand its work on a range of issues that affect access, quality, and
rational use of drugs including the effects of international trade agreements on
access to essential medicines.
The resolution notes that “there are trade issues which require a public health
perspective, ” and takes note of “concern of many WHO Member States about the
impact of trade agreements on access to and prices of pharmaceuticals in
developing and least developed countries.” It urges countries to “ensure that public
health interests are paramount in pharmaceutical and health policies,” and “to
explore and review their options under international agreements, including trade
agreements, to safeguard access to essential drugs.” It charges WHO with
“monitoring and analysing the pharmaceutical and public health implications ” of
trade agreements so that member states can develop pharmaceutical and health
4
policies and regulatory measures that are “able to maximise the positive and mitigate
the negative impact of those agreements.”
The TRIPS Agreement sets out minimum requirements. It also provides options to
incorporate provisions in national patent law to ensure and increase access to drugs.
The RDS resolution gives WHO the mandate to assist countries in developing or
adjusting patent legislation in order to increase access to drugs and to protect public
health. Examples of such options are parallel imports of patented drugs and
compulsory licensing (2).
- Médecins Sans Frontières (MSF)
Médecins Sans Frontières (MSF) is an independent medical relief organisation,
dedicated to assisting vulnerable populations. In over 80 countries world-wide, MSF
provides both life-saving emergency aid and longer-term assistance to make basic
health-care services available to the most vulnerable or excluded communities. MSF
is currently managing about 400 relief programs; it has sections in 18 countries on all
continents.
Thousands of physicians and other health professionals have worked in the field with
MSF over the past 28 years. Their analysis is that the gap between the richest and
the poorest parts of humanity has widening in most cases. MSF has identified the
following four problems that interfere with access to quality drugs:
 poor-quality and counterfeit drugs,
 lack of availability of essential drugs due to fluctuating production or prohibitive
prices,
 insufficient field-based drug research to determine optimum utilisation and to remotivate research and development for new drugs for the developing world,
 potential negative consequences of WTO agreements on the availability of new
essential drugs.
MSF is an active participant in the debate on the consequences of TRIPS for access
to essential drugs and has started a campaign for more humane international trade
agreements that pay increased attention to public health, provide for increased R&D
for tropical diseases, and contribute to re-launching production of abandoned drugs.
Patients and doctors need new essential drugs. But these drugs must be available,
affordable, and properly used. While the rational use of drugs is still a challenge,
affordability is a growing concern. The growing market of generic drugs in developed
and developing countries may give the impression that inexpensive drugs are widely
available for every disease. Many essential drugs are available in a generic form—in
which case price is not an issue. However, this is not true in all cases. More and
more new essential drugs (new antibiotics, drugs against HIV/AIDS, and so on) are
not available as generics.
MSF is concerned that access to essential drugs could be further jeopardised by the
TRIPS Agreement in that TRIPS strengthens the power of patent holders. The
monopoly enjoyed by patent holders often leads to very high prices for new and
innovative drugs. This undermines the affordability of essential drugs for most of the
people in developing countries. This fact is already clear from the world-wide market
for AIDS drugs.
5
MSF believes that Article 31 of TRIPS (which addresses compulsory licences) must
be utilised to lower the price of patented essential drugs along with other means of
lowering prices. This paper outlines a list of patented essential drugs. It describes 10
exemplary cases in which Article 31 may be a solution to the problem of excessive
price.
Examples include essential anti-infectives such as quinolones in multidrug-resistant
tuberculosis or azithromycin in trachoma; an essential drug for a lethal opportunistic
infection (fluconazole); and some of the antiretrovirals (three nucleoside HIV reverse
transcriptase inhibitors including one also used against hepatitis B (lamivudine), one
non-nucleoside HIV reverse transcriptase inhibitor that is involved in preventing
mother-to-child transmission, and the first-choice protease inhibitor). Other
antiretrovials could have been selected here and would certainly qualify for
compulsory licensing. Criteria include:





public-health relevance of the disease (morbidity and/or mortality),
essential nature of the drug (i.e., few alternatives are available),
time remaining before the patent expires,
excessive price; potential alternative sources (example of price differentials),
R&D and production costs; world sales (when available).
We suggest that these drugs be among the first to benefit from compulsory licences.
Countries would allow either a local manufacturer to become an alternative source to
the patent holder, or would import the drug from a supplier other than the patent
holder.
PATENTED DRUGS ON THE WHO'S ESSENTIAL DRUG LIST
Generic Name
ceftriaxone
Therapeutic Class
anti-infective
ciprofloxacin
anti-infective
doxazosin
antihypertensive
eflornithine
imipenem + cilastin
mefloquine
tamoxifen
zidovudine (azt)
trypanosomiasis
anti-infective
malaria
hormonal
AIDS (only for
MTC transmission)
Expiration Date of Patent in US (3)
June 1999 in developing countries,
with patent extension until 2001 in
developed countries
September 2001 in developing
Countries, with patent extension until
2003/04 in developed countries
November 1998 in developing
Countries, with patent extension
Until 2000 in developed countries
August 2000
N/a
October 2004
August 2002
September 2005
The list above is to be read with caution. It is only based on the patent status in the
United States (where the information is the easiest to get, free of charge). In some
countries, patents may last for longer (notably where an extension of the patent term
is possible), or shorter times. Five more drugs from the last WHO Essential Drug List
have been under patent until 1999 (amoxicillin + clavulanic acid, ipratropium
bromide, ivermectin, ketoconazole, and vecuronium).
6
ESSENTIAL DRUGS
The World Health Organisation published the first Essential Drug List (EDL) in 1977.
Essential drugs are “those that satisfy the health needs of the majority of the
population; they should therefore be available at all times in adequate amounts and
in the appropriate dosage form.” The first EDL contained 200 drugs. The EDL is
revised every two years; the current list contains 308 drugs. The inclusion criteria for
the EDL are proven safety and efficacy and reasonable price. Most of the drugs on
the EDL are available as generic drugs.
Because of prohibitive cost, a number of essential drugs have not been included in
the EDL. All the AIDS drugs (except AZT for the prevention of mother-to-child
prevention) and certain new antibiotics are not included even though infectious
diseases such as AIDS and tuberculosis are responsible for a large proportion of
deaths in low- and middle-income countries. Of course there are other obstacles
besides drug prices for implementing AIDS treatment in some countries. But price is
such a barrier that it stops virtually any initiative in this field.
MSF argues that the WHO list should hold at least the following essential drugs:
COMPLEMENTARY LIST OF ESSENTIAL DRUGS ACCORDING TO MSF
Generic Name
azithromycine
didanosine (ddI)
fluconazole
indinavir
lamivudine (3TC)
nevirapine
ofloxacin
Therapeutic Class
anti-infective
AIDS
antifungal
AIDS
AIDS
AIDS
MDR-TB
Expiration Date of Patent in US
November 2005
October 2006
January 2004
May 2013
February 2009
November 2011
September 2001
This list is not a comprehensive one, as the objective is to provide only some
examples here. For instance, it contains only drugs directed to infectious diseases
and AIDS. It contains only some of the AIDS drugs available today.
7
AZITHROMYCIN
(Zithromax®, Pfizer laboratory)
Therapeutic class
- Anti-infective, macrolide group.
Indications
 “ Azithromycin is a nitrogen-containing macrolide or azalide with actions and uses similar
to those of erythromycin [which is on the WHO's essential drug list] ” (4).
 More recently, azithromycin has been shown to be the most appropriate treatment for
trachoma (5).
Public health relevance
Trachoma (due to Chlamydia trachomatis) is a senior threat to public health : endemic in 49
countries (600 million people), mainly Africa (1999) ; 5.6 million total sight loss, visually
impaired, or at immediate risk of blindness (1997) ; 146 million active cases of trachoma in
need of treatment (1997) (6).
Essential drug
 Before azithromycin : “ The best treatment for trachoma is a combination of long acting
sulfamides per os plus local broad spectrum antibiotics for weeks, even three to four
months”(7). “Tetracycline ointment during several months ”(8).
 Today : WHO : “ The drug's efficacy and safety record of azithromycin makes it an
excellent candidate to become the first-line treatment for severe trachoma (though not all
trachoma) ” (6).
 “Azithromycin has already been tested in a number of countries. The initial results look
very promising : one dose of antibiotic per year may eliminate the blinding propensity of
trachoma ” (9).
 A study published in the August 21th 1999 issue of The Lancet provides evidence that
treating entire communities with a short course of azithromycin is more effective than the
standard six-week course of daily tetracycline ointment in controlling development of
trachoma. (5).
Patent status
. 1981: first patent application of Pliva in Croatia for azithromycin. 1986 : Pliva signed a
licensing agreement with Pfizer, granting Pfizer an exclusive right for the sale of
azithromycin in the USA and western Europe.
. 09/07/1987 Pfizer applied for a new patent through the PCT1 procedure.
. 08/07/1988 Pfizer applied for the patent to OAPI (African Intellectual Property Organization,
francophone African countries ). Issued 31/03/89 (estimated expiration date : 2008).
. 15/06/88 ARIPO2 patent application, patent issued 27/07/89 (estimated expiration date:
2008)
. 28/06/1988 Pfizer applied for the European patent (expired on 28/06/2008).
. 1988 Pliva launched azithromycin (Sumamed) for Central and Eastern Europe.
. 1991 Pfizer launched azithromycin (Zithromax) for USA and Western Europe.
. 1996 A Spanish laboratory patented other process for manufacturing azithromycin.
1
The Patent Cooperation Treaty (PCT) makes it possible to seek patent protection for an invention
simultaneously in each of a large number of countries by filing an "international" patent application. Among all
the PCT contracting States, the applicant indicates those in which he wishes his international application to have
effect ("designated States"). The effect of the international application in each designated State is the same as if a
national patent application had been filed with the national patent office of that State.
2
The African Regional Industrial Property Organization (ARIPO) includes most of anglophone African countries
whereas OAPI includes most of francophone African countries.
8
. 1996 Pfizer licensed others to sell azithromycin under new trademarks (e.g. in Spain :
Pharmacia Upjohn, and Almirall Prodesfarma)
. 1998 Zithromax® was the 3rd prescription product in sales in USA” (10).
Pfizer holds US patent n° 4474768 for azithromycin issued October 2nd 19843. Market
authorization for azithromycin was delivered in 1991 and 1992 in the US and France. Patent
will expire in the US in 2005, in France in April 2006 (11). That means 14 years of monopoly.
Price
Cost in France of 6 x 250 mg capsules is 120.3 F (20 FF per capsule: around 3 US$) (12).
"Price ranges from 3.64 to 7.12 US $ for 250 mg capsule in some industrialised countries.
Four capsules are necessary to treat an adult (70 kg), 2 for a child (25 kg). This leads to
14.56 to 28.48 US $ for an adult ; 7.28 to 14.24 $ for a child." (6).
Alternative sources
Vita from Spain is selling azithromycin with 25 % rebate. Other manufacturers from
Bangladesh, India, and Portugal offer the same product at more than 70% less than Pfizer’s
one, and, finally, Cipla from India offers it at 83% rebate (10).
Cost. World sales
“ Global sales of Zithromax®… increased by 44 % to US $ 441 million in the first quarter of
1999, … and continues to be the most prescribed brand-name prescription antibiotic in the
US ” (Pfizer Press release) (10).
Zithromax®'s world sales were 821 million US $ in 1997 (world rank 38) (17).
Conclusion
Azithromycin is the best treatment today for a very disabling disease prevalent in tropical
countries. Pfizer has not discovered azithromycin. It is currently engaged with WHO in a
limited donation program (only five countries covered (13)). The problem of affordability
could better be solved by a reduced price for every people with trachoma. This could be
done either by Pfizer on a voluntary basis either by compulsory licensing to a third
laboratory.
3
Patent information have been collected through the FDA's Orange book and the IBM patent web site :
http://www.patents.ibm.com/
9
CEFTRIAXONE
(Rocephine®, Roche laboratory)
Therapeutic class
- Anti-infective, 3rd generation cephalosporin.
Specific indications
“ Ceftriaxone is a third-generation cephalosporin antibiotic used similarly to cefotaxime for
the treatment of susceptible infections. They include chancroid, endocarditis, gastro-enteritis
(invasive salmonellosis ; shigellosis), gonorrhoea, Lyme disease, meningitis (including
meningococcal meningitis prophylaxis), septicaemia, surgical infection (prophylaxis), syphilis,
typhoid fever, and Whipple's disease ” (4).
Public health relevance
“ Bacterial meningitis is cause of 140 000 deaths every year. It is the 10th leading cause of
global infectious and parasitic diseases mortality.
Global incidence of bacterial meningitis in 0-4 years is approximately 250,000 annually, of
whom 20 % are considered to require ceftriaxone. Mortality is 20 to 50 % ” (6).
Essential drug
Quoted from the WHO Essential drug list : “limited indication, to be use only where no
alternative” (14). This limitation seems only due to the excessive price of Rocephine®.
Another WHO document considers ceftriaxone as an essential drug : “Major therapeutic
needs” (6). Including : bacterial meningitis in children, gonorrhea, etc. “Resistance to the
standard treatment of penicillin and chloramphenicol for childhood bacterial meningitis (0-4
years) is increasing. Ceftriaxone is becoming the best option for first line treatment in many
areas of the world”. (6).
MSF : “ A recent study of bacterial meningitis caused by Streptococcus pneumoniae in
children aged 2 months to 3 years shows that by using ceftriaxone mortality could be
reduced from 66% to 32% compared to treatment with chloramphenicol in oily suspension.
Both antibiotics have a sustained action and require very simple protocols (daily
intramuscular injection for a short period of time): both are therefore equally easy to use
under adverse conditions. However, ceftriaxone is ten-times more expensive than the
chloramphenicol treatment. Streptococcus pneumoniae infection is also one of the main
causes of severe acute respiratory infections – the primary cause of child mortality in Africa.
Ceftriaxone is therefore vital but financially inaccessible to those populations that need it
most of all." (15)
Patent status
US patent n° 4327210 was issued in April 1982. As US patent term was 17 years before
TRIPS, ceftriaxone patent expired in the USA in June 1999. ).
Roche launched Rocephine® in 1985 in the French market. Patent expired in May 1999 (14
years monopoly) but a supplementary protection certificate (SPC) was granted until March
2001 (11).
Price
Cost in France of one 1 g vial (IM or IV) is around 84 FF (13.3 US $) ; 50 F (7.9 $) for 500
mg (12).
" Prices range from 2.03 to 11.67 US $ for 250 mg vial in some industrialised countries. The
cost of treatment for meningitis ranges from 227 to 1307 US $ for an adult (14 days) ; 81 to
467 US $ for a child (15 kg, 10 days) " (6).
10
Alternative sources
In Thailand, ceftriaxone is marketed by 4 different drug industries, including Roche. One 250
mg vial of Rocephine® is 132 bahts (= 22 FF = 3.5 US $) ; one 1 g vial is around 80 FF
(same price in France).
The Thai laboratories Biolab, TP drugs and Siam sell one 1 g vial at about 20 FF (four times
cheaper than Roche).
In Cambodia, ceftriaxone is available from Indian and Korean suppliers between 2.1 and 2.5
US $/inj. Roche's is four times more expensive in this country (16).
Cost. World sales
Rocephine®'s world sales were 1,011 million US $ in 1997 (world rank 27) (17).
Conclusion
Ceftriaxone is an essential antibiotic, for instance for bacterial meningitis. Its is very
expensive but available at 25 % the Roche's price from numerous Asian producers.
11
CIPROFLOXACIN
(Ciflox®, Ciloxan®, Ciproxin®…, Bayer laboratory)
Therapeutic class
- Antibiotic, fluoroquinolone.
Indications
Gram-negative severe infections :
“ Wider spectrum of activity than nalidixic acid and more favourable pharmacokinetics for
use in systemic infections. It has been used in a wide range of infections including (…)
brucellosis, (…) gastroenteritis (including (…) cholera, salmonella enteritis, and shigellosis),
gonorrhoea, (…) meningitis (meningococcal meningitis prophylaxis), (…) lower respiratorytract infections (…), septicaemia, (…) typhoïd and paratyphoïd fever, typhus, and urinarytract infections. Fluoroquinolones such as ciprofloxacin and ofloxacin have been tried in the
treatment of opportunistic mycobacterial infections and tuberculosis. ” (4).
WHO : - shigellosis, typhoid, parathyphoid (fist line treatment in areas of multidrug
resistance)
- gonorrhoea : first-second line treatment in areas of multidrug resistance
- tuberculosis : second line treatment for multidrug resistant tuberculosis (6).
Public health relevance
“ MSF is particularly concerned by Shigella Sd1 dysentery. Shigella dysenteriae Sd1 is
extremely contagious and without an effective treatment is lethal in 5-15% of cases. Since
1979, this disease has been the cause of large epidemics in the African continent; for
example, in Malawi in 1992-93 and in Burundi in 1994. Shigella Sd1 bacteria quickly became
resistant to traditional treatments. The only effective antibiotics today are fluoroquinolones
(ciprofloxacin, norfloxacin). ” (15).
Essential drug
Ciprofloxacin was welcomed at launch as an “ important anti-infective for numerous
infections difficult to treat ” (18).
Ciprofloxacin is mentioned in the WHO Essential drugs list as the representative of the
fluoroquinolones group (14).
Patent status
Bayer Pharma Laboratory is holding ciprofloxacin's patent. US Patent n° 4670444 was filed
in May 1984, issued in June 1987. Ciprofloxacin has been launched in France in 1988, in the
US in 1990.
Patent will expire in the US by December 2003 (3). It may expire later in other countries :
October 2004 in France (11). That means a monopoly time of 13-16 years.
Price
“ Treatment of Shigella Sd1 dysentery with fluroquinolones is ten-times more expensive than
the traditional treatment using nalidixic acid (20 US $ vs. 2 US $). A special agreement was
reached between Bayer Pharma Laboratory and MSF to make available 50,000 treatments
with ciprofloxacin for a unit price of 2 US $ per treatment ” (15).
The price of 12 x 500 mg tablets is 189.10 F in France (around 3 US $/tablet) (12).
According to WHO, the price of 500 mg tablet ranges from 1.9 to 4.9 US $ in some
industrialised countries. This leads to 28.2 to 73.9 US $ for a complete treatment for typhoid
(5 days treatment) (6).
Ciprofloxacin is available from IDA (low profit making generic wholesaler) at around 100 F
for 10 tablets 500 mg (1.5 US $/tablet).
12
Alternative sources
Ciprofloxacin is available from other laboratories than Bayer in countries that have not
considered pharmaceutical patents in the past. In Thaïland for instance, laboratory Olan
Kemed sells 50 x 250 mg tablets at 175 Bahts (around 10 cents/tablet) (19).
In Cambodia, ciprofloxacin is sold by numerous Indian and Korean drug industries. Prices
are between 7 cents (Lyka, India) and 17 cents US (Korea Pharma) (16).
Cost. World sales
Ciprofloxacin and other fluroquinolones are fluorinated 4-quinolones. They are derived from
the previously known quinolone, nalidixic acid.
Ciflox®'s world sales were 1,441 million US $ in 1997 (world rank 12) (17).
Conclusion
Ciprofloxacin is an essential antibacterial where bacteria are resistant to cheaper
antibacterials. Ciflox® has been launched 10 years ago and will be patent protected 5 years
more. It is very expensive but is available today from many sources at 1/30 of the Bayer's
price.
13
DIDANOSINE (ddI)
(Videx®, BMS laboratory)
Therapeutic class
Antiretroviral (HIV nucleoside reverse transcriptase inhibitor).
Specific indications
AIDS, mostly in bi- or tritherapy
Public health relevance
AIDS is now the fourth cause of death in the world, and the first one in Africa, where 2 million
people died in 1998 from this disease.
There were about 35 million cases of HIV/AIDS patients in 1999 in the world, 30 millions of
them living in Africa. The Joint United Nations Program on HIV/AIDS and the World Health
Organisation estimated last year that 11.5 million sub-Saharan Africans have died of the
disease - more than 80 % of the world's AIDS death toll. In the same 1998 report, the United
Nations estimated that 23 million in sub-Saharan Africa were HIV-positive, representing 70
percent of such cases world-wide.
Since the launch of antiproteases in 1996, tritherapy (2 reverse transcriptase inhibitors + 1
antiprotease) led to a reduction of mortality among AIDS patients. Tritherapy with 2
nucleoside reverse transcriptase inhibitors + 1 non nucleoside reverse transcriptase inhibitor
seems to have similar efficacy. But the price of these treatments is such that only AIDS
patients from industrialised countries can be cured. Yearly treatment cost ranges in western
countries between 10 and 15,000 US$. Which is much more than the GDP per capita of
many countries in the world.
Essential drug
Didanosine is currently one of the most used reverse transcriptase inhibitor with zidovudine
and lamivudine. Didanosine has been shown to be an alternative in mono-therapy for
patients intolerant to zidovudine, or in whom zidovudine has failed. In patients who had not
received antiretroviral therapy before, the delta and ACTG 175 studies showed substantial
reductions in mortality at 30 months in patients treated with zidovudine plus either didanosine
or zalcitabine with those receiving zidovudine alone. ACTG 175 showed that didanosine
alone was as effective as the combinations and superior to zidovudine alone (4).
Patent status
Didanosine is protected in US by two patents (US 4861759 and US 5616566) ending both in
Oct 29, 2006. Inventors are in both case Mr Hiroaki Mitsuya and Samuel Broder from the
NIH (same as for zidovudine) and the patent owner is the USA represented by the
Department of Health and Human Services.
The patent was licensed to BMS, in exchange of a 5 to 6 % royalty paid on sales. The
NIH/BMS contract mention : “ Licensee acknowledges the concern of the Government that
there be a reasonable relationship between Licensee's pricing of Licensed Product and the
health and safety needs of the public and that this relationship be supported by evidence. If,
during the exclusive marketing term of this Agreement, as provided under Paragraph 2.1
above, Licensee fails to provide such evidence upon reasonable request of the Director,
Division of Cancer Treatment, National Cancer Institute, NTIS has the right to require
Licensee to grant sublicenses under Licensed Patent(s) to responsible applicants on
reasonable terms when necessary to fulfil health and safety need. ” (20,21).
In Thailand, the Government Pharmaceutical Organisation had the project of marketing
generic didanosine. Four years ago the GPO set up a laboratory supervised by Bristol Myers
Squibb, to investigate the feasibility of producing didanosine. Although the GPO came up
14
with the technology, they discovered that while the laboratory was being set up Bristol Myers
Squibb had been granted a patent in Thailand for a new formulation of ddI that would
prevent the GPO from manufacturing didanosine. Didanosine is not marketed by GPO today
(16,22).
Didanosine's first patent has been issued in US in 1989 and will expire in October 2006.
Videx® has been launched in the US market in 1991 and 1992 in France. Videx® would then
have to enjoy a market monopoly for 15 years.
Price
 -Videx® has been launched in France in 1992 at 623 F for 60 x 100 mg (10 F/tablet = 1.6
US $). Price is 722 F in 1999 (12 F/tablet = 1.9 $). This means 48 F daily (2 x 200 mg),
1,440 F monthly and 17,520 F yearly (2,750 US $). Average price in US is 2,424 US
$/year (23).
 “ Biot recently returned from Thailand, where people begin lining up outside
Bamrasnaradura Hospital in central Bangkok at 3 a.m. for the weekly AIDS clinic run by
his group. "This is not an undeveloped country," he said. "They have labs and the real
opportunity to treat people who are HIV-positive or have opportunistic infections." The
clinic is seeing an increasing number of people who have recently stopped using the
combination of AZT and Videx® or didanosine (ddI), a reverse transcriptase inhibitor made
by Bristol-Myers Squibb. The two drugs taken in combination slow the onset of AIDS.
Because of the Asian financial crisis, those drugs were removed from the government's
list of essential medicines and are no longer distributed at subsidized prices, Biot said. A
spokeswoman for Bristol-Myers said the company still supplies the Thai government with
Videx®, but she refused to discuss negotiations over its price. ” (24).
 In Cambodia, Videx® is available at 100 US $/60 tablet (16).
 In South Africa 100 mg capsule costs 1 US $ (25).
 Videx® is available at 6 FF (95 cents)/tablet in Ivory Coast (50 % French price), Burundi
and Senegal. Price is 1.2 US $ in Burkina Faso, Mali and Niger (26).
Alternative sources
It seems there is no alternative source today for didanosine.
Cost. World sales
In Thailand, didanosine was the 8th drug expenditure in 1995.
Videx® accounted to BMS for 45 millions US $ during the first 1999 quarter. It was up 27 %
(27).
Conclusion
Didanosine is a public sector invention, whose commercial exploitation has been granted to
a BMS on unreasonable conditions.
BMS made unacceptable pressures on Thailand for avoiding a local alternative to start.
Didanosine is available in some developing countries at half the western countries' price.
Didanosine seems not being produced by other than BMS. If a technical producing obstacle
was to exist, solutions should be found for helping the technology transfer.
15
FLUCONAZOLE
(Triflucan® or Diflucan®, Pfizer laboratory)
Therapeutic class
Antifungal.
Specific indications
Candidosis
Cryptococcal meningitis
Coccidiomycosis.
Public health relevance
Oral and oropharyngal candidiasis and cryptococcal meningitis are common HIV-related
diseases (opportunistic infections).
Cryptococcal meningitis : “ It causes disseminated disease ultimately in about 5% of persons
with advance HIV infection. (…) It is the most common life threatening AIDS related fungal
infection (…). Untreated, the diseases runs a slowly progressive and ultimately fatal course ”
(28).
In Thailand, Cryptococcal meningitis is a common opportunistic infection and affects 20-25%
of AIDS patients.
Essential drug
Fluconazole is not included in the WHO's Essential drug list ; it is in MSF's "Essential drugs
manual".
Fluconazole is the second choice treatment for oral and oesophageal candidiasis after
ketoconazole. Fluconazole is the first choice long term treatment of cryptoccocal meningitis
after initial therapy with amphotericin B (4, 28).
Patent status
Pfizer launched fluconazole for candidiasis in 1988, for cryptococcal meningitis in 1990
(dates for France). Fluconazole is protected by patent US 4404216 filed in 1982, who will
expire in January 2004 (March 2005 in France). This means 16 years of marketing
exclusivity.
Price
In France, 100 mg capsules cost about 40 F (6.3 US $), 200 mg capsules twice.
In Thailand, 400 mg daily treatment with Diflucan® used to cost 14 US dollars (7 $/tablet).
The cost of one year of Diflucan® is 100,000 bahts ($ 2,780), an impossible amount for the
average Thai families (GNP per capita was 75,000 bahts in 1996 in Thailand) (16).
In South Africa, 200 mg capsule costs 12.6 US $, as in France (25).
Alternative sources
 Diflucan® has not been patented in Thailand (patent protection for pharmaceutical
products was enacted in 1992, after Diflucan® marketing) but it has been protected by an
administrative barrier, SMP (the US government began to challenge Thailand on
pharmaceutical patents in 1985, which resulted in an interim measure known as the Safety
Monitoring Program (SMP) introduced in 1989. While a drug is in the SMP, no generic
equivalent can be produced). Since the release of fluconazole from SMP in 1998, the
fluconazole's price fell down because three Thai pharmaceutical industries entered into
the market (29).
 In September 1998, price of Pfizer fluconazole was around 6.55 US $ per 200 mg capsule
; Biolab’s was 2.37 US $. In 1999, the competition has led to a further decrease in prices :
around 0.6 US $ per one 200-milligrammes Biolab’s capsule (16, 30).
 Fluconazole is manufactured as well in other countries. For example, by Cipla, from India,
at 0.64 US $ /200 mg caps (according to last visit to India).
16
Cost. World sales
In 1995, fluconazole was the 5th Thai drug expenditure, with 151 millions bahts (around 4
million $).
Diflucan®'s world sales were 881 million US $ in 1997 (rank 33) (17).
Conclusion
Fluconazole is another good example of a drug "candidate for compulsory license" :
fluconazole is an essential drug who addresses a major public health need ; it is very
expensive, and the patent owner makes no effort to adapt its price to the local conditions ; it
is protected for a very long time ahead.
The Thai case clearly shows how much a difference a patent can make in terms of price and
accessibility of medicines in developing countries. And that compulsory license may be a
very relevant solution for solving this problem.
17
INDINAVIR
(Crixivan®, Merck Sharp & Dohme laboratory)
Therapeutic class
Antiretroviral : HIV antiprotease (or protease inhibitor).
Specific indications
AIDS, in tritherapy with two HIV reverse transcriptase inhibitors.
Public health relevance
See didanosine.
Essential drug
“ Today, the main recommended treatment for HIV-infected patients is a 3-drug regimen
combining 2 nucleoside inhibitors plus a protease inhibitor (efficacy on clinical end points).
Indinavir is the best choice among protease inhibitors ” (31). Indinavir received the
Prescrire's Golden Pill Award in 1999.
Patent status
Crixivan® is protected in US by patent n° 5413999 ending in May 2013. Patent holder is
Merck and Co. Crixivan® has been launched in the US market in 1996 and in France.
Crixivan® would then have to enjoy a market monopoly for around 17 years.
Data are protected till 2001.
Price
Crixivan® has been launched in France at 1,830 F for 360 x 200 mg (5 F/tablet) or 180 x 400
mg (10F/tablet). Price is 2,267.6 F in 1999 (6.3 F per 200 mg = 1 US $) (12). This means 76
F daily (3 x 800 mg), 2,268 F monthly and 27,600 F yearly (4,359 US $).
Average price in the US is 5,220 US $/year (23).
- Crixivan® is sold in South Africa at 2.6 US$ per 400 mg (more expensive than in France)
(25).
- Crixivan® is available at French price in Ivory Coast, Senegal and Burundi. It is more
expensive in Burkina Faso and Mali (+ 20 %) (28).
Alternative sources
No alternative source has been identified.
Cost. World sales
Crixivan® accounted for 150 millions US $ of Merck's sales during the first 1999 quarter
(32).
NIH role has been fundamental in funding development of protease inhibitors : “ NIAID
[National Institute of Allergy and Infectious Diseases] research was pivotal to development of
new class of drugs. Indinavir (Crixivan®, Merck) received accelerated approval for
monotherapy and combination therapy for the treatment of HIV infection in adults when
therapy is warranted. “ A number of studies suggest that protease inhibitors, especially when
given in combination with other drugs, can provide significant benefits to HIV-infected
people, ” says Anthony S. Fauci, M.D., NIAID director. “ The concept and feasibility of
protease inhibitors grew in part out of NIAID-supported basic research, and is an excellent
example of research supported by government and industry, working together to benefit
patients. ” NIAID-supported basic research was pivotal to: The discovery and definition of the
importance of the HIV protease enzyme. The definition of the structure of the HIV protease
enzyme. The development of assays to measure the inhibition of the HIV protease enzyme.
“ NIAID-supported research set the stage for a number of companies to do what the
pharmaceutical industry does best : identifying and developing specific medications and
18
ultimately bringing them to market, ” says Jack Killen, M.D., director of the NIAID Division of
AIDS. (March 1996, US NIH fact sheet) (33).
- World sales were 582 millions US $ in 1997 (rank 58) (17).
Conclusion
Indinavir is a first choice drug for tritherapy in AIDS. It is to be patent protected for 14 years
more.
Indinavir is a private/public R&D collaboration. Its price should then be much less.
19
LAMIVUDINE (3TC)
(Epivir®, Glaxo Wellcome laboratory)
Therapeutic class
- Antiretroviral (HIV nucleoside reverse transcriptase inhibitor)
- Anti HBV.
Specific indications
- AIDS, in bi- or tritherapy
- Hepatitis B
Public health relevance
- For AIDS, see didanosine.
- Hepatitis B is a major infectious disease with about 1 million people dying from every year,
mostly in developing countries.
Essential drug
- AIDS : lamivudine is currently used in bitherapy with zidovudine (even in a combination
form : Combivir®) or in tritherapy.
“ Treatment with lamivudine plus zidovudine has produced better responses than either drug
alone in antiretroviral-naive patients, and has produced additional responses in antiretroviral-experienced patients, with little additional toxicity. (…) Combination therapy with
lamivudine and zidovudine delays, and may even reverse, the emergence of zidovudine
resistance and produces a sustained synergistic antiretroviral effect (…) ” (4)
- HBV hepatitis : “ Lamivudine is one of the more promising antiviral drugs being tried as an
alternative to interferon alpha in the treatment of chronic hepatitis B ” (4).
Patent status
Epivir® is protected in US by two patents, with the first one n° US 5047407 expiring by
February 2009. Patent will expire in August 2011 in France.
Patent holder is IAF Biochem International SA (Canada).
“ Glaxo Wellcome is not the inventor of 3TC. Emery, Yale and a Canadian firm have patents
on 3TC for various uses, and there is lots of litigation over the patent rights. Glaxo pays a 14
percent royalty to the Canadian firm for the patent. ” (34).
Epivir® has been launched in the US market in 1995 and 1996 in France. Epivir® would then
have to enjoy a market monopoly for 14-15 years.
Data are protected till November 2000.
Price
Epivir® has been launched in France at 1,060 F for 60 x 150 mg (17.7 F/tablet = 2.8 US $).
Price is 1,212.3 F in 1999 (20.2 F/tablet = 3.2 US $). This means 6.4 $ daily (2 x 150 mg),
192 $ monthly and 2,330 US$ yearly. Average price in the US is 2,868 US $/year (23).
- In Cambodia, Epivir® is available at 2.7 US $/tablet (16).
- Lamivudine is sold in bulk in Uruguay with 18 % rebate (28).
- Epivir® is available at 8.85 FF /tablet (1.4 US $) in Ivory Coast (half the French price), 1.5
US $ in Burkina Faso, 2.5 in Burundi and Senegal (26).
Alternative sources
Lamivudine is produced in India. “ Glaxo had launched its brand, Epivir® (lamivudine), in
India last month though Cipla had pipped it to the post with an early launch of its brand,
Lamivir®, at less than half the multinational's price. Epivir® (150 mg) commands a price of
Rs 4,920 (local taxes extra) for 60 tablets, a whopping 146 per cent higher than competitor
Cipla's Lamivir brand costing approximately Rs 2,000 for 60 tablets. ” (Financial Express,
Monday, June 7, 1999) (34).
20
Cost. World sales
“ The following are US data on the sponsorship of clinical trials involving 3TC, using data
from the AIDS Clinical Trial Information Service (ACTIS). The ACTIS database identifies 90
clinical trials involving 3TC, including trials that involve 3TC in combination with or
comparison to other drugs. The ACTIS data permits us to identify the sponsors of 87 of
those trials. 42 of these trials were sponsored by the federal government, and one was cosponsored by NIAID and two private firms. Of the remaining 44 trials, one was sponsored by
a University, and 43 were sponsored by private firms. Note that this is not definitive
regarding funding of the trials, because trials that were sponsored by private firms may have
been funded (all or in part) by the federal government (35).
“ Researchers at Yale have played key roles in developing two of these compounds, the
reverse transcriptase inhibitor d4T, known commercially as Zerit®, and 3TC, known as
Epivir®. Both are key ingredients of the so-called drug cocktail that has fundamentally
changed the nature of AIDS therapy during the past three years. ” (36).
“ Glaxo Wellcome expects its oral hepatitis B therapy, lamivudine, to become the best selling
Western medicine in China ” (37). GW got a 7.5 years exclusivity in China. “Analysts
estimate that sales could reach around £ 400 millions [570 million US$] within a few years ”.
“ The company says it is considering ways to help Chinese hospitals and provincial
governments to pay for it – this may include a system of cash rebates ” (37).
World sales were 677 millions US $ in 1997 (rank 45) (17).
1999 first half Epivir®'s sales were 169 millions £ (240 million US $). Combivir®'s were 216
million £ (308 millions US $) (38).
Conclusion
Lamivudine is an essential drug for AIDS and hepatitis B. Lamivudine has not been
discovered by Glaxo Wellcome. It is over priced. It is available from India with more than 75
% reduction of western price.
GW seems to consider that lamivudine is more promising (commercially) for hepatitis B.
21
NEVIRAPINE
(Viramune®, Boehringer Ingelheim laboratory)
Therapeutic class
Antiretroviral (non-nucleoside HIV-1 reverse transcriptase inhibitor).
Specific indications
- AIDS, in tritherapy with two nucleoside HIV reverse transcriptase inhibitors for patients that
cannot receive a three-drug regimen combining two nucleoside inhibitors of reverse
transcriptase + a protease inhibitor.
- One-tablet regimen for prevention of mother (vertical) to child transmission (39).
Public health relevance
See didanosine.
600,000 babies worldwide were infected with HIV through mother-to-child transmission in
1997 (40).
Essential drug
Nevirapine may be a promising prevention of the vertical MTC transmission.
“ A joint Uganda-U.S. study has found a highly effective and safe drug regimen for
preventing transmission of HIV from an infected mother to her newborn that is more
affordable and practical than any other examined to date. Interim results from the study,
sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), demonstrate
that a single oral dose of the antiretroviral drug nevirapine (NVP) given to an HIV-infected
woman in labor and another to her baby within three days of birth reduces the transmission
rate by half compared to a similar short course of AZT. If implemented widely in developing
countries, this intervention potentially could prevent some 300,000 to 400,000 newborns per
year from beginning life infected with HIV.
Based on average U.S. wholesale costs, the cost of the drug used in the nevirapine regimen
in the current study is approximately 200 times cheaper than the long-course AZT used in
the United States, and almost 70 times cheaper than a short course of AZT given to the
mother during the last month of pregnancy - a regimen tested in Thailand by the Centers for
Disease Control and Prevention and reported effective in 1998.
“ In this study, the short-course nevirapine regimen resulted in a 47 percent reduction in
mother-to-infant HIV transmission compared with a short course of AZT. The implications of
this study for developing countries, where 95 percent of the AIDS epidemic is occurring, are
profound ”, says Brooks Jackson, M.D., the lead U.S. investigator on the trial (41).
Patent status
Viramune® is protected in US by patent n° US 5366972 ending in November 2011. Patent
holder is Boehringer Ingelheim. Viramune® has been launched in the US market in 1996
and 1998 in France. Viramune® would then have to enjoy a market monopoly for around 15
years.
Data are protected till 2001.
Price
Viramune® have been launched in France at 1,470 F for 60 x 200 mg (25 F/tablet = 3.9 US
$). This means 50 F daily (2 x 200 mg), 1,500 F monthly and 18,000 F yearly (2,825 US$).
Average price in the US is 3,060 US $/year (23).
Short course for MTCT would cost around 4 $ (one tablet).
Alternative sources
No alternative sources have been identified.
22
Cost. World sales
According to a 1996 NIH press release, Nevirapine's approval was based upon NIAID
funded research. “ Central to the FDA's approval of nevirapine was the NIAID clinical trial
ACTG 241, a study of nearly 400 patients with advanced HIV infection who had received
extensive treatment with nucleoside analogs. ACTG 241 showed that nevirapine, combined
with AZT and ddI, was significantly better than the combination of AZT and ddI at reducing
viral load and increasing CD4+ T cell counts in these patients. A second study conducted by
the drug's manufacturer showed that the same three-drug combination also was significantly
better than AZT and ddI for HIV-infected patients who had received no prior treatment. ”
(42).
Conclusion
Nevirapine is an essential drug for AIDS. It may be the first treatment choice for preventing
vertical transmission. Nevirapine has benefited from public funding. Treatment cost is limited
(4 $) because one tablet is enough. This is hiding the fact that this tablet price is expensive
and must be reduced for facilitating large scale use.
23
OFLOXACIN
(Oflocet®, Tarivid®, Floxin®, etc. laboratory HMR, Johnson, etc.)
Therapeutic class
Antibacterial, fluoroquinolone.
Specific indications
Same as ciprofloxacin : “ Wider spectrum of activity than nalidixic acid [from which it is
structurally derivated] and more favourable pharmacokinetics for use in systemic infections.
It has been used in a wide range of infections including (…) brucellosis, (…) gastroenteritis
(including (…) cholera, salmonella enteritis, and shigellosis), gonorrhoea, (…) meningitis
(meningococcal meningitis prophylaxis), (…) lower respiratory-tract infections (…), typhoïd
and paratyphoïd fever, typhus, and urinary-tract infections. Fluoroquinolones such as
ciprofloxacin and ofloxacin have been tried in the treatment of opportunistic mycobacterial
infections and tuberculosis. ” (4).
Public health relevance
In some areas, tuberculosis patients have become resistant to most current drugs (multidrug
resistant). Ofloxacine is an essential alternative for them.
Essential drug
- “ Ofloxacin is a fluoroquinolone antibacterial used similarly to ciprofloxacin. It is also used in
chlamydial infections such as nongonococcal urethritis and in the treatment of mycobacterial
infections such as leprosy. ” (4).
- multidrug resistant tuberculosis (MDR-TB).
Patent status
Oflocet® is protected in US by patent n° 4382892 (issued in 1983). According to FDA, the
patent is to last until September 01 for the injectable forms and September 03 for the oral
forms. Patent holder is the Japanese firm Daiichi. This patent is worked by Johnson in the
US, by HMR (Roussel) in France.
Merck holds a patent since 1983 for the eye topical use (worked by Allergan). This use
holds a 10 years data exclusivity according to Orphan drug status.
Oflocet® has been launched in the US market in 1993, in 1987 in France (only for hospital
use then 1990 for GPs). Oflocet® would then have to enjoy a market monopoly for around
16 years.
Price
Olfocet® has been launched in France in 1987 at 1,870 F HT for 50 x 200 mg (35 F/tablet =
6 US $). When launched for community use, price fell down to 168 F per 10 tablets (16
F/tablet = 2.5 US $). Price is 146.6 F in 1999.
By internationalpharmacy.com, Floxin® is available at 514 US $ for 100 x 400 mg (5 $/caps),
205 US $ for 50 x 200 mg (4 US $/caps), 245 US $ for 50 x 300 mg (5 US $/caps).
Alternative sources
Ofloxacin is produced by many companies including Ranbaxy (India) at a price of 0.55 US $
/tablet (less than 10 %/western price ) (43).
Conclusion
Ofloxacin is an essential drug with special interest for multi-drug resistant tuberculosis.
Treatment is a long term one and then, due to high price per tablet, very expensive.
Ofloxacin has been discovered by a Japanese industry and licensed to western industries.
Much cheaper alternative sources are available from developing countries.
ZIDOVUDINE (AZT)
(Retrovir®, Glaxo-Wellcome laboratory)
24
Therapeutic class
- Antiretroviral (HIV nucleoside reverse transcriptase inhibitor).
Indications
- Antiviral treatment of AIDS, in mono- or best : bi- and tri-therapy
- Prevention of vertical mother-to-child transmission.
Public health relevance
See didanosine.
Essential drug
Zidovudine was the first drug to be launched for AIDS patients, in 1987. Its efficacy is limited
and it is better to use today zidovudine in multitherapy. It has been proved that zidovudine +
lamivudine has more efficacy than zidovudine alone ; the same plus indinavir is even
preferable (31).
Zidovudine is present on the WHO Essential drug list. For some reasons (including the high
price of zidovudine), the list limits the use of zidovudine, “ only for vertical mother to child
transmission ” (14).
Patent status
Glaxo Wellcome holds patent US 4724232 for zidovudine issued February 9th 1985. Twenty
years patent duration will lead to September 2005. Retrovir® has been launched in 1987 in
France and USA, which means a 18 years monopoly.
This patent has been challenged, because zidovudine was known since 1964. Its efficacy
against a retrovirus (Friend's virus) was discovered in 1974. Later in 1984, Broder and
Mitsuya from the NCI showed that zidovudine was active on HIV. “ There are few drugs now
approved in this country that owe more to Government-sponsored research. ” declared
Mitsuya and Broder (44).
The GW patent is regularly challenged in court in the US by Barr laboratories.
Price
When Burroughs Wellcome launched zidovudine on the market, it was at an unprecedented
price, a price that for The Economist “ has more to do with the monopoly BW enjoys than
with research expenses ” (11 april 1987).
In France 60 x 300 mg pack costs 1,613.4 F ; 100 x 100 mg pack costs 901.5 F. This is 9 FF
per 100 mg tablet (1.5 US $) or 26.8 FF per 300 mg tablet (4.2 US $) (12).
Average price in the US is 3,360 US $/year (23).
- GW is selling Retrovir® at about 35 cents per 100 mg tablet in the Thai hospitals because
of local competition. This means a 75 % reduction from the French price for instance. The
Thai state industry GPO offers zidovudine at 22 cents.
- Retrovir® has been sold in bulk in Uruguay at 28 % market price (28).
- Retrovir® is available at 3 FF/capsule (48 cents) in Ivory Coast (30 % of French price), 51
cents in Burkina Faso, 60 in Senegal and 88 in Mali and Burundi (26).
Alternative sources
There are many alternative sources in India, China, Canada, Argentina, Mexico, Spain, etc.
where pharmaceutical patents were not mandatory when zidovudine has been launched.
Price range from 1 US $ (100 mg) for Apotex (Canada) to 40 cents in India (Cipla).
Novopharm (Canada) offers it at 50 cents (45).
Cost. World sales
US Patent n° 4921950 held by GW describes zidovudine fabrication process from D-xylose “
which is a relatively inexpensive and readily commercially available starting material ”.
25
Retrovir®'s world sales were 470 millions US $ in 1997 (rank 73) (17). This limited sales tend
to prove that Retrovir® has not match the demand ; one of the obvious reasons is the
excessive price. 1999 first half Retrovir®'s sales were 47 million £ (67 million US $) (38).
Conclusion
Retrovir enjoys a very long patent protection without any substantial contribution from GW
for its discovery. Zidovudine is already available from other sources. In most countries
competition remains limited because of a limited number of local competitors. In Thailand
where there are several competitors, GW has been able to offer zidovudine at around 25 %
of the price offered in western countries.
26
CONCLUSION
All of the drugs presented above are essential ones, with few alternatives. They all
address major public health needs. Most have been developed recently, in some
cases with a major public-sector contribution. Some are licensed from third parties,
which means that the investment in R&D from the pharmaceutical industry has been
limited. Yet, all of these drugs are very expensive. They have already provided huge
profits to industry, which has been able to recoup its very limited investment. For
these reasons they are perfect candidates for compulsory licenses. By granting
compulsory licenses, countries would allow third parties to produce or import these
drugs from sources other than the patent holder.
Other means may be used to cope with the excessive price of these drugs. For
instance, with the information given above, developing countries may be in a
stronger position to negotiate voluntary licences or lower prices. They know that a
very limited royalty or price would be acceptable.
Industrialised countries accept the need to pay very high prices for drugs. That is
one reason why the pharmaceutical industry no longer tries to adapt its prices to the
poorest countries. In practice, this means that they are no longer interested in these
markets. If industry wanted to avoid the issuance of compulsory licenses, it would
accept a two-tier pricing system, which is the rule for many other industrial products.
This paper is a practical guide to justify compulsory licenses for 10 exemplary drugs.
It also demonstrates more generally that something is wrong in the world
pharmaceutical market today: patients from developing countries are voiceless
victims of a commercial war between industries and industrialised countries.
Compulsory licensing is just one of the many tools necessary to minimise the impact
of a world market that is not interested in more than half of the world’s population.
More must be done to address this growing challenge.
The main argument from industry against compulsory licensing is that intellectual
property is essential for protecting its investments in R&D, which takes about 10
years and costs some $500 millions dollars per new drug. This paper clearly shows
that this assertion has no ground.
27
REFERENCES
1. 't Hoen E "Access to Essential Drugs and Globalisation" Development Journal 1999 ; 42.
Society for International Development.
2. Velasquez G and Boulet P "Globalization and Access to drugs. Perspectives on the
WTO/TRIPS Agreement . Health Economics and Drugs DAP series n° 7. Revised.
Geneva, Switzerland : WHO 1999.
3. FDA's "Orange book" : http://www.fda.gov/cder/ob/default.htm
4. "Martindale The extra Pharmacopoeia" 32nd Edition, The Pharmaceutical Press 1999.
5. Schachter J et al. "Azithromycin in control of trachoma" Lancet 1999 ; 354:630-633.
6. "Access to essential drugs, background paper", EDM, WHO May 1999.
7. Gentilini M and Duflo B "Médecine tropicale" Flammarion, Paris 1982.
8. MSF "Guide clinique et thérapeutique" Hatier, Paris 1988.
9. WHO "Trachoma": http://who.int/pbd/trachoma/introd.htm.
10.Pérez-Casas C "Azithromycin" MSF, 1999.
11.Boulet P (WHO/EDM) personal communication.
12.Dictionnaire Vidal 1999.
13."New approaches to trachoma control" Scrip 1999 ; 2472 : 18.
14.WHO's ED list 1997 : http://who.int/dmp/Model List/edl-10.htm
15.Pécoul B et al "Access to essential drugs in poor countries, a lost battle ?" JAMA 1999;
281 : 361-367.
16.Pérez-Casas C "Access to HIV/AIDS related drugs – Cambodia/Thailand" MSF 1999
17.Pharma Business 1998 July/August issue: 38-40
18.Drug Ther Bull 1987 ; 25 (18) : 69-72.
19.Prices communicated by MSF Bangkok ; information 10-12-98.
20."NIH/BMS license for ddI" quoted by James Love in Ip-health 03-06-99 (iphealth@essential.org).
21."Code of Federal Regulations. Title 37, Vol 1, Part 404 – Licensing of government owned
inventions" quoted by James Love in Ip-health 16-07-99 (ip-health@essential.org).
22.Information communicated by MSF Bangkok on 12-09-99.
23."Average cost of ARV drugs (in USA) HIV/AIDS Antiretroviral Newsletter n°1 WHO
Regional Office for the Western Pacific August 1999 : 3.
24.fights efforts to expand access to AIDS drugs ; Industry protests as
poorer
nations seek local licensing (Baltimore Sun; 04/30/99) reproduced on Ip-health 10-05-99
(ip-health@essential.org).
25.Goemaere E "Intermediary report on South African exploratory mission" MSF September
1999.
26.Data from Aides Fédération quoted in "Dumoulin J and Malville E "Prix et accès aux
médicaments dans les pays du sud : que peuvent faire la communauté internationale et
les laboratoires pharmaceutiques ? " September 1999.
27."BMS's pharma/OTC sales up 12 %" Scrip 1999 ; 2433 : 9.
28."Drugs used in HIV-related infections" WHO 1999.
29.Prices communicated by MSF Bangkok ; information 06-03-99.
30.Boseley S "US attempts to stop developing countries producing cheap Aids drugs have
become a political time bomb" The Guardian, Wednesday August 11, 1999, reproduced
in e-drug 18-08-99 (e-drug@usa.health.net).
31.Inhibiteurs de la protéase du HIV – éléments pour choisir" Rev Prescr 1998 ; 190 (18) :
843-852.
32."Merck &Co's first quarter sales up 24 %" Scrip 1999 ; 2432 : 8.
33.March 1996, US NIH fact sheet (http://www.niaid.nih.gov/factsheets/protease.htm) quoted
by James Love March 1996 in Ip-health 05-05-99 (ip-health@essential.org).
34.Love J "CIPLA's lamivudine cheaper than Glaxo" Ip-health 10-06-99 (iphealth@essential.org).
35."Sponsorship of clinical trials involving 3TC" (http://excalibur.actis.org/aidstrialG.html)
quoted by Balasubramaniam T in Ip-health 11-10-99 99 (ip-health@essential.org).
36."Yale
Medicine
:
Yale
research
produced
d4T
and
3TC"
(http://www.med.yale.edu/external/pubs/ym_su98/cover/cov_hunting11.html)
Yale
28
Medicine, Summer 1998, quoted by Balasubramaniam T in Ip-health 11-10-99 99 (iphealth@essential.org).
37."Glaxo Wellcome pins hopes on Heptodin in China" Scrip 1999 ; 2437 : 9.
38."Glaxo Wellcome back-tracks on double digit growth" Scrip 1999 ; 2460 : 6.
39.Guay L et al "Intrapartum and neonatal single-dose nevirapine compared with zodivudine
for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012
randomised trial" Lancet 1999 ; 354 : 795-802.
40.Marseille E et al "Cost effectiveness of single-dose nevirapine regimen for mothers and
babies to decrease vertical HIV – 1 transmission in Sub-Saharan Africa" Lancet 1999 ;
354 : 803-809.
41.NIH Press release (http://www.niaid.nih.gov/newsroom/simple/exec.htm) quoted in e-drug
19-07-99 (e-drug@usa.health.net).
42."Central to the FDA's approval of nevirapine was the NIAID clinical trial ACTG 241, a
study of nearly 400 patients with advanced HIV infection who had received extensive
treatment
with
nucleoside
analogs."1996
NIH
press
release
(http://www.niaid.nih.gov/publications/agenda/0996/page9.htm), quoted by Love J in Iphealth 02-08-99 (ip-health@essential.org).
43.Goemaere E "Access to 2nd line drugs for MDR-TB – What can be done ?" MSF 1999.
44."Credit Government Scientists With Developing Anti-AIDS Drug" New York Times 28-0989, quoted by Love J in Ip-health 02-06-99 (ip-health@ essential.org).
45.Schulte-Hillen C "Study concerning the availability and prices of azt" MSF 1999.
29