UNTANGLING THE WEB OF ANTIRETROVIRAL PRICE REDUCTIONS
14th Edition July 2011
utw.msfaccess.org Untangling the Web Online! Médecins Sans Frontières’ guide to the prices of AIDS medicines is now in its 14th edition – and is also available in an online version. Stay up-to-date with the latest news on ARV prices and availability by checking: utw.msfaccess.org
The MSF Campaign for Access to Essential Medicines
In 1999, on the heels of Médecins Sans Frontières (MSF) being awarded the Nobel Peace Prize – and largely in response to the inequalities surrounding access to AIDS treatment between rich and poor countries – MSF launched the Campaign for Access to Essential Medicines. Its sole purpose has been to push for access to, and the development of life-saving and life-prolonging medicines, diagnostics and vaccines for patients in MSF programmes and beyond.
Médecins Sans Frontières | July 2011 T Table of contents able
of C
Background: Access to Antiretrovirals ontents 3 Treat AIDS: Save Lives, Stop the Virus 4 Ensuring access to improved first-line treatment options 5 Ensuring access to treatment options for second-line and beyond 6 Ensuring generic production and reining in drug costs 9 Highlights from the 14th edition of ‘Untangling the Web of Antiretroviral Prices’
12 Quality Issues 13 Methodology 14 How to Read the Drug Profiles
Drug Profiles 15 Abacavir (ABC) 17 Atazanavir (ATV) 19 Darunavir (DRV) 21 Didanosine (ddI) 23 Efavirenz (EFV) 25 Emtricitabine (FTC) 26 Enfuvirtide 27 Etravirine (ETV) 28 Fosamprenavir (FPV) 29 Indinavir (IDV) 30 Lamivudine (3TC) 32 Lopinavir/ritonavir (LPV/r) 35 Maraviroc (MVC) 36 Nelfinavir (NFV) 38 Nevirapine (NVP) 40 Raltegravir (RAL) 42 Rilpivirine (TMC 278) 44 Ritonavir (RTV) 46 Saquinavir (SQV) 47 Stavudine (d4T) 49 Tenofovir disoproxil fumarate (TDF) 52 Tipranavir (TPV) 53 Zidovudine (AZT)
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 1 Contents continued ontents
C Fixed-Dose Combinations and Co-Packs of 55 Abacavir/lamivudine (ABC/3TC) 57 Lamivudine/stavudine (3TC/d4T)
able 59 Lamivudine/stavudine/nevirapine (3TC/d4T/NVP) T 61 Lamivudine/stavudine + efavirenz (3TC/d4T + EFV) 63 Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) 65 Tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) 67 Tenofovir disoproxil fumarate/lamivudine (TDF/3TC) 69 Tenofovir disoproxil fumarate/lamivudine/efavirenz (TDF/3TC/EFV) 71 Tenofovir disoproxil fumarate/lamivudine + nevirapine (TDF/3TC + NVP) 72 Zidovudine/lamivudine (AZT/3TC) 74 Zidovudine/lamivudine/abacavir (AZT/3TC/ABC) 76 Zidovudine/lamivudine/nevirapine (AZT/3TC/NVP) 78 Zidovudine/lamivudine + efavirenz (AZT/3TC + EFV)
Annexes 80 Annex 1: Summary Table of All Prices 84 Annex 2: Conditions of Offer by Company 87 Annex 3: Least-Developed Countries (LDCs) 87 Annex 4: Human Development Index (HDI) 87 Annex 5: Sub-Saharan Countries 87 Annex 6: World Bank Classification of Economies 87 Annex 7: Bristol-Myers Squibb Eligible Countries 88 Annex 8: Abbott Eligible Countries 88 Annex 9: Gilead Eligible Countries 88 Annex 10: Merck Eligible Countries 89 Annex 11: Suggested Resources for Further Information 90 Annex 12: Company Contacts 92 Annex 13: The Clinton Health Access Initiative Antiretroviral Price List
95 References 106 Glossary and Abbreviations
2 Médecins Sans Frontières | July 2011 B ac
Background: k ground Access to : A :
Antiretrovirals ccess
to ARV Treat AIDS: save lives, stop the virus s A ntiretrovirals At the United Nations High Level Meeting on AIDS in New York in June 2011, governments committed to reaching 15 million people with HIV treatment by 2015 – nearly nine million more than are on treatment today.1
New data adds to a growing body of Countries will also need to ensure evidence that as well as saving lives, that the medicines needed to break treating HIV can also help prevent the back of the epidemic remain HIV transmission, making the scale-up affordable. And here, the following of treatment all the more urgent. challenges need to be addressed: In May 2011, a study called HPTN • Ensuring access to improved 052 supported by the US National first-line treatment options Institutes of Health found a 96% reduction in transmission when • Ensuring access to treatment options HIV-positive persons in a relationship for second-line and beyond with an HIV-negative person were started early on antiretroviral therapy • Ensuring generic production and © Sven Torfinn compared to people whose treatment reining in drug costs was deferred.9 Early treatment also significantly reduced the development of tuberculosis, which remains the Médecins Sans Frontières (MSF) how simplified patient-friendly number one killer of people living began providing antiretroviral treatment, with several medicines with HIV/AIDS. treatment (ART) for HIV/AIDS in combined into one pill, facilitates 2000 in Thailand, Cameroon and adherence and improves results; If HIV treatment and prevention South Africa, to a limited number how providing treatment for HIV interventions are ambitiously of people living with HIV/AIDS in and TB under the same roof by expanded, according to UNAIDS, 3 urgent need of treatment. Today, the same health worker reduces twelve million infections and more MSF treats more than 170,000 the burden on patients; and than seven million deaths can be people in 19 countries, and some how tasks can be shifted, so that averted by 2020. The number of new MSF projects have been able to nurses can perform many of the infections could be reduced by more reach and maintain ‘universal access’ duties previously reserved for than half by 2015.ii i to treatment in their districts. doctors to overcome health worker In order to reach such a target, The past ten years have been rich shortages. For more details on countries need to commit significant in lessons learnt: how bringing these and other issues on HIV/AIDS financial resources to the epidemic treatment to primary health treatment, read MSF’s May 2011 – an additional US$ 6 billion annual centres and rural clinics, closer to report Getting Ahead of the Wave: top up by 2015.ii However, funding for where people lives, means more Lessons for the Next Decade of the ii AIDS declined in both 2009 and 2010, people can be reached with care; AIDS Response. leaving the Global Fund to Fight AIDS, TB and Malaria, the US government’s PEPFAR and national programmes i Defined as reaching 80% of people in need of HIV/AIDS treatment. short of resources. ii Available in English, French, Spanish and Portuguese.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 3 Ensuring access to improved first-line treatment options options
Today, the majority of people on first-line of ARVs in low- and middle-income countries receive the combination of lamivudine/stavudine/nevirapine (3TC/d4T/NVP).4 Thanks to generic competition, this regimen now costs $61 per patient per year (ppy).
treatment Stavudine (d4T) has played a crucial likely to have to switch regimens But in some lower middle-income
role in ART scale-up in resource- compared to those taking d4T and countries, patents prevent access to limited settings, due to its availability twice less likely than AZT.10 It is therefore generic products, meaning that countries line - in fixed-dose combinations and, most critical that treatment providers move have to rely on the ‘discounted’ price significantly its low cost. But despite away from d4T as has been done for offered by originator companies – $1,033 its affordability, using this standard example in Zambia, Lesotho, Guyana, ppy for tenofovir/emtricitabine/efavirenz first
combination comes at a medical cost South Africa and Botswana. A survey (TDF/FTC/EFV), nearly six times the cost of for some patients. Stavudine causes conducted in 16 countries where MSF the alternative equivalent generic version. serious side effects, some intolerable works showed that seven had changed Companies are increasingly excluding (peripheral neuropathy), stigmatising their protocols to provide all new patients middle-income countries from even (lipodystrophy) and potentially life- with better-tolerated ARVs.10 This is these offers of discounted prices, iii
improved threatening (lactic acidosis). For these encouraging news, but some countries however. ViiV considers Global
reasons, stavudine is virtually no longer have been prevented from making the Fund-financed programmes in middle-
to switch because of funding constraints. income countries to be ineligible for
used in wealthy countries (in 2006, for discounted prices, which will have to example, fewer than 2% of patients In the price analysis for this edition we 5 negotiate prices on a case-by-case basis. in Switzerland were taking the drug), found a noteworthy downward trend in Merck has ceased to offer standardised where patients are offered better-tolerated the prices of improved (tenofovir-based)
access price discounts to all lower middle- and
alternatives, such as tenofovir (TDF). first-line combinations, and prices can upper middle-income countries. Abbott Since 2006, WHO has recommended be expected to fall further as demand specifically excludes lower middle- in its HIV/AIDS treatment guidelines increases. In countries where the drugs are income and low-income countries that treatment providers begin moving not under patent or where patents owners outside of Africa from standardised price permit generic competition, the one-pill- nsuring away from d4T because of its long- discounts for the heat-stable ritonavir E term irreversible side effects, towards once-a-day generic triple combination 100mg tablet. Tibotec / Johnson & TDF or zidovudine (AZT).6 This call containing tenofovir/lamivudine/efavirenz Johnson are also excluding all middle- was repeated in the latest guidelines (TDF/3TC/EFV) is now available for income countries from standardised released by WHO in 2010,7 with a clear $173 ppy (see graph 1). price discounts for all their ARVs. recommendation to phase out d4T. In February 2011, the European Medicines Graph 1: Patents as a barrier Agency recommended that, in view of to improved treatment. its long-term toxicities, d4T be used As demand has increased, the price of improved first-line regimens has fallen for as short a time as possible and only considerably for countries where the absence of patent barriers means the generic when no appropriate alternatives exist.8 versions can be accessed. Lower middle-income countries (LMIC) unable to access But until now, the higher cost of these the generic price have not benefitted. alternatives has largely prevented this switch in many developing countries. TDF/FTC/EFV originator (LMIC) Price comparisons of TDF/FTC/EFV originator (LIC) Better-tolerated first-line regimens are TDF + 3TC or FTC + EFV TDF/3TC + EFV generic still at best more than double the price TDF/3TC/EFV generic of the d4T-based first-line regimen. 1200 1033 1033 The price of treatment is clearly a critical 1000 concern. But the long-term benefits of people being able to tolerate and stay on 800 their first ARV combination longer can 613 613 outweigh the costs. As one of the main 600 reasons people stop adhering to their 426 400 treatment is side effects, using medicines 422 with fewer side effects can also improve adherence, and delay the need to switch 200 173 143 to a much more expensive second-line 0 regimen because of resistance. A study June 2007 June 2008 Dec 2009 June 2010 June 2011 by MSF in Lesotho showed that people taking TDF were almost six times less
iii Least-developed countries, low-income countries, middle-income countries, etc: each pharmaceutical company defines its own eligibility criteria to assess which country is entitled to price discounts. Please consult the Untangling the Web annexes for details about individual companies’ differential pricing schemes.
4 Médecins Sans Frontières | July 2011 E Ensuring access to treatment options nsuring for second-line and beyond
access Sustaining HIV treatment over the long-term requires continued access to effective treatments such that patients who develop side-effects or drug resistance, or have to take medications that adversely interact with certain antiretroviral drugs, are able to switch to other antiretrovirals. With growing numbers of
patients in developing countries having been on treatment for a number of years, ensuring the effectiveness to of treatment as well as their long-term survival depends on access to newer and more potent drugs when
they inevitably develop resistance to their medicines over time. treatment
In one of MSF’s longest-running HIV/AIDS treatment programmes, Treatment failure under-diagnosed in Khayelitsha, South Africa, 12.2%11 of patients on treatment for five The routine, six-monthly, Viral load testing is crucially important options years needed to switch to a second- measurement of viral load is a for deciding when it is necessary to line drug combination because of WHO-recommended diagnostic switch a patient to expensive second- 19, 21, 46 virological failure. As some patients in tool for monitoring all HIV positive line drugs. Unfortunately, due to patients on ART.6 The use of the high cost and complexity of the developing countries will inevitably routine viral load monitoring can currently available laboratory-based for require treatment options beyond successfully diagnose treatment tests, viral load monitoring is not
their second-line regimen, it is crucial
failure early enough to prevent the widely implemented in resource- second to secure further treatment options to development of drug resistance limited settings; with the consequence ensure long-term treatment success through adherence counselling. that treatment failure is largely for all patients. under-diagnosed.100 - MSF’s Khayelitsha data provide a line window into the growing need Graph 2: The treatment time bomb: the impact for access to newer HIV/AIDS drug and regimens across the developing world on the price of ARV treatment of switching in the coming years. Demand for newer to second-line regimens and beyond.
AIDS drugs is growing fast – it is Changing a patient’s regimen because of the emergence of resistance means be estimated that the need for second-line relying on newer, patented, and therefore more expensive drugs. The price of y ond medicines will reach almost half a possible third-line regimen is close to 20 times more than the most affordable a million by 2012.13 WHO recommended first-line regimen, and over six times more than the most affordable second-line regimen. Patients and treatment providers are once again However, the price of newer medicines faced with the prospect of drugs being priced out of reach. remains a major barrier to access.
The second-line regimen with Price comparisons of first-line, zidovudine and atazanavir recommended second-line and possible third-line by WHO is today priced at $442 3000 (see graph 2). Although price has $2766 come down, this is still three times 2500 more than the TDF-based first-line 2000 regimen recommended by WHO. x 19.3 x 6.3
In its 2010 treatment guidelines, 1500 WHO for the first time raised the need 1000 for treatment options after potential x 3.1 failure of second-line therapy. Many $442 500 studies are ongoing, and the drugs $143 likely to have anti-HIV activity in 0 Lowest generic price Lowest generic price RAL+DRV+r+ETV third-line regimens are raltegravir, TDF/3TC+EFV* AZT/3TC+ATV+r darunavir (boosted with ritonavir), Regimens and etravirine.7
* Although a quality-assured generic TDF/3TC/EFV fixed-dose combination exists (and as one pill once a day is better suited for use in resource-limited settings that a TDF/3TC + EFV co-pack), its price ($173) remains higher than the co-pack ($143), in the absence of competition from further manufacturers.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 5 Ensuring access to treatment options for second-line and beyond continued
ond Because of patent barriers, there Without generic competition to bring already failing on their second-line y is no generic version for either prices down, a potential third-line combination, this unaffordable price be etravirine, darunavir or raltegravir, regimen could thus be available for the will mean they almost certainly once and company price discounts are not poorest countries for the prohibitive again face death. and affordable for developing countries. price of $2,766 ppy, at best. This price Tibotec / Johnson & Johnson, who applies to Africa and least-developed
line manufactures etravirine and darunavir, - countries only, with middle-income has announced ‘discounted’ prices for countries again paying substantially sub-Saharan Africa and least-developed more. In Brazil, for example, the cost countries, at $913 and $1,095 ppy, of raltegravir reaches $5,870 ppy, and
second respectively. Raltegravir is also widely darunavir (boosted with ritonavir), patented, and its manufacturer, costs over $6,000 ppy.
for Merck, has ceased giving standardised
price discounts to lower middle- There is no room for complacency income countries. about these prices. For those people © Sven Torfinn options
Innovations: looking to the pipeline
There are promising new drugs for of rilpivirine has been developed be very potent at low doses, which the treatment of HIV in the future, and showed promise for monthly suggests it could be produced at a including new classes of drugs that dosing.14 More research is needed low cost.15 S/GSK1265744, also
treatment have new ways of preventing the however to determine the safety an integrase inhibitor, is being
virus from replicating. Some have and efficacy of higher doses. developed as a long-acting injectable. to the potential to be administered as Other drugs also hold potential In 2010, Tibotec (a subsidiary long-acting formulations that would for long-acting formulation, like of Johnson & Johnson) signed allow once-weekly or once-monthly elvucitabine and CMX157. Thanks agreements with generic producers dosing. And some of the drugs could to long-acting formulations, some of access
to manufacture, market and be potentially cheaper than the ARVs these drugs might be more effective most commonly used today. distribute rilpivirine. These licences or durable than the ARVs we use in exclude many developing countries first-line today. Rilpivirine, for example, received where Tibotec / Johnson & Johnson US FDA approval in 2011. Rilpivirine will likely charge high prices. All of nsuring Ensuring access to promising drugs
E has a number of disadvantages, but Latin America, Central Asia and most in the development pipeline, so that one major advantage for resource- Caribbean and South East Asian people in developing countries can limited settings is the fact that it can countries will not be able to access benefit from therapeutic advances, be produced for as little as $10 per generic versions of the medicine. will require surmounting patent patient per year 14 – and its potential barriers that prevent access. for use in long-acting formulations Dolutegravir, from the new integrase – an injectable nano-suspension inhibitor class, has been shown to
Ensuring generic production and reining in drug costs
Competition among multiple generic to 2008 were manufactured in India, pharmaceutical manufacturers in and more than 80% of the ARVs MSF countries where medicines were uses are sourced from India.16 not patented, especially India, is what brought the cost of HIV/AIDS The lack of patents in India additionally treatment down by 99% over the allowed for the production of fixed- past decade (see graph 3). India has dose combination (FDC) pills, which is thus been called the ‘pharmacy of the both supportive of patient adherence developing world’: more than 80% of and crucial to the simplification of donor-funded purchases of ARVs for treatment that has been central to use in developing countries from 2003 global scale-up of treatment. © Bruno De Cock
6 Médecins Sans Frontières | July 2011 E nsuring originator products generic products 12000 Lowest Originator $10439
10000 generic
Lowest Originator $727 8000 Lowest Originator $555 Brazil $2767
production 6000 Lowest Originator $336
Lowest Originator $347 Hetero $295 4000 Cipla $255 Matrix $99
Varichem $61 2000
and
0 Jun 11
reining
Graph 3: Generic competition as a catalyst for price reductions.
The fall in the price of first-line combination of stavudine (d4T), lamivudine (3TC), and nevirapine (NVP), since 2000. in
drug Prices fall as the number of generic competitors increases – securing generic
competition has therefore been essential Price of generic TDF and number price of generic TDF number of generic(s) costs to bringing the cost of drugs down to of quality-assured generic(s) quality-assured affordable levels (see graph 4). 250 5 But increased product patenting in 2766 developing countries threatens the 200 4 production of affordable generic $195 versions of newer medicines and the 150 3 development of new FDCs. International $158
trade rules now require the patenting ) q ualit y -assured s of medicines in key producing countries 100 2 ( like India and Brazil, essentially blocking the kind of generic competition for the 50 $100 $85 $76 1 future that brought prices down so No. generic substantially in the past. 0 0 If stricter patent laws and other June 2007 June 2008 June 2009 June 2010 June 2011 intellectual property measures mean that generic competition from India cannot act as a catalyst to bring down the prices of medicines, tomorrow’s battle for access to affordable ARVs will Graph 4: Prices fall as more competitors need to be fought in a different way. enter the market.
Differential prices, compulsory licences, voluntary licences: what solutions for access?
Company-led access schemes have When drugs are patented, and right, under international trade laws, proven to be minimally effective. pharmaceutical companies fail to to issue compulsory licences (CLs) to Primarily, the threat of losing a make patented medicines available ensure generic competition. CLs are patent or having a patent barrier and affordable to patients in one of the public health safeguards removed is what makes companies developing countries, governments enshrined in the TRIPS Agreement, respond and reduce prices. should therefore make use of their which allows a government to
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 7 Differential prices, compulsory licences, voluntary licences: what solutions for access? continued costs
override a patent by issuing a licence market, stipulating conditions such The licensee could then produce to a third party to produce or import as which source the active ingredient generic versions of the patented the drug. CLs have proven to bring must be purchased from, as well inventions and export them to drug prices down dramatically by opening as to which countries the drugs countries covered by the licence. in
up the market to competition and can be exported. Such restrictive The Pool could facilitate the thereby increasing access. VLs ultimately do not lead to the production of cheaper medicines for unhindered competition that allows Alternatively, a patent holder can developing countries, and to allow patients to benefit from the lowest choose to grant voluntary licences
reining the production of needed fixed-dose
prices possible, nor do they increase (VL) to other manufacturers, combinations that would otherwise access in all countries where the allowing them to produce and require lengthy negotiations with and medicines are needed. export the drug in exchange for numerous different patent holders. royalty payments. When these VLs The Medicines Patent Pool, It is important that future licences are offered to multiple producers established in 2010, is a voluntary be public health-driven; meet the within a market or in several mechanism whereby companies, health needs of people living with countries and are not restrictive in researchers or universities license the HIV/AIDS in developing countries terms of where the licensees are patents on their inventions to one and do not contain restrictive
production allowed to export the drug, they can entity – the Pool. Any company that or anti-competitive terms that be a useful way to increase access. wants to use the patented inventions limit competition and sources of However, restrictive VLs can also can seek a licence from the pool, manufacturing and distribution of serve merely to extend the originator in exchange for the payment of the active pharmaceutical ingredient generic
company’s control over a given royalties to the patent holder. and final products.
Ensuring newer and better medicines are affordable generics; like Thailand in generic companies to continue to nsuring
E made affordable for people in developing 2007, in a move which brought the manufacture, supply and export of countries means supporting policies to price of lopinavir/ritonavir down by these AIDS medicines to the rest of ensure generic competition and drive 75%, or Brazil, which overcame a the developing world. down prices, as well as refraining from patent on efavirenz in the same year, • World Trade Organization members thereby enabling the government pushing policies that prevent price- reviewing and reforming the to import a generic version from busting competition by imposing even August 30 Decision, designed to India at one third of the originator greater intellectual property protection. allow the exporting and importing company price, or Ecuador in 2010 of medicines under a compulsory Supporting the policies needed to which thereby halved the cost of licence to countries which have no ensure generic competition and contain lopinavir/ritonavir to the public manufacturing capacity and cannot the cost of drugs is a political choice health system. produce their own generic medicines. – one that countries have committed The experience of the only use of to at the UN since 2001 and re-iterated • Developing countries designing flexible patent laws that favour this flexibility in Canada has shown in the 2011 UN High Level Meeting on access to medicines. India’s patent that what was intended to be an HIV/AIDS Declaration. Access to HIV law contains key health safeguards, ‘expeditious solution’ fails to meet the medicines will depend on: reserving monopoly status only for needs of developing countries with no • Least-developed countries using those drugs that show a therapeutic or insufficient manufacturing capacity to import medicines patented in their right not to grant or enforce benefit over ones that already exist drug-producing countries.324 medicines patents until 2016, – this restricts frivolous patenting and members of the World Trade and evergreening. The law also • Developed countries immediately Organization extending this deadline allows any interested party to stopping to push measures beyond 2016. This period expires oppose a patent before or after it – like data exclusivity, patent term in barely five years, and if it is is granted (‘pre-grant’ and ‘post- extensions, enforcement measures not extended LDCs that have not grant’ oppositions) so undeserved and investment measures – that go already introduced product patent patents can be challenged. The use beyond TRIPS in trade agreements. protection will then face the same of these safeguards in the Indian law The European Union and the patent barriers that other developing has resulted in the withdrawal of the European Free Trade Association countries are already struggling with. patent application on lamivudine/ countries are currently pushing for zidovudine and the rejection of key policies to be included in trade deals • Developing countries exercising their patent applications on tenofovir, with India that will further restrain right to issue ‘compulsory licences’ darunavir, nevirapine syrup and competition and directly damage to allow for production of more lopinavir/ritonavir allowing Indian access to affordable medicines,
8 Médecins Sans Frontières | July 2011 H
for example. By attacking the their domestic laws above those • Pharmaceutical companies pursuing ighlights ‘pharmacy of the developing world’, required by international trade law. voluntary methods that enable generic such policies also directly undermine • All countries refraining from competition in a way that meets any effort by donor governments introducing intellectual property the needs of people in developing to finance and support treatment enforcement measures that limit countries and keep costs down.
scale up. The United States’ Special the production, export, transit and MSF is urging all entities that hold from 301 mechanism is another example importation of generic medicines, patents on HIV drugs to share their of a bilateral punitive measure to such as the Anti-Counterfeiting Trade patents through the Medicines Patent Agreement (ACTA), as well as laws
challenge efforts by developing Pool. The Pool could help overcome the and measures that conflate legitimate countries to ensure access to intellectual property hurdles, with generic medicines with deliberately medicines for their populations, falsified medicines under the term a major impact if the licences cover 14 and to drive countries to implement ‘counterfeit’, such as the Kenya all developing countries. th
intellectual property measures into Anti-Counterfeit Act of 2008. edition
Free Trade Agreements: Hands Off our Medicine!
of In 2010, MSF launched the MSF and other treatment providers – that threaten to block the generic HANDS OFF campaign to call on depend on a sustainable flow of production of medicines. U the European Union (EU) to drop affordable generics from India to ntangling the policies harmful to access to treat people across the developing These measures – and other free medicines being pushed as a part of world – MSF sources more than 80% trade agreements, bilateral and the EU-India free trade agreement of the HIV medicines it uses to treat multilateral initiatives that restrict (FTA). In March 2011, around 4,000 more than 170,000 people living access to medicines – undermine people from across Asia living with with HIV/AIDS from manufacturers past successes in putting millions of the HIV/AIDS and other life-threatening of generics in India. But this access people on treatment, and endanger diseases marched in the streets of is under threat, as the EU pushes future scale up of treatment. New Delhi to protest the impact measures – like data exclusivity, W the FTA could have on access to intellectual property enforcement Join the campaign. eb
affordable medicines. measures and investment measures Visit action.msf.org of A ntiretroviral
Highlights from the 14th edition of Untangling the Web of Antiretroviral Prices
Pharmaceutical companies are concerning for access to medicines to negotiate discounted prices charging very high prices in in middle-income countries as case- on a case-by-case basis, based
middle-income countries. by-case negotiations are likely to on country income and disease P
lead to higher prices: rices • Middle-income countries pay high burden. This is of great concern for the affordability of products prices for AIDS medicines. The cost • ViiV has clarified that their and sustainability of government of the improved first-line containing standardised price discounts were treatment programmes, especially tenofovir costs over $1000 for a not in fact available to all fully- given that Merck’s previous pricing year’s treatment, almost six times financed Global Fund or PEPFAR strategy (published in previous more than in countries where the programmes, contrary to previous editions of Untangling the Web) generic can be purchased. Newer announcements. Global Fund- was to offer middle-income treatment options fetch extremely financed programmes in middle- countries prices that were up to high prices, with Brazil paying income countries have not been and more than ten times the price $5,870 for raltegravir, and over will not be eligible for these prices, of generic versions. The price of $6,000 for darunavir (boosted and will have to negotiate prices with raltegravir is of particular concern, with ritonavir). the company on a case-by-case basis. given the extremely high prices • Pharmaceutical companies are also • Merck ceased to offer standardised charged in wealthy countries, actively excluding middle-income price discounts to all lower middle- at $8,000 ppy. countries from accessing standardised and upper middle-income countries. price discounts. These moves are The company proposes instead
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 9 Highlights from the 14th edition of Untangling the Web of Antiretroviral Prices continued rices • Although Abbott offers two tiers of • There is a need for studies in
P tolerated than d4T-based and AZT- standardised price discounts for the based regimens. But their higher children to be conducted to ensure heat-stable fixed-dose combination price forms a barrier to scale up of that further treatment options of lopinavir/ritonavir, (with one better treatment in some countries exist. New drugs such as raltegravir price offered to all African countries with funding constraints. TDF/FTC/ and etravirine are still lacking and all least-developed countries EFV is a patented combination in paediatric indication. outside Africa, and another to many developing countries, with • There is a need to harmonise adult other low-income and lower originator companies charging at
ntiretroviral and paediatric regimens in order middle-income economies), best $613 for a year’s treatment A to simplify treatment and ensure Abbott specifically excludes low- ($1033 in middle-income countries).
of treatment options are available income and lower middle-income Only one generic producer of for children as they grow into
eb economies from standardised price three-in-one TDF/3TC/EFV is young adults. But tenofovir is still
W discounts for the standalone heat- quality-assured by US FDA or lacking an indication for children stable ritonavir 100mg tablet. WHO prequalification, and in the below 12 years of age. Gilead’s the absence of competition, there has • Tibotec / Johnson & Johnson also been little downward movement of Phase II trial involving children exclude all middle-income countries the price, which is just $6 less than (aged between two and 12 years), from standardised price discounts last year, at $173 ppy. using an oral powder formulation for all their ARVs – including is still on-going. Such data, promising new drugs such as • While these prices are still higher provided appropriate formulations
ntangling rilpivirine, as well as darunavir and than those for a d4T-based regimen, are developed, will be crucial to U etravirine (both important drugs for there is a need to generate greater address the urgent needs of this
of treatment-experienced patients that demand for TDF which will, in
paediatric population. have been listed in WHO treatment turn, increase the competition and guidelines as potential components the economies of scale needed to • The absence of dosing studies for of a salvage regimen). further decrease prices. efavirenz in children below 3 years of age remains a problem for TB/ edition The price of tenofovir (TDF) • Countries like India and Brazil have HIV co-infected infants, for whom th continues to fall, but the price of used strict patentability criteria to no adequate solution therefore
14 fixed-dose combinations containing ensure that new forms of tenofovir exists to the problem of nevirapine TDF hamper treatment scale-up. remain off-patent. Still, multiple interacting with anti-tuberculosis the • Thanks to an increase in purchase pending patent applications on medicines. volumes and to a new synthesis TDF and TDF-based combinations • The lack of adapted formulations process which reduces the price continue to threaten the future from
also acts as a barrier. The most of the active pharmaceutical of generic competition for commonly used protease inhibitor ingredient, the price of one year’s these medicines. for the youngest children, a LPV/r treatment with quality-assured Children continue to be solution, is not palatable and not generic TDF by itself now stands at an afterthought. adapted to resource-poor settings, $76. This compares with a lowest
ighlights • With the virtual elimination of as it needs refrigeration. price of $88 for zidovudine (AZT), H paediatric AIDS in the developed the second drug recommended • One positive step is the entry of world, research on paediatric by WHO for first-line treatment the Drugs for Neglected Diseases formulations is not a priority to replace stavudine (d4T). Initiative into the field of paediatric for pharmaceutical companies. HIV drug development, following • This should encourage countries Despite the lack of a lucrative an R&D needs assessment that to follow WHO recommendations market in the developing world, showed how HIV infected children and move away from d4T-based patents on newer medicines are a neglected population. first-line regimens in favour of are nevertheless hampering the TDF-based regimens. creation of paediatric versions. Generic competition continues to bring down the price of some • TDF-containing first-line regimens • Of the 23 antiretrovirals approved key medicines. such as TDF/3TC/EFV, TDF/FTC/ by the US FDA today, five are EFV, (both of which are one pill, not approved for use in children, • The price of the most affordable once a day) or TDF/3TC + NVP and seven do not come in any generic source of heat-stable are very efficient and much better paediatric formulations. lopinavir/ritonavir ($402 ppy Continued above right
10 Médecins Sans Frontières | July 2011 H ighlights Continued from previous page
– offered for all countries) is lower Price remains a barrier for newer to secure local production can be than the most discounted price medicines, however. an important way to ensure access offered by Abbott ($410 ppy • Rilpivirine, approved this year to medicines, the terms on which
– reserved for least-developed by US FDA, has the potential for such agreements are made and the from countries and sub-Saharan use in long-acting formulations,14 price discounts achieved are critically and its potential low price. At the important. There may be a risk that Africa). The entry of generic this approach does not ensure prices the manufacturers is having a positive time of going to press, neither come down as much as through effect on the market, and prices Johnson & Johnson nor the generic unrestricted generic competition; 14 are declining for this crucial companies that had signed licensing
if so, this would establish a precedent th second-line drug. However agreements with Johnson & Johnson for accessing other newer medicines had announced any discounted edition Abbott’s product continues to price for developing countries. at higher prices in the future, both dominate the developing world in Brazil and beyond. Countries where the company captured • Prices for salvage therapy are will need to carefully consider the 81% of the market share in 2008.16 particularly concerning. The prices possibility of price increases in the
Compulsory licences on lopinavir/ offered by Johnson & Johnson short-term and ensure that there are of
ritonavir issued by Thailand in remain unaffordable for the supporting policies in place to ensure U 2007 and Ecuador in 2010 brought developing world with darunavir that health budgets can continue ntangling the price of the drug down priced at $1,095 ppy and etravirine to support any such increases. at $913 ppy. For the first time considerably in those countries. a price has been announced for • The Medicines Patent Pool, • The price of efavirenz also LDCs and sub-Saharan Africa for formally created in July 2010, decreased significantly (to $52 ppy), maraviroc, but at $1,584 ppy, received its first licence from the
US National Institutes of Health the due to an increase in purchase this is too high. in September 2010 for a patent volumes, and to a new synthesis Pharmaceutical companies must on DRV. Yet the licence itself does W process which reduces the price do more to ensure access to not allow for the production of eb of the active pharmaceutical medicines through voluntary DRV, as further patents are held by of ingredient. Compulsory licences measures. Johnson & Johnson. Significantly,
on efavirenz issued by Thailand and A • Tibotec / Johnson & Johnson the licence was for all developing Brazil in 2007 brought the price signed licensing agreements countries, including those in the ntiretroviral of the drug down considerably with a limited number of generic middle-income bracket. The pool in those countries. manufacturers for darunavir (DRV), has received significant political etravirine (ETV), and rilpivirine, backing from WHO, the G8, • In late 2010, patent applications but the terms are too restrictive. and a number of countries who were rejected in India for First, they exclude all of Latin have made it clear that collective atazanavir and lopinavir/ritonavir, America, Central Asia and most action is needed from companies both recommended by WHO to match the commitments
Caribbean and South-East Asian P for second-line AIDS treatment, countries. Second, they do not from countries to tackle the HIV rices in rulings that allow generic open competition up enough. epidemic. Four pharmaceutical production to continue and act The licence for ETV is only with one companies are currently in as an encouragement to other company and only for distribution negotiations with the Pool (Gilead, producers to compete for the in sub-Saharan Africa. The DRV Roche, ViiV and Sequoia), but market and lower the price licence includes in addition one MSF is urging all entities that hold further. The decisions also serve to Indian company for distribution in patents on HIV drugs to share their highlight India’s role as pharmacy India. Licences such as these show patents with the Pool. the limits of voluntary licences and of the developing world, and the • Given the implementation of leave many developing countries risks of any further tightening of the TRIPS Agreement in generic- with HIV/AIDS burdens without intellectual property protection producing countries, governments access to affordable versions of through the EU-India or EFTA-India will need systematically to pursue these new medicines. free trade agreements currently compulsory licences, as authorised under negotiation. • Brazil has announced that under TRIPS, to enable generic it is working on technology production that will reduce the • A divisional patent application was transfer agreements with certain price of newer AIDS medicines. also rejected in Brazil on tenofovir, manufacturers in order to secure Countries should be supported in after opposition from civil society local production for raltegravir their right to do so and should not organisations in 2011. and atazanavir. While seeking face retaliatory measures.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 11 Quality Issues ssues y I
This report is a pricing guide, and as such does not include detailed information about the quality
ualit of the products listed. However, quality is important and price should not be the only factor
Q determining procurement decisions.
Readers and purchasers wishing to US FDA Quality of drugs in obtain more information about drug In May 2004, in support of the US the data provided in quality are therefore encouraged to President’s Emergency Plan for AIDS Untangling the Web consult the WHO List of Prequalified Relief (PEPFAR), US FDA announced Manufacturers who have at least one Medicinal Products which contains the a new initiative to help ensure that antiretroviral quality-assured by WHO products that ‘meet unified standards those being served by PEPFAR would Prequalification or US FDA were invited of quality, safety and efficacy for receive safe, effective, and quality to participate in this publication. HIV/AIDS, malaria and tuberculosis manufactured antiretroviral drugs. medicines’ or the US FDA Approved But not all the products listed in this Donor Procurement and Tentatively Approved report have been quality-assured by Policies Antiretrovirals List. WHO Prequalification or US FDA, and The Global Fund to Fight AIDS, only some of them are used by MSF WHO Prequalification Tuberculosis and Malaria has recently in its own projects. Products included More commonly known as WHO changed its quality assurance policy in the List of Prequalified Medicinal Prequalification, the WHO List of so that Global Fund grant funds may Products (as of May 2011), including Prequalified Medicinal Products was only be used to procure antiretrovirals, the ones approved by Health Canada, initiated by the WHO and developed anti-tuberculosis and anti-malarial the European Medicines Agency (EMA) in collaboration with other United finished products that are either through article 58, or in the US FDA Nations organisations, principally prequalified by the WHO Prequalification Approved and Tentatively Approved for procurement by UN agencies. Programme, authorised for use by a Antiretrovirals List, appear in bold The project evaluates pharmaceutical Stringent Drug Regulatory Authority in the tables of drug prices. manufacturers and products according (SRA), or recommended for use by to WHO-recommended standards of an Expert Review Panel (ERP). Please consult the websites for WHO 17 quality and compliance with Good Prequalification and the US FDA Unfortunately, the majority of donors Manufacturing Practices. Approved and Tentatively Approved today do not have sufficient quality Antiretrovirals18 for the latest list of WHO’s Prequalification Programme assurance criteria, giving a wrong prequalified products and for information is a benchmark for the identification signal to manufacturers by removing on the status of dossier assessment. of quality essential medicines and the incentive to comply with WHO has significantly improved access to norms and standards, and ultimately quality medicines over the past years. endangering patients’ health in A key factor of success has been countries where the regulatory system that financial support to national remains weak. Donors and drug programmes has been dependent on purchasers should take heed from purchasing medicines respecting clear the Global Fund’s example and make quality assurance criteria. In this the sure that they implement an effective WHO Prequalification Programme has quality assurance policy for medicines played an important role, providing bought on behalf of developing guidance to purchasers on the quality countries. of medicines and thereby creating a positive market dynamic where manufacturers strive to reach WHO standards in order to comply with procurement policies.
12 Médecins Sans Frontières | July 2011 M Methodology ethodolog
Questionnaires were sent to both originator and generic companies manufacturing antiretrovirals (ARVs),
requesting information on prices for developing countries, restrictions that apply to each of the prices y quoted (eligibility criteria), and any additional specificity applicable to the quoted prices. The data were collected up to May 2011.
All originator companies marketing • Companies use different trade terms • Information on patents is only ARVs were included in the survey. (known as incoterms). These trade indicative and should be checked But the list of generic producers is by terms outline the responsibilities with national authorities. It should no means exhaustive. Only generic of the manufacturer and purchasers in no way form the basis of companies that have at least one ARV with regard to transport, international a procurement decision. quality-assured by WHO Prequalification freight and insurance costs. Additional • As the information on the WHO or US FDA on the date of requesting information and definitions of Prequalification and the US FDA price information were included in this incoterms can be found in the lists are updated regularly, the lists publication. Initial questionnaires were ‘Glossary and Abbreviations’ section should be consulted for up-to-date sent to companies in early April 2011. at the end of this guide. Prices in the information regarding quality. publication have not been adjusted A few generic manufacturers – Huahai, to incorporate the different terms. In Combino Pharm S.L. and Macleods – 2005, the U.S. General Accountability were invited to contribute to this Office demonstrated that these publication but have chosen not to differences do not undermine their provide price information. essential comparability. Some important preliminary • Originator and some generic remarks on the data companies have different eligibility presented in this report: criteria for differential pricing for • The information on prices given countries and entities, meaning not in this publication only relates to all countries and entities can access ARVs. It does not include other costs the price that is mentioned in this linked to antiretroviral treatment, guide. The different categories of such as diagnosis, monitoring or prices are detailed on the drug profile treatment of opportunistic infections. pages. More detailed information For information on the prices of on the different eligibility criteria these products, please refer to is provided in Annexes 2 -10. ‘International Drug Price Indicator Guide’ and for paediatric drugs, • The Clinton Foundation’s Health ‘Sources and prices of selected Access Initiative negotiates prices medicines for children’. for ARVs and diagnostic tests with generic companies on behalf of • The manufacturers provide the prices national AIDS programmes included listed in this publication. The prices in their consortium. The Clinton paid by the purchaser might be higher Foundation has reached agreements because of add-ons (such as import with eight ARV manufacturers to taxes and distribution mark-ups), lower the prices of 40 different ARV or may be lower after negotiations. formulations, both paediatric and The document should not be viewed adult. The current CHAI price list as a manufacturers’ price list, and can be found in Annex 13. procurement agents are advised to contact manufacturers directly to confirm prices.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 13 How to read the profiles drug profiles drug
the General information access to price discounts Clinton prices
General information on the history of – Categories 1 and 2 The Clinton Health Access Initiative the product and relevant WHO guidance When originator companies apply (CHAI) negotiates with several read
is provided for each of the antiretrovirals discounted prices on ARVs, each has manufacturers for reduced prices for (ARVs) included in this publication. different eligibility criteria. This means almost 40 different ARV formulations to that a country that is eligible for a for countries in their pooled procurement Table on price information price discount from one company may consortium. Manufacturers who have ow
H – Developing Country Prices be excluded from the list of eligible a product included in the most recent As Quoted by Companies countries by another company. In this price announcement are indicated by a All prices are quoted in United States document, the term ‘first category’ (CF) in the header of the table. Further Dollars (US$). Currency conversions or ‘category 1’ is used to describe details of the specifics of the product were made on the day the price those countries that are eligible for can be found in Annex 13. the most discounted price offered by a information was received using the company. The term ‘second category’ Price Changes Over time – currency converter site www.oanda.com or ‘category 2’ is used to describe Chart on the Evolution of Prices are rounded up to the third countries that are not eligible for the the lowest price quoted decimal for unit price and to the lowest prices reserved for category 1 for developing countries nearest whole number for yearly countries, but are nevertheless offered This chart shows the price evolution price per patient. a discount by companies – crucially, over time, for both originator and The annual cost of treatment per this discount is usually considerably generic products, as quoted to MSF patient year (ppy) has been calculated smaller than the discount offered to for the purpose of this document according to the WHO dosing category 1 countries. since 2001.
6 schedules multiplying the unit price To know whether a country is eligible If a generic product quality-assured (one tablet, capsule or millilitre) by the for a discounted price offered by a by WHO Prequalification or US FDA is number of units required for the daily given company, or to find out in which available, the graph shows the lowest- dose, and by 365. The price of the category a given country is placed by priced quality-assured generic product. smallest unit is included in brackets. different companies, please refer to If no generic product is quality-assured Where no WHO guidelines exist for the annexes. by WHO Prequalification or US FDA, the a product, the dosage used is the lowest-priced product is considered in 20 Quality US FDA approved dosage. the graph, regardless of quality status. The WHO Prequalification Programme For paediatric treatments, prices are is a service provided by the World Spotlight on access issues calculated for a 10kg child using Health Organization (WHO) to – a look at patents and recommended dosing based on facilitate access to medicines that meet paediatrics weight bands, as it appears in the unified standards of quality, safety The most salient issues related to 6 WHO treatment guidelines. This is and efficacy for HIV/AIDS, malaria and access to each product are summarised an estimate, as the weight of a child tuberculosis. Products quality-assured here. The focus is on the availability of increases during any given year. by WHO Prequalification Programme products, their affordability and their When it was not possible to calculate or US FDA (as of May 2011) are in adaptability for the developing world. the dose for a 10kg child, only the unit bold in the tables of drug prices. price is indicated. For paediatric FDCs, A special comment has been included Readers and purchasers wishing to the dosages used for the calculation when appropriate with regard to obtain more information about the are those recommended by the patents and paediatrics. quality of ARVs are encouraged to Paediatric Antiretroviral Working consult the WHO Prequalification 22 Group at WHO. 1 Programme website and the US FDA 1 http://apps.who.int/prequal/ 2 website for approved and tentatively 2 http://www.fda.gov/InternationalPrograms/ approved ARVs, as these lists are FDABeyondOurBordersForeignOffices/ updated regularly. AsiaandAfrica/ucm119231.htm
14 Médecins Sans Frontières | July 2011 ABACAVIR ( ABC ) ( ABACAVIR
ABC
GENERAL INFORMATION )
• Therapeutic class: Nucleoside reverse • First approval by U.S. Food and • Patents: The basic patents on ABC transcriptase inhibitor (NRTI). Drug Administration (FDA): were applied for by GSK in 1989 83 23 December 1998. and 1990,31 and these expired in • WHO guidelines: Indicated for first- and second-line for adults, • WHO Model List of Essential 2009 and 2010, respectively. GSK adolescents and children.6, 22 Medicines (EML): Included in subsequently applied for additional the 17th edition.24 patents related to new intermediates • Originator company and product in 1995,32 to the hemisulfate salt of brand name: GlaxoSmithKline • World sales of originator product: ABC in 199833 and to compositions (GSK), Ziagen. In April 2009, Pfizer 2010: Sales not reported. 2009: and GSK jointly announced the US$ 160 million; 2008: $175 million; of ABC particularly relevant for 34 creation of ViiV, a new joint venture 2007: $215 million; 2006: $230 million; paediatric use in 1999, which are focusing solely on the R&D and 2005: $268 million; 2004: due to expire in 2015, 2018 and commercialisation of HIV medicines. $290 million.25, 26, 27, 28, 29, 30 2019, respectively.
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet/ml of oral solution. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily ViiV Aspen Aurobindo (CF) Cipla (CF) Hetero Matrix (CF) Ranbaxy Strides dose Who can access See annex 2 this price? ABC 20mg/ml 347 153 212 139 10 ml oral solution (0.095/ml) (0.042/ml) (0.058/ml) (0.038/ml) 146 158 134 ABC 60mg tablet 4 (0.100) (0.108) (0.092) 382 195 231 231 183 261 292 ABC 300mg tablet 2 (0.523) (0.267) (0.317) (0.317) (0.250) (0.358) (0.400)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for eligible developing countries since 2001:
As of May 2011, six generic sources of ABC 300mg tablet were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
Since 2001, the originator price has decreased by 72%, while generic prices have dropped by 93%. 382 183 Jun 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 15 )
ABC
Abacavir ( ABC ) continued
Spotlight on access issues ABACAVIR (
In 2010, WHO released new Patents ABC will continue to be an recommendations for antiretroviral The price of ABC decreased important drug for HIV/TB co- therapy for HIV in adults and significantly with the arrival of infected young children, not least adolescents. For second-line generic competition. GSK could because children have limited treatment, protease inhibitors such not apply for the basic patents treatment options – there are as ritonavir-boosted atazanavir on ABC in countries with generic interactions between TB drugs and (ATV/r) or lopinavir (LPV/r), production capacity such as India, nevirapine (NVP), and the dosage and simplified NRTI options are which did not grant patents on data on efavirenz (EFV) for children recommended. Abacavir (ABC) pharmaceuticals at the time. under three is lacking. (along with didanosine (ddI)) is However, a recent survey regarding therefore no longer recommended However, patents have been 38 paediatric second-line carried out as one of the NRTI backbones in granted in China. second-line therapy.7 by the TREAT Asia Paediatric HIV In addition, GSK applied for patents Observational Database (TApHOD) Price remains an issue. Even though on the hemisulfate salt of ABC in found that ABC was more difficult to the generic price of ABC has fallen India but withdrew this application access in Asia and that its relatively by 93% since 2001, the current in October 2007 after it was high cost could act as a deterrent to lowest price is more than twice opposed by civil society groups in a wider use.41 This applies particularly 39 the lowest price of tenofovir (TDF) pre-grant opposition procedure. in countries where ABC is patented, or zidovudine (AZT). GSK also applied for a patent on where the generic ABC 60mg tablet In addition, in 2011, ViiV clarified compositions of ABC particularly is not available. In the public sector their pricing structure (see annex 2), relevant for paediatric use, which in Malaysia, ViiV’s ABC solution costs 42 confirming that their standardised was granted in December 2007.40 more than $1200 ppy. price discounts were not in fact This patent raises concerns over the Paediatric ABC comes in a liquid available to all fully-financed Global continued generic availability of the formulation. In addition, as of April Fund or PEPFAR programmes, contrary ABC paediatric formulation, which 2011, three generic sources of ABC to previous announcements. Global is an important option for young 60mg paediatric tablet are quality- Fund financed programmes in middle- children with HIV/TB co-infection. assured by either US FDA or WHO income countries have not been and prequalification. Paediatrics will not be eligible for those prices, and will have to negotiate prices ABC is approved for use in Generic manufacturers have also on a case-by-case basis. With some children. In its 2010 guidelines been developing both double and developed countries paying over for antiretroviral therapy for HIV triple fixed-dose combinations $3,500 ppy, the price is prohibitive in infants and children, WHO containing ABC. As of May 2011, for many developing countries that recommends ABC as one of the two sources of paediatric double need to access the product.35 possible NRTIs to be given with FDC and one triple FDCs containing 3TC and either an NNRTI or a PI ABC were quality-assured by either In February 2011, Shionogi-ViiV in the first-line. WHO guidelines US FDA or WHO prequalification. Healthcare announced the start recommend a preferential order All are produced by generic of a phase III trial for a new fixed- of NRTIs to be used in first-line companies. dose combination including ABC, regimens, with AZT preferred over lamivudine (3TC)36 and a new Once-daily dosing of ABC is only ABC, and ABC preferred over d4T.22 integrase inhibitor S/GSK1349572 recommended for patients over (an investigational drug known ABC can also be part of second-line 12 years of age; more studies are as dolutegravir, now in phase III regimens, depending on what has needed to confirm the safety of clinical development).37 been used as a first-line.22 daily dosing of ABC in children.43
16 Médecins Sans Frontières | July 2011 A ATAZANAVIR ( ATV ) tazanavir (
GENERAL INFORMATION ATV
) • Therapeutic class: Protease inhibitor (PI). • WHO Model List of Essential • Patents: The basic patent was filed Medicines (EML): Included in in April 1997 by Novartis and is • WHO guidelines: Boosted ATV is 24 expected to expire in April 2017.50 indicated for second-line for adults the 17th edition. and adolescents.6 Bristol-Myers Squibb is manufacturing • World sales of originator product: ATV under licence from Novartis. • Originator company and product brand 2010: US$ 1.5 billion; 2009: BMS also applied for patents on the name: Bristol-Myers Squibb (BMS), $1.4 billion; 2008: $1.3 billion; crystalline bisulfate salt of ATV in Reyataz. 2007: $1.1 billion; 2006: $931 million; December 199851 and on a process • First approval by U.S. Food and Drug 2005: $696 million; 2004: $369 million; for preparing the bisulfate salt and Administration (FDA): June 2003.23 2003: $81 million.44, 45, 116, 47, 48, 49 novel forms in 2005.52
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one capsule. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
BMS Daily Emcure (CF) Matrix (CF) dose Category 1 Category 2 countries countries
Who can access this price? See annex 2 & annex 7 See annex 2
ATV 100mg capsule 3* (0.267)
412 547 268 426 ATV 150mg capsule 2* (0.565) (0.749) (0.367) (0.583)
ATV 200mg capsule - (0.677) (0.942) (0.483)
268 250 ATV 300mg capsule 1* (0.733) (0.686)
* The dose of ATV must be boosted with RTV 100mg once a day in treatment experienced patients. (CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
ATV 150mg capsule
450 400 412
Evolution of the lowest price quoted 350 353 for eligible developing countries 300 318 268 since 2007: 250 200 As of May 2011, two generic sources of ATV 150mg capsule were quality-assured by 150 US FDA or WHO prequalification. The one 100 with the lowest price is shown here. 50 0 Last year, for the first time since 2007, the June 2007 June 2008 Dec 2009 June 2010 June 2011 originator price increased by 17%, while generic prices have dropped by 16% since 2009.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 17 )
ATV
( Atazanavir ( ATV ) continued
Spotlight on access issues
tazanavir In 2010, WHO recommendations for addition, a single patent application treatment regimens. Civil society A second-line therapy included two filed by BMS in 2006 contained groups then urged the government ‘preferred’ protease inhibitors (PI), claims that covered the most to issue a compulsory licence (CL) to be taken in combination with two efficient route of manufacturing arguing Brazilian law justified the NRTIs. They are atazanavir (ATV) ATV and its bisulphate salt.67 This measure.79 After the second shortage boosted with ritonavir (RTV) and application was opposed by generic however, the government announced lopinavir/ritonavir (LPV/r).7 With its companies and the patent office the creation of a public-private once-a-day dosing ATV is the more recently rejected the application.68 partnership for the local production patient-friendly PI of the two. However, BMS had already filed a of ATV,80 preferring to negotiate divisional patent application69 which with BMS rather than issue a CL to ATV, like all PIs (with the exception is pending before the Indian patent of nelfinavir (NFV), requires boosting stimulate the local production of office. These divisional and other with RTV. Abbott’s heat-stable more affordable generic versions. patent applications on ATV and its ritonavir received marketing approval The reasons for this choice remain use in combination with other unclear, and civil society groups in the U.S. and Europe in early 2010. 70, 71, 72, 73 ARVs warrant additional continue to demand transparency on Registering this new formulation in pre-grant oppositions.74 developing countries will be crucial this agreement, particularly since it 81 in order to allow the use of other PIs In addition, Abbott has filed patent involves a publicly-owned laboratory. than lopinavir. A generic heat-stable applications on RTV in India and To date, no information concerning RTV is now available and was WHO other developing countries which, price reductions or sales restrictions for prequalified in late 2010. if granted, will block the development this product has been made available. of and access to generic ATV/r As ATV is one of the two PIs In 2011, a year’s treatment using the fixed-dose combinations. recommended by WHO, there 300mg tablet in Brazil cost $1,022. is an urgent need for generic In February 2006, BMS granted By April 2011, around 40,450 manufacturers to supply a technology transfer and voluntary patients in Brazil were taking ATV 82 heat-stable ATV/r fixed-dose licences to two generic manufacturers as part of their treatment regimen. combination. Currently this fixed- (Emcure and Aspen) to manufacture Paediatrics dose combination is not produced and sell ATV. In February 2008, In March 2008, ATV was approved by the originator companies. Emcure received US FDA tentative for use in children between six and approval for the 100mg, 150mg In some African countries including 18 years of age.23 No formulation and 200mg ATV capsules. Under the Ethiopia, Ghana, Kenya, Nigeria, exists for children. terms of the licences, however, sales Tanzania and Uganda, Bristol-Myers of these products are royalty-free but Squibb (BMS) discontinued all In addition, ATV must be given are restricted to sub-Saharan Africa. commercial activities by the end with a RTV booster, but the RTV BMS has a separate agreement with of 2009, including deregistration solution currently available has a Emcure that covers India.75 of all BMS products.53 bitter aftertaste and contains 43% Licensing agreements in India alcohol, and is thus not adapted for Patents should not be necessary if patent children, limiting the use of ATV In most developing countries with oppositions are successful. If patents in this population. generic pharmaceutical production are granted, India and other capacity, including Brazil, China and In 2008, WHO recommended countries could issue compulsory India, Novartis and BMS filed patent early treatment for all HIV-positive licences to enable unrestricted applications related to the ATV children, and children who have competition from generic compound,54 bisulphate salt,55 which been exposed to nevirapine (NVP) manufacturers, in order to bring is the best route to making ATV56 either through their mother prices down, increase access and and its combination with other or through a single dose in a facilitate the development of an ARVs.57, 58, 59, 60 Most patents have prevention of mother-to-child ATV/r fixed-dose combination. been granted in Brazil and China. transmission programme. WHO BMS’s differential pricing structure recommends these children should In India, where ATV is already under 22 is limited to sub-Saharan Africa and be started on a PI-based regimen. generic production, patent applications low-income countries. This structure Today, the only option for these are still under examination. Civil leaves middle-income countries such children is the LPV/r formulation. society organisations filed a pre-grant as Brazil paying more than $1,000 61 To simplify treatment for all opposition to Novartis’s basic patent per patient per year, a prohibitive 62 76 children, there is an urgent need for application on the grounds of lack of price for many of these countries. novelty.63 The patent application has studies on ATV to be completed in since been abandoned,64 but several In Brazil, BMS’s monopoly led to infants and children under six, and divisional patent applications65, 66 shortages of ATV in 200577 and 2011,78 child-adapted formulations of ATV have been filed by Novartis. In and several patients had to change and ATV/r to be made available.
18 Médecins Sans Frontières | July 2011 D DARUNAVIR ( DRV ) arunavir (
DRV GENERAL INFORMATION
) • Therapeutic class: Protease inhibitor (PI). • Originator company and product • World sales of originator product: brand name: Tibotec (a subsidiary More than US$ 1 billion.84 • WHO guidelines: Boosted DRV is listed as a potential third-line drug.6 of Johnson & Johnson), Prezista. • Patents: The basic patent was applied for by Searle and Monsanto in August • First approval by U.S. Food and Drug • Indication: For treatment-experienced 85 1993, and is due to expire in 2013. Administration (FDA): June 2006.23 patients, such as those with HIV-1 Subsequently, NIH and the University strains resistant to more than one • WHO Model List of Essential of Illinois applied for patents more protease inhibitor (adults). It is also specifically related to darunavir Medicines (EML): Not included in indicated in developed countries for in 1999 86 and licenced them to 83 24 treatment-naive adult patients. the 17th edition. Tibotec for development.87 Tibotec later applied for patents related to improved forms and combinations of darunavir.
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet.
Daily dose Tibotec
Who can access this price? See annex 2 1095 DRV 300mg tablet 4* (0.750)
* The dose of DRV must be boosted with RTV 100mg twice a day.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 19 )
DRV
( Darunavir ( DRV ) continued
Spotlight on access issues arunavir D In 2010, WHO released new There is a need for generic at $6,037 per patient per year (boosted recommendations which for the first manufacturers to supply a heat-stable with ritonavir), it is very expensive. time call for the need of third-line DRV/r fixed-dose combination, which therapy. Many studies are ongoing is currently not produced by the In September 2010, the U.S. – drugs likely to have anti-HIV originator companies. National Institutes of Health (NIH) activity in third-line regimens are licensed a patent on darunavir to Patents the Medicines Patent Pool,263 a boosted darunavir (DRV), etravirine 90 7 The basic patents related to DRV (ETV), and raltegravir (RAL). mechanism designed to boost access could not be applied for in India as to more affordable AIDS drugs in DRV, like all protease inhibitors (PIs) the country did not grant patents the developing world, in a move (with the exception of nelfinavir on pharmaceuticals before 1995. that demostrates political backing (NFV)), requires boosting with Tibotec has nevertheless applied for the Medicines Patent Pool to ritonavir (RTV). Abbott’s heat-stable for several patents in India related benefit all developing countries. ritonavir received marketing approval to the pseudo-polymorphic form,91 The NIH patent will not free the way in the U.S. and Europe in early 2010. the method for preparation of for generic versions of darunavir, Registering this new formulation in key intermediates 92 of DRV and however, because additional patents developing countries will be crucial combinations of DRV with RTV 93 are held by Tibotec. in order to allow the use of other PIs and with both TDF and RTV.94 Some Paediatrics than lopinavir. A generic heat-stable of these applications have been In December 2008, DRV was RTV is now available and was WHO opposed by generic manufacturers. approved for use in children prequalified in late 2010. The Indian patent office recently between six and 18 years of age.23 Patient numbers in Africa for DRV rejected several applications related To simplify treatment for all children, 95 are still small. to pseudo-polymorph, the method there is an urgent need for studies for preparation of key intermediates on DRV to be completed in infants Tibotec (a subsidiary of Johnson and the combination of DRV with and children under six. & Johnson) signed a royalty-free, RTV.96 The patent application on the non-exclusive licence agreement combination of DRV with TDF was A paediatric 75mg tablet is available, with Aspen of South Africa in April withdrawn after opposition.97 The but Tibotec has not provided 2007. This grants Aspen the right to patent threat to the combination on price information for this product. register, package and distribute DRV DRV with RTV continues as Tibotec There is no generic paediatric in sub-Saharan Africa. In December filed a divisional application98 product yet available. The Tibotec 2008, Tibotec announced the signing (still-pending) at the Indian patent product is however available on a of a similar agreement with Emcure office, along with appeals compassionate use basis (free of to distribute DRV in India.88 In 2011, to the rejections. charge) for sub-Saharan Africa and Tibotec completed a second supply least-developed countries, until a with Aspen covering the 300mg In addition, Abbott has filed patent pre-approval access programme is applications on RTV in India and tablet but also the 600mg tablet. established with a local partner. other developing countries which, The tablet is only suitable for Aspen will distribute the medicine if granted, will block the development children with the ability to swallow. at $1,095 per patient per year, and of and access to generic DRV/r plans to replace the DVR 300 mg fixed-dose combinations. An added complexity is that DRV tablet with the 600 mg tablet, once must be given with a RTV booster, it has been approved in most sub- In China, Tibotec38 was granted but the RTV solution currently Saharan Africa countries. Despite the patents related to racemic and available has a bitter aftertaste and VL, the price remains unaffordable for pseudo-polymorphic forms of DRV, contains 43% alcohol, and is thus the developing world. At the time methods for preparing intermediate not adapted for children, limiting of writing, the Aspen/Tibotec product compounds of DRV and use of DRV the use of DRV in this population. is registered in at least eighteen in combination with other ARVs.38 countries with applications in process There is therefore a need for child- in four others. The price per patient Similarly, more than 10 patent adapted formulations of DRV/r to per year will remain the same for applications have been filed in be made more widely available. both presentations. Brazil, such as those related to the The Paediatric Antiretroviral combination of DRV with TDF and Working Group of WHO considers These agreements exclude other RTV, as well as those related to the the development of a fixed-dose low- and middle-income countries, preparation of key intermediates combination containing darunavir for which the price paid in wealthy and the pseudo-polymorphic form. and ritonavir to be a high priority, countries, at over $13,100 per In Brazil, DRV was included in the though it is still unclear what the patient per year, is prohibitive.89 government’s guidelines in 2008, but ratio of the co-formulation will be.22
20 Médecins Sans Frontières | July 2011 DIDANOSINE ( ddI ) ( DIDANOSINE
GENERAL INFORMATION dd I
)
• Therapeutic class: Nucleoside reverse • WHO Model List of Essential • Patents: The basic patent on ddI filed transcriptase inhibitor (NRTI). Medicines (EML): Included in in 1985 by the National Institutes the 17th edition.24 of Health (NIH), a U.S. government • WHO guidelines: Indicated for research institute, has expired, but second-line for children.22 • World sales of originator product: BMS holds patents on improved 2005: US$ 174 million; 2004: • Originator company and product brand formulations in some countries, $274 million; 2003: $354 million. name: Bristol-Myers Squibb (BMS), which run until 2012 and 2018.101 Videx / Videx EC. After 2005, there are no sales figures listed in the company’s • First approval by U.S. Food and Drug annual report.115 Administration (FDA): October 1991 for chewable tablets; October 2000 for enteric-coated capsules.23
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet / capsule / ml of oral solution. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
BMS Daily Aurobindo Cipla Matrix Ranbaxy dose Category 1 Category 2 countries countries Who can access this price? See annex 2 & annex 7 See annex 2
ddl 2g powder for reconstitution 276 12 ml (final concentration 10mg/ml) (12.590/2g) 256 138 252 ddl 25mg tablet 6 (0.117) (0.063) (0.115)
ddl 50mg tablet - (0.159) (0.079) (0.125)
ddl 100mg tablet - (0.213) (0.133) (0.129) (0.166)
110 119 ddl 125mg enteric-coated capsule 1 (0.300) (0.325)
ddl 150mg tablet - (0.225) (0.167)
ddl 200mg tablet - (0.267) (0.257)
ddl 200mg enteric-coated capsule - (0.383) (0.489)
223 316 170 103 172 134 ddl 250mg enteric-coated capsule 1 (0.612) (0.866) (0.467) (0.283) (0.471) (0.367) 288 408 256 132 268 183 ddl 400mg enteric-coated capsule 1 (0.789) (1.118) (0.700) (0.363) (0.733) (0.500)
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 21 )
I dd
Didanosine ( ddI ) continued
ddI EC 400mg Evolution of the lowest price quoted enteric-coated capsule for developing countries since 2003:
As of May 2011, three generic sources of ddI
DIDANOSINE ( 400mg enteric-coated capsule were quality- 278 256 assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
The first generic source of ddI 400mg enteric- coated capsule was quality-assured by WHO prequalification in June 2008 – the generic price in the graph above corresponds to the lowest generic price until that date, and to the lowest quality-assured generic price from that date on Jun which explains the price increase. 11
Spotlight on access issues
In 2010, WHO released new deregistration of all BMS products. water and then with an antacid, to recommendations for antiretroviral BMS also discontinued the marketing obtain the final concentration. Once therapy for HIV in adults and of didanosine products in South reconstituted, the solution must be adolescents. For second-line Africa in December 2010.106 refrigerated and discarded after 30 days. treatment, protease inhibitors such as For older children who can swallow, ritonavir-boosted atazanavir (ATV/r) Patents the best-adapted option is the ddI or lopinavir (LPV/r), and simplified No application claiming a patent EC 125mg capsule, but BMS offers NRTI options are recommended. on enteric-coated capsules has no differential price for this product. Didanosine (ddI) (along with been published in India, allowing a generic version to be launched. abacavir (ABC)) is therefore no longer In 2007, BMS announced its intention However, where the patent has recommended as one of the NRTI to restructure the company, with 7 been granted in other developing backbones in second-line therapy. plans to reduce the number of brands countries, as in Brazil, China, and in the company’s mature products Bristol-Myers Squibb (BMS)’s in ARIPO and OAPI countries, the portfolio by 60% and reduce the differential pricing structure limits the importation of the more affordable company’s manufacturing facilities by prices quoted in this publication to version from India is blocked. more than 50% by 2011.103 The BMS sub-Saharan Africa and low-income In Brazil, the active ingredient is manufacturing plant in Meymac, countries only. Some wealthy countries in the public domain, which has France, was closed in June 2010. pay more than $4,100 per patient per allowed the government to produce Fearing disruption in stocks for the year for ddI 400mg enteric-coated (EC) locally the generic version as a developing world – and particularly capsules, a price which is prohibitive powder for oral solution.107 However, for up to 7,000 paediatric patients for many developing countries.102 104 the enteric-coated capsule remains in UNITAID-supported programmes under patent protection. – due to lack of alternative quality- The enteric-coated capsules are assured generic sources of ddI, civil better suited as they can be taken 109 Paediatrics society organisations demanded that once daily and, unlike the tablets, In October 1991, ddI was approved BMS address the foreseen shortage of do not contain a buffer. The buffer for use in children between two didanosine 25mg and 50mg tablets has been associated with stomach 104 weeks and 18 years old.108 ensuing from the plant closure. The upsets and a bitter and chalky taste. WHO also issued a memo warning In 2006, BMS discontinued the sale In its 2010 guidelines for antiretroviral developing countries of the impending of the chewable / dispersible buffered therapy for HIV in infants and shortage and recommended strategies tablets in the U.S. In December 2009, children, WHO recommends ddI be to avoid treatment disruption including the company also discontinued given as part of second-line regimens, changing regimen.105 BMS responded the sale and manufacturing of ddI depending on what has been used by fast-tracking the application for 200mg tablet globally due to low as a first-line.22 approval of the new plant with WHO demand for the product. prequalification programme by the Paediatric formulations are available. end of 2010. In some African countries including For younger children, however, the Ethiopia, Ghana, Kenya, Nigeria, only options are buffered tablets that There is an urgent need for generic Tanzania and Uganda, BMS come with a high pill burden, or the paediatric ddI 25mg tablets discontinued all commercial activities ddI powder for reconstitution, which to be quality-assured by WHO by the end of 2009, including requires multiple dilutions, first with prequalification.
22 Médecins Sans Frontières | July 2011 EFAVIRENZ ( EFV ) ( EFAVIRENZ
EFV
GENERAL INFORMATION )
• Therapeutic class: Non-nucleoside • First approval by U.S. Food and 2004: $621 million; and 2003: reverse transcriptase inhibitor Drug Administration (FDA): $544 million.111, 112, 113, 114, 115, 116 (NNRTI). September 1998.23 • Patents: The basic patent on EFV was • WHO guidelines: Indicated for • WHO Model List of Essential Medicines filed in 1993 by Merck, and is due to first- and second-line for adults, (EML): Included in the 17th edition.24 expire in 2013.117 Subsequently, Merck adolescents and children.110, 22 filed for patent applications related • World sales of originator product: 2010: to crystallized forms, due to expire • Originator company and product brand US$ 1.4 billion; 2009: $1.2 billion; in 2018.118 name: Bristol-Myers Squibb (BMS), 2008: $1.1 billion; 2007: $956 million; Sustiva; or Merck, Stocrin. 2006: $791 million; 2005: $680 million;
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet/capsule/suspension dose or oral solution. Products included in the WHO List of Prequalified Medicinal Products (as of May 2011) are in bold.
Daily Aurobindo Matrix Strides Merck Aspen Cipla Emcure Hetero Micro Labs Ranbaxy dose (CF) (CF) (CF) Who can access See annex 2 See annex 2 this price? & annex 10* EFV 30mg/ml - (0.094/ml) oral solution
EFV 50mg capsule - (0.083) (0.047)
EFV 50mg tablet - (0.120) (0.050)
EFV 100mg capsule - (0.042)
EFV 100mg tablet (0.117) (0.150)
116 134 152 80 97 EFV 200mg capsule 3 (0.106) (0.122) (0.139) (0.073) (0.089) 394 183 113 EFV 200mg tablet 3 (0.360) (0.167) (0.103) 237 62 73 79 61 67 55 58 72 52 EFV 600mg tablet 1 (0.650) (0.170) (0.200) (0.217) (0.167) (0.183) (0.150) (0.158) (0.197) (0.143)
* For the first time this year, Merck decided not to givestandardised price discounts to Category 2 countries. See ‘Spotlight on access issues’ below. (CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
347 Evolution of the lowest price quoted for developing countries since 2002:
As of May 2011, seven generic sources of EFV 600mg tablet were quality-assured by US FDA or
WHO prequalification. The one with the lowest 52 price is shown here. Jun Since 2002, the originator price has decreased by 11 32%, while generic prices have dropped by 89%.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 23 )
EFV
Efavirenz ( EFV ) continued
Spotlight on access issues EFAVIRENZ (
Efavirenz (EFV) is a key drug for for manufacturing EFV. This patent has Law Project, acting on behalf of the first-line treatment, as it is very therefore been opposed by Indian Treatment Action Campaign, to file potent, with once-daily dosing, civil society organisations using the a complaint before the Competition and is well-tolerated. post-grant opposition procedures Commission in November 2007. enshrined in India’s patent law.120 As a result, Merck recently agreed In its new 2010 guidelines, WHO to license its product to other recommends the use of EFV – in 121 In addition, Gilead and BMS producers, opening the opportunity combination with two NRTIs, one of filed patent applications related for generic competition in South which should be zidovudine (AZT) to combinations of EFV with other Africa, where six suppliers now or tenofovir (TDF) – as a preferred ARVs. The patent office has already market EFV or EFV-containing first-line antiretroviral treatment.7 122 rejected Gilead’s application, as combination products.127 EFV is also recommended as the combinations of known molecules Paediatrics preferred NNRTI for patients starting are not patentable under India’s ART while on tuberculosis treatment. patent law. BMS’s efforts to receive In 2010, WHO issued updated Rifampicin, one of the main drugs used a patent for the once-a-day pill EFV/ guidelines for antiretroviral use 123 to treat TB, interacts with nevirapine FTC/TDF could impact on access in paediatric HIV infection. These (NVP), resulting in lower blood levels to improved first-line ARV treatment guidelines recommend that children of NVP. EFV, however, does not have in the developing world and under three be given two NRTIs the same degree of interaction, and therefore warrants pre-grant patent plus nevirapine (to be replaced can be used as an alternative. opposition, particularly in India. with lopinavir/ritonavir in case of peripartum nevirapin exposure); for Merck has phased out the 200 mg EFV remains expensive in countries children > 3 years the recommended and 50mg capsule formulations, where Merck holds patents that block regime is two NRTIs plus efavirenz which have been replaced by tablets. the production and sale of generics. (or lopinavir/ritonavir). In countries where EFV is patented, In 2011, Merck ceased offering governments and civil society groups Although EFV was approved by US standardised price discounts to all have taken various measures to FDA for use in adults in 1998, there lower middle- and upper middle- ensure generic competition and is still no established dosing of the income countries according to the lower prices, including: medicine for children less than three World Bank Classification (see annex 6 years of age. There is an urgent need for a list of these countries). • In November 2006, Thailand issued to establish the dosing of EFV for The company proposes instead to a compulsory licence to import this age group, which is critical for negotiate discounted prices on a generic versions of EFV from India. children with HIV/TB co-infection. case-by case basis, based on country As a result, the Thai government income and disease burden. is now purchasing EFV at $106 In the absence of such data, ppy, considerably lower than the treatment options for children remain This is concerning for the previous price of $511 ppy.124, 125 limited, particularly for HIV/TB co- affordability of products in middle- infected young children who cannot income countries, especially given • In May 2007, Brazil, after numerous be given NVP because of interactions that Merck’s previous pricing unsuccessful negotiations with between NVP and TB drugs. strategy (published in previous Merck, issued a compulsory licence editions of Untangling the Web) to import more affordable generic Paediatric formulations exist. In was to offer middle-income versions of EFV from India. At the early 2008 however, BMS, which countries the EFV 600mg tablet at time, the price of EFV in Brazil was markets EFV in Europe, discontinued prices more than ten times more $580 ppy and had not changed the manufacture of the 100mg expensive than the generic version. since 2003. After the compulsory capsule, further limiting options licence, Brazil began to import a for paediatric patients. Patents generic version prequalified by Merck does not hold a product WHO for $190 ppy. In February The oral solution, while allowing patent for EFV in India. Generic 2009, the public manufacturer more flexibility in dosing, must be competition from a number Farmanguinhos (Fiocruz) launched discarded 30 days after opening, of Indian manufacturers has the national generic version for use and is not interchangeable on a mg thus brought the price down in the Brazilian health system.126 per mg basis with the solid dosage significantly. However, a patent for forms. The bioavailability of the oral the process of preparing form 1 of • In South Africa, Merck’s refusal to solution is also less than 70% of crystalline EFV was granted in June allow sufficient generic competition the oral dosage forms, and hence 2005.119 This process patent appears contributed significantly to the high a larger dose is required to obtain to protect a key process price of the drug. This led the AIDS the same blood levels.
24 Médecins Sans Frontières | July 2011 EMTRICITABINE (FTC) ( EMTRICITABINE
GENERAL INFORMATION
FTC
• Therapeutic class: Nucleoside reverse • World sales of originator product: 2010: Emory University also applied for a
) transcriptase inhibitor (NRTI). US$ 28 million; 2009: $28 million; series of patents that relate to FTC 2008: $31 million; 2007: $32 million; between 1990 and 1992.135, 136 These • WHO guidelines: Indicated for 6 2006: $36 million; 2005: $47 million; are due to expire between 2010 first- and second-line for adults. 2004: $58 million.128, 129, 130, 131, 132 and 2012. In 2005, Gilead acquired • Originator company and product the royalty interest for FTC under • Patents: The basic patent on FTC brand name: Gilead, Emtriva. a $525 million agreement with and lamivudine (3TC) was filed by Emory University.137 • First approval by U.S. Food and Drug IAF Biochem in 1990 and is due to Administration (FDA): July 2003.23 expire in 2010. As the molecular • WHO Model List of Essential structure of FTC and 3TC are very Medicines (EML): Included in closely related, the same patent the 17th edition.24 covers both these drugs.133, 134
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one capsule. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily dose Aurobindo Cipla
Who can access this price? See annex 2 61 97 FTC 200mg capsule 1 (0.167) (0.267)
Spotlight on access issues
Emtricitabine (FTC) is not offered as The latest WHO 2010 guidelines Paediatrics part of Gilead’s Access Program and recommend using TDF with either FTC is approved for use in children is neither registered nor marketed in FTC- or 3TC-containing antiretroviral from three months through to developing countries. It is, however, regimens in all HIV/HBV co-infected 17 years and has the advantage 7 available in co-formulation with individuals needing treatment. of once-daily dosing.140 tenofovir (TDF) and efavirenz (EFV). Patents Paediatric formulations are available. It is a widely-used ARV both in Although basic patents on FTC The solution produced by Gilead is not first- and second-line regimens. could not be applied for in India adapted to developing world needs, because the country did not grant According to the WHO treatment however, as it requires refrigeration patents on pharmaceuticals at guidelines, “FTC is an equivalent prior to dispensing and must be used the time, Gilead reported holding alternative to lamivudine (3TC) as it within three months of opening and patent rights on FTC in 45 other stored at temperatures below 25°C. is structurally related to 3TC, shares developing countries.138 the same efficacy against HIV and In addition, Gilead offers no reduced hepatitis B virus (HBV) and has the In mid-2006, Gilead signed licensing pricing for the developing world. same resistance profile.”6 agreements with generic manufacturers in India, allowing them to manufacture To simplify treatment for all children, FTC or 3TC are also recommended for and export generic versions of Gilead’s there is an urgent need for child- second-line treatment, to be used with TDF in combination with other ARVs adapted formulations of FTC to be either zidovudine (AZT) or tenofovir – including FTC – to a limited list of made available, and generic paediatric (TDF), to which a boosted protease countries, in return for the payment FTC formulations to be quality-assured inhibitor (PI) should be added. of a 5% royalty.139 by WHO prequalification.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 25 Enfuvirtide nfuvirtide E GENERAL INFORMATION
• Therapeutic class: Fusion inhibitor. • WHO Model List of Essential which began development of Medicines (EML): Not included in enfuvirtide (previously called T-20) in • WHO guidelines: Not currently the 17th edition.24 1996. In 1999, Trimeris entered into included in WHO guidelines. partnership with Hoffmann-La Roche Indicated for treatment-experienced • World sales of originator product: to complete the development of adult patients who have evidence There are no sales figures listed in the drug. Chiron also owns patents of viral HIV-1 replication despite the companies’ annual report. ongoing antiretroviral therapy.141 related to processes for producing • Patents: The basic patent on enfuvirtide,143 which expired in 2005, • Originator company and product brand enfuvirtide was applied for by but protection has been extended name: Roche and Trimeris, Fuzeon. Duke University in June 1994,142 until 2010 in some European • First approval by U.S. Food and and is due to expire in 2014. countries. A licensing agreement Drug Administration (FDA): Duke researchers founded the was established between Roche March 2003.23 pharmaceutical company Trimeris, and Chiron in 2004.144
Price INFORMATION Roche was invited to contribute a price for this publication and communicated that it does not offer a lower price for developing countries and is not planning to offer one in the future.
Spotlight on access issues
Enfuvirtide is the first drug There is no generic version of Paediatrics developed in the fusion inhibitor this drug yet available and Roche Enfuvirtide is approved for use class, whose novel mechanism of offers no reduced pricing for the in children over six years of age.148 action prevents the penetration developing world. The current price To simplify treatment for all of target cells by the HIV virus. in some developed countries of children, there is an urgent need This new drug is predominately nearly $28,000 per patient per year for studies on enfurvitide to be used in the developed world as is prohibitive for many developing completed in infants and children ‘salvage therapy’ for patients who countries that may have a need for under six, and for child-adapted are already resistant to multiple this product.145 formulations to be made available. antiretroviral agents. Patents Enfuvirtide is formulated as an In developing countries such as injection and requires the patient China and Brazil, Trimeris filed for or caregiver to learn how to patents related to methods for reconstitute powder vials with synthesizing enfuvirtide, which sterile water. Since the vials are may run until 2019.146 formulated for single use, the The patent was granted in China.38 patient or caregiver needs to accurately syringe out the required In Brazil, enfuvirtide is available dose and volume. This makes at $12,812 ppy.147 the drug ill-adapted for use in resource-limited settings.
26 Médecins Sans Frontières | July 2011 ETRAVIRINE (ETV) (ETV) ETRAVIRINE
GENERAL INFORMATION
• Therapeutic class: Non-nucleoside • Originator company and product • Patents: The basic patent on reverse transcriptase inhibitor (NNRTI). brand name: Tibotec (a subsidiary etravirine was applied for by Janssen of Johnson & Johnson), Intelence. Pharmaceutica in 1999 and is due to • WHO guidelines: Listed in the WHO 150 • First approval by U.S. Food and Drug expire in 2019. In 2006, Tibotec guideline as potential third-line drug.6 Administration (FDA): January 2008.23 applied for subsequent patents Approved by U.S. Food and Drug related to novel series of bisaryl Administration (FDA) for treatment • WHO Model List of Essential Medicines substituted pyrimidine derivatives. (EML): Not included in the 17th edition.24 experienced adult patients who have Both Janssen Pharmaceutica and evidence of resistance to an NNRTI • World sales of originator product: Tibotec are subsidiaries of Johnson and other antiretroviral agents.149 There are no sales figures listed in & Johnson.151, 152 the companies’ annual report.
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet.
Daily dose Tibotec
Who can access this price? See annex 2 913 ETV 100mg tablet 4 (0.625)
Spotlight on access issues
In 2010, WHO released new sub-Saharan Africa with applications In India, Tibotec has filed additional recommendations which for the first in process in sixteen others. patent applications154 on new forms time call for the need of third-line which, if granted, will extend its The price of ETV, at $913 ppy, therapy. Many studies are ongoing; monopoly in India from 2021 is prohibitive for developing countries. drugs likely to have anti-HIV activity to 2027. There is no generic version of this in third-line regimens are etravirine drug yet available. Paediatrics (ETV), boosted darunavir (DRV), and raltegravir (RAL).7 Patents ETV is not approved for use in children Patents have been applied for widely today. A waiver of paediatric studies In August 2009, Tibotec (a subsidiary in the developing world, including from birth to two months was of Johnson & Johnson) signed a in Africa. Janssen Pharmaceutica granted by EMA on grounds that the royalty-free, non-exclusive licence obtained the molecule patent in medicine does not represent significant agreement with Aspen of South India 153 and China.38 therapeutic benefit over existing Africa covering all of sub-Saharan treatments.155 Africa for all ETV formulations. This patent will block the development Under this agreement, Aspen will of generic formulations of ETV, unless As few treatment options exist handle regulatory and distribution licences – voluntary or compulsory for children with HIV, it is critical activities. At the time of writing, – are issued to generic companies that paediatric studies of ETV be Aspen/ Tibotec ETV 100 mg tablet is for the manufacture of affordable completed and adapted formulations registered in at least six countries in versions of the drug. be made available.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 27 ) FOSAMPRENAVIR -APV f ( FPV or f-APV ) or FPV
( GENERAL INFORMATION
• Therapeutic class: Protease inhibitor (PI). • First approval by U.S. Food and • Patents: The basic patent was applied Drug Administration (FDA): for by Vertex Pharmaceuticals in • WHO guidelines: Not currently 23 156 included in WHO guidelines. October 2003. March 1998, and due to expire in 2018. Fosamprenavir, a phosphate • WHO Model List of Essential • Originator company and product ester prodrug of amprenavir,157 was Medicines (EML): Not included in
osamprenavir brand name: GlaxoSmithKline (GSK) developed and launched by GSK, F and Vertex Pharmaceuticals, Lexiva. the 17th edition.24 under licence from Vertex. GSK also In April 2009, Pfizer and GSK jointly announced the creation of ViiV, a • World sales of originator product: holds patents related to a crystalline new joint venture focusing solely There are no sales figures listed in form of the calcium salt of FPV,158 on the R&D and commercialisation the companies’ annual report. due to expire in 2019. of HIV medicines.
Price INFORMATION
Daily dose ViiV Developing country prices in US$ per patient per year, as quoted by companies. Who can access this price? See annex 2 The price in brackets corresponds to the price of one 837 FPV 50mg/ml oral suspension 12 ml* tablet / ml of oral suspension. (0.191/ml) 1131 * The dose of FPV must be boosted with RTV 100mg FPV 700 mg tablet 2* (1.549) twice a day.
Spotlight on access issues
In 2010, WHO recommendations formulation in developing countries against the decision. for second-line therapy included will be crucial in order to allow the use In China, South Africa, ARIPO and two ‘preferred’ protease inhibitors of other PIs than lopinavir. A generic OAPI countries,160 most patents have (PI), to be taken in combination heat-stable RTV is now available and been granted. with two NRTIs. They are atazanavir was WHO prequalified in late 2010. (ATV) boosted with ritonavir (RTV) In June 2010, India granted a and lopinavir/ritonavir (LPV/r).7 In 2011, ViiV clarified their pricing patent to Vertex Pharmaceuticals As fosemprenavir (FPV) was not structure (see annex 2), confirming that covers fosamprenavir salts, identified as one of the priority that their standardised price including calcium which is the products, its use will be limited discounts were not in fact available marketed salt.323 in the developing world.7 to all fully-financed Global Fund or There are no generic formulations PEPFAR programmes, contrary to of this product available today. While FPV/r based regimens show previous announcements. Global good antiviral efficacy and are Fund financed programmes in Paediatrics generally well tolerated in treatment- middle-income countries have not FPV was approved for use in naïve patients, the experience of this been and will not be eligible for those children above the age of two drug in developed countries is limited 23 prices, and will have to negotiate in October 2007. and little comparative data is available prices on a case-by-case basis. in treatment-experienced patients.159 A paediatric suspension is available. Patents However, FPV must be given with a FPV, like all PIs (with the exception Patent applications have been filed RTV booster, but the RTV solution of nelfinavir (NFV)), requires boosting in many developing countries. currently available has a bitter aftertaste with ritonavir (RTV). Abbott’s heat- and contains 43% alcohol, and is thus In Brazil, the basic patent was rejected stable ritonavir received marketing not adapted for children, limiting approval in the U.S. and Europe in by the patent office, although in the use of FPV in this population. early 2010. Registering this new December 2009 ViiV filed an appeal
28 Médecins Sans Frontières | July 2011 I INDINAVIR ( IDV ) ndinavir (
IDV GENERAL INFORMATION
)
• Therapeutic class: Protease inhibitor (PI). • First approval by U.S. Food and Drug • World sales of originator product: 23 There are no sales figures listed in • WHO guidelines: Not currently Administration (FDA): March 1996. the companies’ annual report. included in WHO guidelines. • WHO Model List of Essential • Patents: The basic patent was filed • Originator company and product Medicines (EML): Included in by Merck in 1992 and is due to brand name: Merck, Crixivan. the 17th edition.24 expire in 2012 in countries granting 20-year patents.161 Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one capsule. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily Merck Aurobindo Cipla Hetero dose
Who can access this price? See annex 2 & annex 10** See annex 2 394 292 422 406 IDV 400mg capsule 4* (0.270) (0.200) (0.289) (0.278)
* The dose of IDV must be boosted with RTV 100mg twice a day. **For the first time this year, Merck has decided not 700 to give standardised price discounts to Category 2 600 countries. See ‘Spotlight on access issues’ below. 584 500 406 400 400 394 Evolution of the lowest price quoted 300 for developing countries since 2001: 200 As of May 2011, two generic sources of IDV 400mg 100 capsule were quality-assured by US FDA or WHO 0 Jun prequalification. Only one of these sources provided 11 prices for this document, and is the one shown here.
Spotlight on access issues
In 2010, WHO recommendations developing countries will be crucial The company proposes instead to for second-line therapy included in order to allow the use of other PIs negotiate discounted prices on a two ‘preferred’ protease inhibitors than lopinavir. A generic heat-stable case-by case basis, based on country (PI), to be taken in combination RTV is now available and was WHO income and disease burden. prequalified in late 2010. with two NRTIs. They are atazanavir Patents (ATV) boosted with ritonavir (RTV) Some generic manufacturers have In Brazil, indinavir is one of the and lopinavir/ritonavir (LPV/r). As stopped production of IDV, or only ARVs produced locally. The patent IDV was not identified as one of manufacture it for specific orders, application was filed in 1994, at the priority products, its use will be because of a decrease in demand a time when the country did not 7 limited in the developing world. for this product. grant patents on pharmaceuticals, and was therefore rejected. IDV, like all PIs (with the exception In 2011, Merck ceased offering of nelfinavir (NFV)), requires boosting standardised price discounts to all Paediatrics with RTV. Abbott’s heat-stable lower middle- and upper middle- The optimal dosing regimen for the use of IDV in paediatric patients has ritonavir received marketing approval income countries according to not been established.162 in the U.S. and Europe in early 2010. the World Bank Classification (see Registering this new formulation in annex 6 for a list of these countries). No paediatric formulation exists.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 29 )
3TC LAMIVUDINE ( 3TC ) (
GENERAL INFORMATION amivudine L • Therapeutic class: Nucleoside reverse • First approval by U.S. Food and • Patents: The basic patent on transcriptase inhibitor (NRTI). Drug Administration (FDA): emtricitabine (FTC) and 3TC was filed November 1995.23 by IAF Biochem in 1990 and should • WHO guidelines: Indicated for first- therefore have expired in 2010 in and second-line for adults, adolescents • WHO Model List of Essential countries with 20-year patent terms. and children.6, 22 Medicines (EML): Included in As the molecular structure of FTC and 3TC are very closely related, the same the 17th edition.24 • Originator company and product patent covers both these drugs.133 brand name: GlaxoSmithKline (GSK), • World sales of originator product: 2010: GSK obtained a licence from IAF to manufacture 3TC and filed additional Epivir. In April 2009, Pfizer and GSK US$ 186 million; 2009: $197 million; patents on new forms of 3TC in jointly announced the creation of ViiV, 2008: $225 million; 2007: $309 million; 1992, which are due to expire in June a new joint venture focusing solely 2006: $398 million; 2005: $398 million; 2012.164 GSK also applied for on the R&D and commercialisation 2004: $549 million.163, 25, 28, 29, 30 a new formulation patent in 1998. of HIV medicines. This patent was granted in Brazil, China and in ARIPO countries.165
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet / ml of oral solution. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily Aurobindo Cipla Hetero Matrix Micro ViiV Alkem Aspen Ranbaxy Strides dose (CF) (CF) (CF) (CF) Labs
Who can access See annex 2 this price?
3TC 10mg/ml 212 33 29 55 37 10 ml oral solution (0.058/ml) (0.009/ml) (0.008/ml) (0.015/ml) (0.010/ml)
80 42 29 34 33 33 31 31 34 29 3TC 150mg tablet 2 (0.109) (0.058) (0.040) (0.047) (0.045) (0.045) (0.042) (0.042) (0.047) (0.040)
24 41 38 26 3TC 300mg tablet 1 (0.067) (0.113) (0.103) (0.071)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2001:
As of May 2011, nine generic sources of 3TC 150mg tablet were quality-assured by US FDA or 80 WHO prequalification. The one with the lowest price is shown here. 29
Since 2001, the originator price has decreased Jun by 66%, while generic prices have dropped 11 by 68%.
30 Médecins Sans Frontières | July 2011 L amivudine (
Spotlight on access issues 3TC
) Lamivudine (3TC) is a widely-used In February 2011, Shionogi-ViiV Today, once-daily dosing of 3TC ARV both in first- and second-line Healthcare announced 36 the start is only recommended for patients regimens. It has been an important of a phase III trial for a new fixed- over 16; more studies are needed component of fixed-dose dose combination including ABC, to confirm the safety of daily dosing combinations that have fostered lamivudine (3TC) and a new of 3TC in children.43 treatment scale-up in resource- integrase inhibitor S/GSK1349572 An oral solution of 3TC is limited settings. (an investigational drug known available. As of May 2011, two as dolutegravir, now in phase III According to the WHO treatment generic sources were quality- clinical development).37 guidelines, “FTC is an equivalent assured by either US FDA or alternative to lamivudine (3TC) as it Patents WHO prequalification. is structurally related to 3TC, shares Generic competition for 3TC Generic manufacturers have been the same efficacy against HIV and originated in countries with developing both double and triple hepatitis B virus (HBV) and has manufacturing capacity where fixed-dose combinations containing the same resistance profile.”6 the drug is not under patent, 3TC. As of May 2011, ten sources such as India, Thailand and Brazil. The latest WHO 2010 guidelines of paediatric triple FDCs containing also recommend using TDF with Paediatrics 3TC were quality-assured by either either FTC- or 3TC-containing 3TC is approved for use and is US FDA or WHO prequalification. All antiretroviral regimens in all HIV/HBV widely used in children. In its 2010 are produced by generic companies. co-infected individuals needing guidelines for antiretroviral therapy treatment.7 for HIV in infants and children, WHO recommends 3TC to be In 2011, ViiV clarified their pricing given with either ABC, d4T or AZT structure (see annex 2), confirming and either an NNRTI or a PI in the that their standardised price first-line. 3TC can also be part of discounts were not in fact available second-line regimens, depending to all fully-financed Global Fund or on what has been used as a first- PEPFAR programmes, contrary to line. 3TC is part of both of the most previous announcements. Global commonly used first-line regimens Fund financed programmes in for children today (3TC/d4T/NVP middle-income countries have not and AZT/3TC/NVP). been and will not be eligible for those prices, and will have to negotiate prices on a case-by-case basis.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 31 ) LOPINAVIR/ r LPV/ RITONAVIR ( LPV/r )
GENERAL INFORMATION
• Therapeutic class: Boosted protease • First approval by U.S. Food and Drug • Patents: Most patents related to inhibitor (PI) in a double fixed-dose Administration (FDA): September 2000 ritonavir (RTV) also cover LPV/r. The combination. (soft-gel capsules); October 2005 basic patent related to LPV was applied 23 (heat-stable tablets). for by Abbott in 1996.170 In addition, • WHO guidelines: Indicated for • WHO Model List of Essential Medicines Abbott applied for patents more second-line, for adults, adolescents (EML): Included in the 17th edition.24 specifically related to LPV/r soft-gel 6, 22
LOPINAVIR/RITONAVIR LOPINAVIR/RITONAVIR ( and children. capsules in 1997171 which are due to • World sales of originator product: 2010: • Originator company and product US$1.26 billion; 2009: $1.37 billion; expire in 2017. An application for brand name: Abbott, Kaletra/Aluvia. 2008: $1.47 billion; 2007: $1.32 billion; a patent on the heat-stable tablet 2004: $897 million; 2003: $754 million; formulation was also filed in 2004,172 2002: $551 million; 2001: which could potentially run until 2024, $292 million.166, 167, 168, 169 in countries where granted. PRICE INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one capsule / tablet / ml of oral solution. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Abbott Daily Aurobindo (CF) Cipla (CF) Hetero Matrix (CF) dose Category 1 Category 2 countries countries Who can access this price? See annex 2 & annex 8 See annex 2
256 LPV/r 80/20mg/ml oral solution 4 ml 164 400 (0.112/ml) (0.274/ml) (0.175/ml)
LPV/r 100/25mg tablet (heat-stable) 3 153 376 175 164 (0.140) (0.343) (0.160) (0.150) LPV/r 133/33mg soft-gel capsule 633 6 500 1000 (non heat-stable) (0.228) (0.457) (0.289) 493 LPV/r 200/50mg tablet (heat-stable) 4 410 1000 438 499 402 (0.281) (0.457) (0.300) (0.342) (0.338) (0.275) (CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest quoted price for developing countries since 2002:
As of May 2011, there was no generic source of LPV/r 133/33mg soft-gel capsule quality- assured by US FDA or WHO prequalification, so the lowest-priced generic is shown in this graph. There were however three quality-assured generic sources of LPV/r 200/50mg heat-stable tablet. The one with the lowest price is shown here. 633
The generic price of LPV/r 200/50mg heat-stable 410 tablet has decreased by 61% since 2007. 402
Jun 11
32 Médecins Sans Frontières | July 2011 OIAI/IOAI ( LOPINAVIR/RITONAVIR
SPOTLIGHT ON ACCESS ISSUES
In 2010, WHO recommendations for application was rejected by the licence, Abbott reduced the price second-line therapy included two Indian patent office.181 While an for 40 middle-income countries for
‘preferred’ protease inhibitors (PI), appeal is pending to the rejection, both the soft-gel and the heat-stable LPV/ to be taken in combination with two Abbott has abandoned the two version to $1,000 ppy, including NRTIs. They are lopinavir/ritonavir divisional patent applications it Brazil which at the time was paying r
(LPV/r) and atazanavir (ATV) boosted had filed on the tablet formulation ) $1,380.3 with ritonavir (RTV).7 With its once-a- of LPV/r.182, 183 The Indian patent day dosing ATV is the more patient- office also rejected a patent The basic patent for LPV/r is friendly PI of the two. application on lopinavir crystalline protected in Brazil under the so-called polymorphs.184 The heat-stable formulation of ‘pipeline mechanism’, a provision in LPV/r manufactured by Abbott and In a welcome move, Abbott has Brazilian patent law deemed to be in Indian generic companies is now also abandoned several applications excess of the minimum standards for marketed in developing countries. including the divisional on the RTV intellectual property protection under In comparison with the older, crystalline polymorph. However, the TRIPS Agreement. In 2007, the soft-gel capsule formulation, the key applications, relating to the National Federation of Pharmacists new formulation has a lower pill RTV stable polymorph,185 the solid (Fenafar) – on behalf of the Brazilian count (reducing the burden from pharmaceutical dosage (tablet) Network for the Integration of six to four pills per day), there is no formulation of LPV/r,179 and to the need for refrigeration, and there LPV process186 are still pending Peoples (Rebrip) – made a request are no dietary restrictions. It is now before the Indian patent office. to the Brazilian Prosecutor General approved as once-a-day dosing in If one of these patent applications to consider overturning the pipeline treatment-experienced patients with is granted, current generic mechanism on the grounds that it is fewer than three lopinavir resistance- competition, which is bringing unconstitutional. A key argument in associated mutations.23 This should prices substantially down as demand favour of overturning the mechanism enhance adherence. However, pill increases, will be under threat. India is that these patents should not be burden remains an issue. and other countries could urgently granted in Brazil, since they were The entry of generic manufacturers issue compulsory licences to enable already in the public domain and is having a positive effect on the unrestricted competition from that granting the patents in this market, and prices are declining. generic manufacturers to continue. However Abbott’s sales of this drug way is against the public interest. In In Thailand, where Abbott holds dominates the developing world 2009, the Prosecutor General lodged patents, the price of LPV/r was where it captured 81% of the a case for unconstitutionality with $2,200 ppy in 2007. In January 2007, market share in 2008.16 the Supreme Court.187 MSF-Brazil is the Ministry of Public Health issued 188 Patents a compulsory licence to import actively following the case. more affordable generic versions In India, Abbott has applied for In 2005, the Brazilian government several patents on the polymorphic of the drug from India.124 Thailand entered into negotiations with forms of LPV173 and RTV,174, 175, 176, 177 faced fierce criticism from developed Abbott to reduce the price of on the combination of LPV/r in a countries and multinational tablet formulation,178, 179 and on the pharmaceutical companies and LPV/r and in June of the same year, LPV process. A number of these Abbott’s response was to withdraw the Ministry of Health declared applications have been opposed all registration applications in the drug to be of public interest, by civil society organisations180 Thailand for its new products, which is the first step towards and generic companies. including the heat-stable LPV/r. issuing a compulsory licence. Thailand today imports generic LPV/r Following a pre-grant opposition However, in October 2005 an from India for $793 ppy.125 to the application related to the agreement between Abbott and tablet formulation of LPV/r, the In response to Thailand’s compulsory the government was signed.
Continued overleaf Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 33 )
r LPV/
Lopinavir/Ritonavir ( LPV/r ) continued (
Spotlight on access issues itonavir
/R The deal included clauses such Paediatrics of 42% alcohol and has a very as an obligation not to issue a LPV/r is approved for use in children unpleasant taste. In addition, safety compulsory licence. Civil society from two weeks old.23 concerns were raised in March groups considered this agreement 2011 when US FDA revised labelling Recent changes in the WHO a huge setback189 and filed a civil to warn against the use of LPV/r
opinavir guidelines recommending that
L public action against Abbott and solution in premature babies until all HIV-positive children under the government demanding that a 14 days after their due date, after one year of age start ARV therapy compulsory licence be issued.190 The serious health problems had been as soon as possible regardless of 195 case received a negative preliminary reported in premature babies. clinical status, combined with decision, in which it was said that There is an urgent need for more Brazil should not “break patents” the recommendation to start all adapted heat-stable paediatric since the country was included in children exposed to nevirapine formulations of LPV/r (such as the US government’s priority watch on a PI-based regimen, should soluble granules or sprinkles) list for infraction of IP rules.191 The result in an increased demand for for young children who can not civil public action is still awaiting this combination for very young 194, 113 swallow the existing tablet. A final judgment. children. heat-stable sprinkle in a paediatric In 2006, civil society groups also Paediatric formulations exist. In dose is under development by filed an opposition contesting a early 2007, Abbott released a generic companies. The Paediatric divisional patent application for paediatric LPV/r 100/25mg heat- Antiretroviral Working Group of LPV/r filed by Abbott.192 As the first stable tablet. As of May 2011, WHO considers the development patent was granted through the two generic sources of heat-stable of a LPV/r 40/10mg heat-stable pipeline mechanism, it was argued LPV/r 100/25mg were quality- sprinkle to be a high priority.22 that there is no legal provision for assured by either US FDA or divisional applications of pipeline WHO prequalification. While this patents. In July 2010, the divisional formulation is welcome, it does not patent application was rejected by help the youngest patients, as the the Brazilian Patent Office (INPI). tablet is 15mm long and cannot be crushed, leaving this formulation The patent issued trough the unsuitable for children who cannot pipeline mechanism in Brazil covers swallow tablets. the compound and the soft-gel capsule until 2017. However, at The alternative for these young least two other patent applications children is a solution that requires for the tablet formulation are refrigeration until dispensing, after under analysis at INPI.193 If they are which it must be stored below granted, Abbott’s monopoly may 25°C for no more than six weeks. be extended until 2026. Furthermore, the solution consists
34 Médecins Sans Frontières | July 2011 M MARAVIROC ( MVC ) araviroc (
MVC GENERAL INFORMATION
) • Therapeutic class: Chemokine • Originator company and product • WHO Model List of Essential co-receptor 5 (CCR5) antagonist brand name: Pfizer, Selzentry (US) Medicines (EML): Not included in 24 (entry inhibitor). and Celsentri (Europe). In April 2009, the 17th edition. • WHO guidelines: Not currently Pfizer and GlaxoSmithKline jointly • World sales of originator product: included in WHO guidelines. announced the creation of ViiV, a There are no sales figures listed in Indicated for treatment-experienced new joint venture focusing solely the company’s annual report. adult patients infected with only on the R&D and commercialisation • Patents: The basic patent was applied CCR5 tropic HIV-1 detectable strains, of HIV medicines. for by Pfizer in December 1999197 and is who have evidence of viral replication due to expire in 2019. Pfizer also owns and HIV-1 strains resistant to multiple • First approval by U.S. Food and Drug an additional patent more specifically antiretroviral agents.196 Administration (FDA): August 2007.23 related to crystalline maraviroc,198 which may run up to 2021. Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet.
* The dose is dependent on Daily dose ViiV concurrent administered Who can access this price? See annex 2 medications. 1584 MVC 150mg tablet 4* (1.085)
Spotlight on access issues
Maraviroc (MVC) is classed as that their standardised price MVC at about one-fifth the price.201 a CCR5 co-receptor antagonist discounts were not in fact available If negotiations with Pfizer fail, Natco that targets the penetration of to all fully-financed Global Fund or can seek a compulsory licence under cells by the HIV virus. This drug PEPFAR programmes, contrary to the terms of the Indian patent law. option is predominately used in previous announcements. Global Pfizer has applied for product the developed world as ‘salvage Fund financed programmes in patents and patents for the crystal therapy’ for patients who are middle-income countries have not form in Brazil, South Africa, already resistant to multiple drug been and will not be eligible for those India, China, ARIPO 202 and OAPI classes. Not all patients will benefit prices, and will have to negotiate countries.203 To date, patents on the from this drug, as only some HIV prices on a case-by-case basis. crystal form have been granted viruses use this CCR5 co-receptor. Patents in India,204, 205 China, and in ARIPO The recommendation is for patients Pfizer obtained a patent in India and OAPI countries. to have a tropism test to look for in 2007.200 This patent blocks the Paediatrics this co-receptor prior to treatment. manufacture of generic formulations The safety and efficacy of MVC In developing countries, where of MVC in India, limiting the much- in patients under 16 years of age basic laboratory monitoring is not needed competition that historically have not been established. always available, the reality of this has been shown to lead to price type of testing being available reductions. As few treatment options exist is limited. Today, this test is not for children with HIV, it is critical An Indian pharmaceutical company, widely available and is expensive, that paediatric studies of MVC Natco Pharmaceuticals reportedly costing approximately $1,900.199 be completed and adapted sent a notice for a voluntary licence formulations be made available. In 2011, ViiV clarified their pricing to Pfizer in November 2010 seeking structure (see annex 2), confirming to manufacture and sell its generic
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 35 )
NFV NELFINAVIR ( NFV ) (
GENERAL INFORMATION elfinavir N • Therapeutic class: Protease inhibitor (PI). • WHO Model List of Essential • Patents: The basic patent was applied Medicines (EML): Not included in for in 1994 by Agouron Pharmaceuticals • WHO guidelines: Not currently the 17th edition.24 Inc.,207 and is due to expire in 2014. included in WHO guidelines. Agouron Pharmaceuticals is now a • World sales of originator product: • Originator company and product subsidiary of Pfizer. NFV was developed 2004: US$ 259 million. After 2004, brand name: Roche, Viracept. by Agouron as part of a joint venture there are no sales figures listed in with Japan Tobacco, Inc. NFV is 206 • First approval by U.S. Food and Drug the company’s annual report. supplied by Roche outside the U.S., Administration (FDA): March 1997.23 Canada and Japan.208
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet / gram of oral powder. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Roche Daily dose Category 1 Category 2 countries countries Who can access this price? See annex 2
2742 3171 NFV 50mg/g oral powder 24g (0.313/g) (0.362/g) 2018 3132 NFV 250mg tablet 10 (0.553) (0.858)
Evolution of the lowest quoted price for developing countries since 2001:
For the first time since 2001, no generic 3489 companies provided prices this year for nelfinavir 3249 250mg tablet for this publication.
After a sharp decrease of the price of the 2018 originator between 2002 and 2003, this price has then steadily increased every year since 2006, by a total of 166%. 945
183 Jun 11
36 Médecins Sans Frontières | July 2011 N elfinavir (
NFV Spotlight on access issues
)
Nelfinavir (NFV) is the only protease another PI. The recall highlights Paediatrics inhibitor (PI) that does not require the risks associated with relying on In 1997, NFV was approved for boosting with ritonavir (RTV). a single producer for a medicine. use in children.210
The large pill burden (10 tablets a It is unknown if there will continue The use of NFV oral powder in day for an adult) and its high price to be demand for the NFV children is extremely complex. make it a less-desirable option formulation in the future. NFV was To obtain the correct dose for a when selecting a PI. also deleted from the 16th edition 10kg child, 12g of the oral powder In June 2007, Roche recalled all of the WHO Model List of Essential must be mixed with water. Access batches of NFV due to high levels Medicines (EML). to clean, safe water is often not of Ethyl Methane Sulphonate (EMS), assured in all developing countries. Patents a by-product of the manufacturing Not only is the paediatric NFV process and a known carcinogen Although basic patents on NFV formulation ill-adapted, but its in animals. Roche’s marketing could not be applied for in India price remains prohibitive. licence for NFV was suspended in because the country did not grant Europe and WHO Prequalification patents on pharmaceuticals at the temporarily suspended the product. time, Agouron applied for patents In September 2007, the suspensions in many other developing countries. were lifted and marketing licences This factor contributes to the high reinstated.209 As a result of the recall, price of the drug, together with many patients were changed to the small demand.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 37 )
NVP NEVIRAPINE ( NVP )
GENERAL INFORMATION NEVIRAPINE ( • Therapeutic class: Non-nucleoside • First approval by U.S. Food and Drug • Patents: The basic patents on NVP reverse transcriptase inhibitor Administration (FDA): June 1996.23 were applied for by BI in November (NNRTI). • WHO Model List of Essential Medicines 1990, and expired in November 215 24 2010. BI also holds patents on the • WHO guidelines: Indicated for first- (EML): Included in the 17th edition. hemihydrate form of NVP, used in the and second-line for adults, adolescents • World sales of originator product: suspension in 1998, which are due to and children.6, 22 2007: US$ 412 million; 2006: expire 2018.216 Additionally, BI applied $370 million; 2005: $386 million; • Originator company and product 2004: $378 million.211, 212, 213, 214 for a patent on the extended release brand name: Boehringer Ingelheim After 2007, there are no sales figures formulation of nevirapine in 2008, (BI), Viramune and Viramune XR. quoted in the company’s annual report. which is due to expire in 2028.217
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet/ml of suspension. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Boehringer Ingelheim Daily Aspen Aurobindo (CF) Cipla (CF) Hetero (CF) Matrix (CF) Ranbaxy Strides dose Category 1 Category 2 countries countries Who can access this See annex 2 price? NVP 380 533 58 110 10mg/ml 20 ml (0.052/ml) (0.073/ml) (0.008/ml) (0.015/ml) suspension NVP 219 438 37 37 39 37 31 37 32 200 mg 2 (0.300) (0.600) (0.051) (0.050) (0.054) (0.050) (0.043) (0.050) (0.044) tablet
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2001:
As of May 2011, 10 generic sources of NVP 200mg tablet were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
Although the originator price dropped by 50% in 2007, the generic price has decreased by almost 80% since 2001, and today is approximately 14% of the originator price.
31
Jun 11
38 Médecins Sans Frontières | July 2011 NEVIRAPINE ( NEVIRAPINE
NVP Spotlight on access issues
) Nevirapine (NVP) is a widely-used suspension. Civil society groups NVP is part of both of the most ARV, predominately in first-line filed a pre-grant opposition to BI’s commonly used first-line regimens regimens. It has been an important application in May 2006. In June for children today (3TC/d4T/NVP component of the fixed-dose 2008, the application was rejected and AZT/3TC/NVP). With both of combinations that have fostered by the Indian patent office, allowing these regimens, there is a need to treatment scale-up in resource- for unrestricted competition on start NVP at a lower dose for the limited settings. the paediatric formulation. This first two weeks to minimise the side However NVP interacts with one of constituted an important victory for effects. This can be done by giving the most commonly used TB drugs, Indian civil society, as this was the one tablet of a double FDC and one rifampicin, requiring a patient to first patent application related to a tablet of a triple FDC once a day. HIV medicine to have been rejected switch to EFV during the course With the increased prevalence of as a result of a pre-grant opposition of TB treatment. TB/HIV co-infection, there is a process, in accordance with the need for further studies into the The price of NVP has decreased 2005 Indian Patents Act.219 dramatically over the past years as interactions between NVP and the a result of generic competition. In 2008, BI filed a PCT application 220 TB drugs rifampicin and rifabutin for an extended release formulation in children.199 For this reason, it is An extended release formulation of of NVP – in India the same application critical to have EFV studied for use NVP was approved by the US FDA was published in 2010.221 This in children below three years of age. in March 2011, shortly after the application relates to the once a patent expiry of NVP worldwide.218 An oral suspension is available. As day dosing of NVP. While it offers once a day dosing, of May 2011, two generic sources a lead in dose of 200mg once daily In African countries, low-income were quality-assured by either US is still required for the first 14 days countries and least-developed FDA or WHO prequalification. One for patients newly started on NVP. countries BI has a non-assert generic source of NVP 50mg tablet It will remain as a stand-alone tablet policy for its patents, which is quality-assured by US FDA. due to the specific slow release overcomes some of the barriers to The WHO Paediatric Antiretroviral property in this formulation. generic competition, but only for Working Group suggests a new the countries concerned. Many Patents formulation of NVP 20mg scored developing countries in Asia, Latin Boehringer Ingelheim obtained tablet be developed for the new America and the Caribbean are the basic patent on NVP in several WHO PMTCT guidelines for infant excluded from the policy. developing countries, but no patent prophylaxis.22 could be obtained in countries such Paediatrics Generic manufacturers have as India, Brazil, China or Thailand, NVP is approved for use and is been developing triple fixed-dose which were not granting patents widely used in children. In 2010, combinations including NVP, and on medicines at the time. Many WHO issued updated guidelines as of May 2011, three paediatric developing countries, where NVP for antiretroviral use in paediatric is under patent, import generic triple FDCs that include NVP were HIV infection. These guidelines versions of NVP by making use of quality-assured by either US FDA recommend that children under TRIPS flexibilities. The basic patent or WHO prequalification. All are three be given two NRTIs plus expired in many countries in 2010. produced by generic companies. nevirapine (to be replaced with However, after India introduced lopinavir/ritonavir in case of patent protection for pharmaceutical peripartum nevirapin exposure); for products in 2005, BI applied for a children > 3 years the recommended patent on the hemihydrate form of regime is two NRTIs plus efavirenz NVP, which relates to the paediatric (or lopinavir/ritonavir).
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 39 )
RAL RALTEGRAVIR ( RAL )
GENERAL INFORMATION
RALTEGRAVIR ( • Therapeutic class: Integrase inhibitor. • First approval by U.S. Food and • Patents: The basic patent was applied Drug Administration (FDA): for in October 2002 by the Institute • WHO guidelines: Listed in the WHO October 2007.23 for Research in Molecular Biology guideline as potential third-line drug.6 (IRBM), Pomezia, Italy, one of Merck’s
• WHO Model List of Essential 226 • Indication: Indicated for treatment- research sites. The patent is due to experienced adult patients who Medicines (EML): Not included in expire in 2022. In 2005, Merck and 24 have evidence of viral replication the 17th edition. IRBM applied for another patent on and HIV-1 strains resistant to • World sales of originator product: the potassium salt of RAL which can multiple antiretroviral agents.222 227 2010: US$ 1.09 billion; 2009: run up to 2025. • Originator company and product $752 million; 2008: $361 million; brand name: Merck, Isentress. 2007: $41 million.223, 224, 225
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet.
Daily dose Merck Who can access this price? See annex 2 & annex 10*
675 RAL 400mg tablet 2 (0.925)
* For the first time this year, Merck decided not to give standardised price discounts to Category 2 countries. See ‘Spotlight on access issues’ below.
40 Médecins Sans Frontières | July 2011 RALTEGRAVIR ( RALTEGRAVIR
Spotlight on access issues RAL
Raltegravir (RAL) is the first of a new There is no generic raltegravir access challenges Brazil experiences ) class of drugs integrase inhibitors, available. today will be faced by other which has a novel mechanism developing countries in coming Patents of action and no apparent cross- years, and Brazil’s actions to improve Merck and IRBM applied for resistance with other ARVs. This the accessibility and affordability of international patent applications229, 230, 231 new drug option will be very RAL and other newer medications under the Patent Cooperation Treaty important for patients who are will have wider implications for (PCT) that facilitated the filing of treatment-experienced and may all developing countries. Price these patent applications in many already be resistant to multiple reductions achieved by Brazil will set PCT member states, including some antiretroviral agents. a target price for other countries, developing countries with generic especially for other middle- and RAL, unlike most drugs from the drug manufacturing capacity, like lower middle-income countries. protease inhibitors class, does not Brazil, China, India and South Africa. require boosting with ritonavir (RTV). IRBM was granted a patent in India in The size of Brazil’s cohort is also December 2007 which will not expire critical. With approximately 4,450 In 2010, WHO released new until 2022.232 In India, an application people taking RAL, the country is one recommendations which for the on potassium salt of RAL233 is also of the largest developing country first time call for the need of third- pending review before the Indian consumers of the medicine, 82 and line therapy. Many studies are patent office and warrants a pre- could thus stimulate an international ongoing – drugs likely to have anti- grant opposition. If granted, Merck’s generic market where prices are HIV activity in third-line regimens monopoly in India will be extended reduced through competition and are RAL, etravirine (ETV), and by an additional five years to 2027. economies of scale. boosted darunavir (DRV).7 In Brazil, the Ministry of Health has In India, Merck is charging Price remains an issue. The announced that it is working on $2,500 ppy.236 lowest price offered by Merck for a technology transfer agreement some countries (see annex 10) is Paediatrics with Merck for RAL.234 In 2010, the extremely high and unaffordable The safety and efficacy of RAL in Brazilian government was paying for developing countries. In 2011, patients under 16 years of age have $5,870 ppy, a price that is expected Merck ceased offering standardised not been established.237 to decrease with the technology price discounts to all lower middle- transfer to $4,000 in 2015.235 This Paediatric studies are ongoing in and upper middle-income countries approach – which is unlikely to children from four weeks old. 238 according to the World Bank ensure that prices are reduced to As few treatment options exist Classification (see annex 6 for a list a level that is possible through for children with HIV, it is critical of these countries). The company unrestricted generic competition that paediatric studies of RAL proposes instead to negotiate – may well establish a precedent for be completed and adapted discounted prices on a case-by case accessing other newer medicines in formulations be made available. basis, based on country income and the future, both in Brazil and beyond. disease burden. This is concerning for the affordability of products in As Brazil has one of the oldest middle-income countries, especially HIV patient cohorts in developing given the extremely high prices countries, the need to access newer charged in wealthy countries, HIV medications is occurring earlier at $8,000.228 than in many other countries. The
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 41 ) Rilpivirine ( TMC 278 ) TMC 278
(
GENERAL INFORMATION
• Therapeutic class: Non-nucleoside • Originator company and product • Janssen Pharmaceutica filed patents
ilpivirine reverse transcriptase inhibitor brand name: Tibotec (a subsidiary on rilpivirine in 2002 which are due R (NNRTI). of Johnson & Johnson), Edurant. to expire in 2022. Tibotec, one of • First approval by U.S. Food and Drug the companies that compose the • WHO guidelines: Not currently Administration (FDA): 20 May 2011.239 Janssen Pharmaceutical companies included in WHO guidelines. • WHO Model List of Essential of Johnson & Johnson, further Medicines (EML): Not included developed the drug and is now in the 17th edition.24 selling and managing it.24
Price INFORMATION Tibotec and generic companies were invited to contribute a price for this publication and communicated that they do not offer a lower price for developing countries.
Spotlight on access issues
Rilpivirine is approved for use in produced for as little as $10 warrants a pre-grant opposition to HIV-1 treatment-naïve patients per patient per year. Although prevent the extension of the patent in combination with other questions need to be surmounted monopoly by several years. antiretrovirals. concerning its lack of efficacy for In 2010, Tibotec (now a subsidiary patients starting at higher viral load The registration of rilpivirine in of Johnson & Johnson) signed and interactions with TB drugs, developing countries will be crucial voluntary licence (VL) agreements its usefulness in resource-limited for accessing the drug in the with generic producers to settings comes from its potential for developing world. However, due manufacture, market and distribute use in long-acting formulations, and to the complexities of use at the rilpivirine and its fixed-dose its potential low price. approved dose and interactions combination with other ARVs.
240 with TB drugs, it is uncertain to However patents and patent Indian generic companies – Hetero, what extent rilpivirine will be useful applications filed by two companies Emcure and Matrix – who signed for resource-limited settings. – Janssen Pharmaceutica and Tibotec – the VL can manufacture and sell in India and to the countries listed Indeed, the approved dose of 25 mg are preventing generic production. in the VL (sub-Saharan Africa, once a day comes with a heightened Janssen Pharmaceutica applied for Afghanistan, Bangladesh, Bhutan, risk of virological failure when starting a basic patent on rilpivirine in 2003 Cambodia, Haiti, Kiribati, Laos, therapy for patients with high viral 244, 245 in PCT, which was granted in Maldives, Myanmar, Nepal, Samoa, loads ( >100,000 copies/ml ). TMC Africa246 and countries like South Solomon Islands Timor-Leste, 278 is also less robust compared to Africa,247 China248 and India249 and Tuvalu, Vanuatu, and Yemen). efavirenz. More research is needed to is under review in countries like Aspen will have rights to market determine the safety and efficacy of Brazil.250 In addition, Tibotec applied the product in sub-Saharan Africa higher doses.241 for a patent in PCT 251 that covers including South Africa.242, 243 Patents the combinations of rilpivirine/ But the benefits will not be felt Without patent barriers blocking 3TC/TDF and rilpivirine/FTC/TDF. in Latin America, Central Asia generic manufacture in developing This application is now pending and most Caribbean and South countries, rilpivirine could be review in Brazil 252 and India253 and Continued above right
42 Médecins Sans Frontières | July 2011 R ilpivirine (
TMC 278 TMC Continued from below left
East Asian countries as they are Other conditions of the VL that impact As few treatment options exist
ineligible to receive generic versions the price or availability of rilpivirine for children with HIV, it is critical ) of the medicine under Tibotec’s can only be analysed once the terms that paediatric studies of rilpivirine agreement.254 Among the middle- of the VL are made public. be completed and adapted income countries with significant formulations be made available. Paediatrics disease burden, besides India only The safety and efficacy of rilpivirine South Africa can be supplied with in paediatric patients have not been the generic version. established. Studies are ongoing Given these restrictive licensing from 12 years old.255 policies, these countries may not be able to import generic versions from Indian companies, even if they override patents in their countries through compulsory licences.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 43 )
RTV Ritonavir ( r or RTV ) or
r
(
GENERAL INFORMATION
• Therapeutic class: Protease inhibitor (PI). • WHO Model List of Essential • Patents: The basic patent was applied itonavir 257 R Medicines (EML): Included in for by Abbott in 1993. Subsequently, • WHO guidelines: Indicated for the 17th edition.24 Abbott applied for patents related to second-line as a booster, for adults, 171, 258 6, 22 polymorphic forms of RTV and adolescents and children. • World sales of originator product: 2004: to a soft-gel capsule formulation.259 US$ 194 million; 2003: $93 million; • Originator company and product These are due to expire respectively 2002: $122 million.256 After 2004, brand name: Abbott, Norvir. in 2019 and 2020. there are no sales figures listed in the • First approval by U.S. Food and Drug company’s annual report. Administration (FDA): March 1996 for the oral solution and June 1999 for capsules.23
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one capsule / tablet / ml of oral solution. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily dose Abbott Matrix (CF)
Category 1 Category 2 countries countries
Who can access this price? See annex 2 & annex 8 See annex 2
RTV 80mg/ml oral solution - (0.093/ml)
RTV 100mg soft-gel capsule 83 2* (non heat-stable) (0.114)
83 183 RTV 100mg tablet (heat-stable) 2* (0.114) (0.250)
* Dosing frequency depending on which drug ritonavir is used with as a booster. (CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
700
600 584 500
Evolution of the lowest price quoted 400 for eligible developing countries 323 since 2001: 300 200 180 183 As of May 2011, one generic source of RTV 83 100mg heat-stable tablet was quality-assured by 100 WHO prequalification. Its price is shown here. 83 83 0 Dec Jun 10 11
44 Médecins Sans Frontières | July 2011 R itonavir (
r
Spotlight on access issues or RTV
Ritonavir (RTV) is of crucial importance Patents for Cipla, to manufacture, offer
for the scaling-up and management The basic patent on RTV could for sale, sell, use or import RTV, ) of second-line treatment, as all not be applied for in India as the or compositions including RTV, protease inhibitors (PI) (with the country did not grant patents on for public non-commercial use, exception of nelfinavir (NFV)), medicines at the time. Nevertheless, against the payment of royalties to must be boosted with this drug. Abbott has filed a number of Abbott, until the patent expiration patent applications and divisional date in 2014.264 The compulsory Abbott developed a heat-stable applications on new forms of RTV licence followed a decree by fixed-dose combination of lopinavir that are pending before the Indian President Rafael Correa in October and RTV (LPV/r) that was approved patent office.174, 175, 176, 177 A pre-grant 2009, declaring access to essential in the U.S. in 2005. However, it opposition to an application related medicines to be in the public took until early 2010 – 12 years to a polymorph of RTV 260, 261 was interest of the population and after its RTV soft-gel capsule first filed by civil society organisations allowing the national intellectual received regulatory approval – for 180 property office to issue compulsory Abbott to receive U.S. FDA and in India in September 2006. The licences to this end, based on EMA approval for a heat-stable outcome of this opposition will Article 31 of the TRIPS Agreement.265 stand-alone RTV 100mg tablet. be crucial to the management of PI-based second-line treatment According to the Ministry of Health, The market authorisation of a throughout the developing world. the compulsory licence already has heat-stable version of ritonavir as yielded savings of $150,000. a separate pill finally put an end Abbott abandoned a 2001 patent to the stranglehold by Abbott on application including its divisionals Paediatrics 262 the treatment options available to on the RTV crystalline polymorph. RTV is approved for use in children people living with HIV/AIDS. As a However, another relating to from one month of age.266 result of Abbott’s inaction, many the RTV stable polymorph is still A liquid formulation is available. people living with HIV have been pending before the Indian patent However, the solution has a bitter deprived of additional, improved office and warrants a pre-grant aftertaste and contains 43% and vital treatment options for opposition to safeguard generic alcohol, and hence is not adapted many years. It also brought to an production. for children. This limits the use end the medical double standards Patents related to polymorphic of all protease inhibitors which the company has promoted by forms of RTV have also been filed require boosting with RTV and do failing to prioritise the development in other middle-income countries not come in a paediatric fixed-dose of safer versions of its medicines. such as China and Brazil where they combination. The registration of this new are pending. In Brazil, RTV is locally The Paediatric Antiretroviral formulation in developing countries produced, as the basic patent is Working Group of WHO considers will be crucial to allow the use of being opposed by Brazilian generic the development of a RTV 50mg other PIs than LPV. manufacturers in the courts. heat-stable sprinkle or tablet to For the first time, a generic heat- In April 2010, Ecuador issued its be a high priority.22 stable RTV 100 mg tablet was WHO first compulsory licence allowing prequalified in December 2010. Eskegroup SA, the local distributor
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 45 )
SQV SAQUINAVIR ( SQV ) (
GENERAL INFORMATION aquinavir S • Therapeutic class: Protease inhibitor (PI). • First approval by U.S. Food and Drug • Patents: The basic patent was Administration (FDA): December 1995.23 applied for by Roche in 1990267 and • WHO guidelines: Not currently should have expired in countries not included in WHO guidelines. • WHO Model List of Essential Medicines (EML): Included in the granting patent extensions. A patent • Originator company and product 17th edition.24 related to oral dosage form was brand name: Roche, Invirase. applied by Roche in 2004 and is due • World sales of originator product: to expire in 2024.268 There are no sales figures listed in the company’s annual report. Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one capsule / tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Roche * The dose of SQV must be Daily dose Category 1 Category 2 boosted with RTV 100mg countries countries twice a day. Who can access this price? See annex 2
1566 3132 SQV 200mg hard capsule 10* (0.429) (0.858)
1435 3130 SQV 500mg tablet 4* (0.983) (2.144)
Spotlight on access issues
In 2010, WHO recommendations A generic heat-stable RTV is now Patents for second-line therapy included available and was WHO prequalified The basic patent was rejected in two ‘preferred’ protease inhibitors in late 2010. Brazil where this medicine is locally (PI), to be taken in combination produced. It was however granted in SQV/r appears to be slightly less with two NRTIs. They are atazanavir potent than other boosted PIs and in many other countries including China, (ATV) boosted with ritonavir (RTV) the original formulation has a high South Africa and OAPI countries. and lopinavir/ ritonavir (LPV/r). As pill count (10 capsules).159 In 2004, saquinavir (SQV) was not identified Patents related to the oral dosage Roche marketed a 500 mg tablet of form are pending in Brazil and as one of the priority products, SQV in the U.S. that reduced the pill China and have been granted its use in the developing world count from 10 tablets to four. While 7 in South Africa. will be limited. this new formulation should improve
269, 270, 271 SQV, like all PIs (with the exception adherence, it is only registered and In India, three patents on of nelfinavir (NFV)), requires boosting marketed in selected developing improved compositions and SQV countries. with ritonavir (RTV). Abbott’s heat- mesylate have been granted, stable ritonavir received marketing As with other protease inhibitors, blocking generic production till 2024. approval in the U.S. and Europe in the high price of SQV continues Paediatrics early 2010. Registering this new to be a barrier. Solid competition SQV has not been approved for formulation in developing countries and economies of scale among use in children in the US. will be crucial in order to allow producers are minimal, as its use the use of other PIs than lopinavir. is fairly limited. No paediatric is formulation available.
46 Médecins Sans Frontières | July 2011 S STAVUDINE ( d4T ) tavudine (
d GENERAL INFORMATION 4T
)
• Therapeutic class: Nucleoside reverse • WHO Model List of Essential Medicines December 1987, mostly in developed transcriptase inhibitor (NRTI). (EML): Included in the 17th edition.24 countries, for the use of d4T to treat patients infected with retroviruses.274 • WHO guidelines: Indicated for first-line • World sales of originator product: 2006: Patent protection was extended until for children. WHO 2009 guidelines also US$ 155 million; 2005: $216 million; the end of 2008 in the U.S. and until recommended to move away from d4T 2004: $272 million; 2003: $354 million. 2011 in most European countries. first-line in adults and adolescents.6, 22 After 2006, there are no sales figures BMS markets d4T under a marketing WHO updated the 2006 guidelines 48, 100 listed in the company’s annual report. and distribution licence from Yale to recommend a reduction in dose of University. Patents should have d4T 40mg to d4T 30mg for all weight • Patents: d4T was the result of U.S. expired in most other countries categories of patients.272 public sector research. It was originally synthesised by the Michigan Cancer at this point. • Originator company and product Foundation in 1966 under a grant brand name: Bristol-Myers Squibb from the National Cancer Institute.273 (BMS), Zerit. Researchers from Yale University • First approval by U.S. Food and Drug then discovered its antiretroviral Administration (FDA): December 1994.23 activity and applied for a patent in
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one capsule/ml of oral solution. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
BMS Daily Aspen Aurobindo (CF) Cipla Hetero Ranbaxy Strides dose Category 1 Category 2 countries countries Who can access See annex 2 & annex 7 See annex 2 this price? d4T 1mg/ml 58 58 51 powder for 20 ml (0.008/ml) (0.008/ml) (0.007/ml) oral solution d4T 15mg - (0.083) (0.118) (0.027) (0.024) (0.025) capsule d4T 20mg - (0.094) (0.118) (0.031) (0.025) (0.028) capsule d4T 30mg 48 86 20 21 24 22 2 capsule (0.066) (0.118) (0.027) (0.029) (0.033) (0.030)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 47 )
4T d
( Stavudine ( d4T ) continued
Evolution of the lowest price quoted for developing countries since 2003:
tavudine As of May 2011, seven generic sources of d4T S 30mg capsule were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
The first generic source of d4T 30mg capsule was quality-assured by WHO prequalification in June 2005 – the generic price in the graph above corresponds to the lowest generic price until that date, and to the lowest quality-assured generic price from that date on. Jun 11
Spotlight on access issues
In 2010, WHO released new commercial activities by the end therapy for HIV in infants and recommendations for of 2009, including deregistration children, WHO recommends d4T as antiretroviral therapy for HIV in of all BMS products.276 BMS also one of the possible NRTIs to be given adults and adolescents. These new discontinued the marketing of with 3TC and either an NNRTI or a PI recommendations advise countries d4T products in South Africa in in the first-line.22 to phase out stavudine- (d4T) December 2010. Because of the long-term risks of based regimens because of their Patents toxicity, particularly lipoatrophy in long-term irreversible side effects Yale University did not apply for patents children treated with d4T-containing and to move towards zidovudine- in most developing countries except regimens, the use of AZT is preferred. (AZT) or tenofovir- (TDF) based for South Africa. Generic manufacturers Toxicity risks are also associated first-line regimens. from countries with manufacturing with AZT, with possible anaemia For many years, the regimen capacity, such as Brazil, China, India developing over the first few months containing d4T has played a crucial or Thailand could therefore legally of therapy, but the drug remains role in ART scale-up in resource-limited manufacture and export affordable much better tolerated than d4T.22 settings, due to its availability in a generic versions of d4T. WHO guidelines recommend a fixed-dose combination and most preferential order of NRTIs to be In South Africa, where BMS marketed importantly its low cost. d4T remains a used in first-line regimens, with d4T under an exclusive licence from widely used ARV in first-line regimens. AZT preferred over ABC, and ABC Yale, the drug was 34 times more preferred over d4T. During the review of the marketing expensive than generic versions authorisation of this medicine available in other countries. This The paediatric formulation of in February 2011, the European prompted controversy in March d4T is not adapted for resource- Medicines Agency (EMA) decided 2001, particularly as the medicine limited settings as it is supplied as a to severely restrict its use in both had been developed with public powder that requires reconstitution adults and children, recommending funds. After pressure from researchers, with clean, safe water, and once that in view of its long-term toxicities, students, and access advocates, reconstituted, must be refrigerated. d4T be used for as short a time Yale renegotiated its licence with Generic manufacturers have however as possible and only when no BMS to allow the importation of been developing both double and appropriate alternatives8 exist. more affordable generic versions triple fixed-dose combinations of d4T to South Africa.273 In some African countries including including d4T. As of May 2011, four Ethiopia, Ghana, Kenya, Nigeria, Paediatrics d4t-containing FDCs for paediatric Tanzania and Uganda, Bristol-Myers d4T is approved for use in children.277 use were quality-assured by either Squibb (BMS) discontinued all In its 2010 guidelines for antiretroviral US FDA or WHO prequalification.
48 Médecins Sans Frontières | July 2011 T
TENOFOVIR DISOPROXIL enofovir FUMARATE ( TDF ) D isopro GENERAL INFORMATION
• Therapeutic class: Nucleotide reverse • WHO Model List of Essential countries.280 Gilead subsequently x
transcriptase inhibitor (NtRTI). Medicines (EML): Included in the applied for additional patents related il 24 281 17th edition. to tenofovir disoproxil in 1997 F
• WHO guidelines: Indicated for umarate and to the fumarate salt of tenofovir first- and second-line for adults, • World sales of originator product: 2010: disoproxil in 1998.282 These are adolescents and children.6, 22 US$ 732 million; 2009: $667 million; due to expire in 2017 and 2018, 2008: $621 million; 2007: $613 million; respectively. In addition, Gilead and • Originator company and product 2006: $689 million; 2005: $778 million; brand name: Gilead, Viread. 128, 129, 130, 131, 132, 278, 279 BMS have applied for patents on
2004: $783 million. ( fixed-dose combinations of TDF/
TDF • First approval by U.S. Food and Drug • Patents: The basic patent on tenofovir FTC and TDF/FTC/EFV which will 23 Administration (FDA): October 2001. was applied for by the Academy of not expire before 2024 and 2026
Sciences of the former Czechoslovakia respectively,120, 121 in countries ) in 1986. It has now expired in most where granted.
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Gilead Daily Aurobindo Cipla Hetero Matrix Ranbaxy Aspen Strides dose Category 1 Category 2 (CF) (CF) (CF) (CF) (CF) countries countries Who can access See annex 2 & annex 9 See annex 2 this price? 204 360 87 88 83 103 76 97 79 TDF 300mg tablet 1 (0.559) (0.986) (0.237) (0.242) (0.227) (0.283) (0.208) (0.267) (0.217)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2003:
As of May 2011, five generic sources of TDF 300mg tablet were quality-assured by US FDA and WHO prequalification. The one with the lowest price is shown here.
Since 2003, the originator price has decreased by 57%, while generic prices have dropped by 79%.
76
Jun 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 49 )
TDF
( Tenofovir Disoproxil Fumarate ( TDF ) continued
Spotlight on access issues umarate F
il In 2010, WHO released new regimens in all HIV/HBV co-infected its generic TDF – both domestically x recommendations for antiretroviral individuals needing treatment.7 and for export. therapy for HIV in adults and Patents Under the terms of the VL, Gilead and adolescents. These new Gilead has applied for patents related participating Indian manufacturers isopro recommendations advise countries to TDF in many developing countries, have divided up developing country D to phase out stavudine- (d4T) including Brazil, India and China. markets for TDF and TDF-based based regimens because of their fixed-dose combinations, whereby long-term irreversible side effects Thanks to generic production the generic manufacturers like and to move towards zidovudine- that started in India in 2005 and Matrix could only export to a limited (AZT) or tenofovir- (TDF) based to the patent oppositions filed by enofovir civil society groups in 2006283 and pre-defined list of countries, against
T first-line regimens. 139 2007284 to safeguard production, the payment of a 5% royalty. For many years, the regimen the price of TDF fell dramatically The VLs also include geographic containing d4T has played a between 2005 and 2010. In a major market limitations. Participating crucial role in ART scale-up in victory for access to medicines, manufacturers are unable to supply resource-limited settings, due the Indian patent office rejected countries such as Brazil, Sri Lanka and to its availability in a fixed-dose in September 2009 several patent China, leaving these countries unable combination and most importantly applications, relating to the pro- to benefit from competitive prices its low cost. d4T remains a widely drug,285 the fumarate form286 and the or to improve access. Following 287 used ARV in first-line regimens. intermediate, and the use of TDF negotiations with Gilead, Brazil is in combination with FTC and EFV. today paying $715 ppy for TDF. This It is time for countries to invest The patents were rejected on the is over nine times the best available in a more robust, TDF-containing grounds that they lack an inventive generic price.76 first-line regimen, such as TDF/3TC/ step – they do not meet the EFV or TDF/FTC/EFV, which is one requirement of enhanced efficacy In Brazil, civil society groups filed pill, once a day or TDF/3TC + NVP stipulated under Section 3(d) of an opposition contesting Gilead’s (available in co-pack). While the India’s patent law.285, 286, 287 Further, patent application for TDF in 292 price today is still higher than a d4T- combinations of known molecules December 2006. In April 2008, based regimen, there is a need to are not patentable under Indian the government declared TDF as 288 generate greater demand which will, patent law. a medicine of public interest for priority examination purposes, and in turn, increase the competition Nevertheless, divisional applications in September 2008, the Brazilian and the economies of scale needed have already been filed by Gilead 7 patent office published the patent to further decrease prices. for key applications covering pro- rejection. However, in January 2010, drug289 and fumarate salt290 and the TDF is also used in second-line Gilead launched a legal challenge combinations of TDF with FTC, treatment as the NRTI backbone – in EFV and LPV/r.290, 291 These warrant against the patent office’s decision combination with either lamivudine additional pre-grant oppositions. to reject the patent. Gilead also (3TC) or emtricitabine (FTC), to requested a divisional patent, which a boosted protease inhibitor In 2006, while the oppositions by which was opposed by civil society (PI) should be added – if d4T or AZT members of Indian and Brazilian civil groups,293 and in another victory have been used in first-line treatment. society to the patent applications for access to medicines, rejected in were still pending, Gilead signed May 2011.294 TDF is also active against the voluntary licensing (VL) agreements hepatitis B virus (HBV) and with key generic manufacturers in In February 2011, the Brazilian therefore plays an important role India and one in South Africa. One government announced the beginning in co-infected patients. The latest generic manufacturer – Cipla – did of local production of TDF through a WHO 2010 guidelines recommend not accept the VL and instead opted partnership between Brazilian public using TDF with either FTC- or to file patent oppositions to protect and private manufacturers.295 3TC-containing antiretroviral the manufacture and availability of Continued above right
50 Médecins Sans Frontières | July 2011 T enofovir D isopro Continued from below left
The access challenges Brazil Paediatrics regimens are also the preferred x
experiences today will be faced by In March 2010, TDF was approved option for adults. il
other developing countries in coming by US FDA for use in adolescents F
In March 2009, US FDA granted umarate years, and Brazil’s actions to improve older than 12 years old and TDF an Orphan Drug designation the accessibility and affordability of weighing more than 35kg.297 147 for treatment of paediatric HIV TDF and other newer medications Gilead’s Phase II trial involving infections.298 Gilead is now entitled to will have wider implications for children (aged between two and seven years of marketing exclusivity all developing countries. Price 12 years), using an oral powder reductions achieved by Brazil will set for the designated paediatric (
formulation is still on-going. TDF a target price for other countries, Such data, provided appropriate indication, tax credits for clinical especially for other middle- and research and can apply for grants
formulations are developed, will ) 299 lower middle-income countries. be crucial to address the urgent to defray the cost of clinical trials. The size of Brazil’s cohort is also needs of this paediatric population. critical. With approximately 64,000 Having safety and efficacy data in people taking TDF,147 the country paediatric populations would enable could stimulate an international children to stay longer on the same generic market where prices are treatment regimen, and would reduced through competition and facilitate harmonisation with adult economies of scale. regimens, as TDF-based first-line
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 51 )
TPV TIPRANAVIR ( TPV ) (
GENERAL INFORMATION ipranavir T • Therapeutic class: Protease inhibitor (PI).5 • First approval by U.S. Food and Drug • Patents: The basic patent was applied Administration (FDA): June 2005.23 for by Upjohn in May 1995,301 and • WHO guidelines: Not currently is due to expire in 2015. In 1998, included in WHO guidelines. TPV is • WHO Model List of Essential Pharmacia & Upjohn applied indicated for combination treatment Medicines (EML): Not included in of HIV-1 infected adult patients for additional patents related to the 17th edition.24 who are treatment-experienced and pharmaceutical formulations suitable infected with HIV-1 strains resistant to • World sales of originator product: for the oral administration of TPV.302, 303 300 more than one protease inhibitor. There are no sales figures listed in In January 2000, BI acquired • Originator company and product the company’s annual report. worldwide rights for TPV. brand name: Boehringer Ingelheim (BI), Aptivus.
Price INFORMATION Boehringer Ingelheim was invited to contribute a price for this publication and has communicated it does not offer a reduced price for developing countries.
Spotlight on access issues
In 2010, WHO recommendations Boehringer Ingelheim has considerable civil society pressure, for second-line therapy included communicated that TPV is available the registration was eventually two ‘preferred’ protease inhibitors through its Compassionate Use filed with ANVISA at the end of (PI), to be taken in combination Program and that the company February 2008, almost three years with two NRTIs. They are atazanavir is currently filing for registration after US FDA and EMA approvals. (ATV) boosted with ritonavir (RTV) in various countries. The intervention by Brazilian civil and lopinavir / ritonavir (LPV/r). As Patents society was partly based in response tipranavir (TPV) was not identified TPV patents have been filed to suspicions that Boehringer as one of the priority products, widely in developing countries Ingelheim did not want to register its use in the developing world with generic production capacity, the product in the country, unless will be limited.7 such as Brazil and China.38 they had the guarantee that the TPV, like all PIs (with the exception patent would be granted by the In Brazil, where the patent of nelfinavir (NFV)), requires boosting patent office.305, 306, 307 applications are under review, the with RTV. Abbott’s heat-stable drug regulatory agency (ANVISA), Paediatrics ritonavir received marketing which has to give ‘prior consent’ for TPV is currently approved for use approval in the U.S. and Europe any patent application related to a in children from two years of age in early 2010. Registering this new medicine, advised for the rejection 23 formulation in developing countries and older. of the basic patent application.304 will be crucial in order to allow In early 2007, civil society expressed A paediatric oral solution exists. the use of other PIs than lopinavir. concerns over the delays to the However, TPV must be given A generic heat-stable RTV is now registration procedure of TPV in with a RTV booster, but the RTV available and was WHO prequalified Brazil – the medicine had been solution currently available has a in late 2010. tested in Brazilian patients in bitter aftertaste and contains 43% One further limitation concerning 14 research centres since February alcohol, and is thus not adapted for TPV is that the capsules require 2004, but the drug was not actually children, limiting the use of TPV refrigeration until dispensing. registered in the country. After in this population.
52 Médecins Sans Frontières | July 2011 Z ZIDOVUDINE ( AZT or ZDV ) idovudine (
AZT AZT GENERAL INFORMATION or • Therapeutic class: Nucleoside reverse • First approval by U.S. Food and Drug • Patents: AZT was first discovered in ZDV transcriptase inhibitor (NRTI). Administration (FDA): March 1987.23 1964 as an anti-cancer medicine. The U.S. National Institutes of Health
• WHO guidelines: Indicated for • WHO Model List of Essential ) funded the majority of the research first- and second-line for adults, Medicines (EML): Included in the that showed the drug’s effectiveness adolescents and children.6, 22 17th edition.24 as an antiretroviral. Glaxo Wellcome • Originator company and product • World sales of originator product: 2005: filed patents on AZT for the treatment brand name: GlaxoSmithKline (GSK), US$ 84 million; 2004: $80 million. of AIDS and brought the drug onto Retrovir. In April 2009, Pfizer and After 2005, there are no sales figures the market in 1987 as one of the most GSK jointly announced the creation for this product listed in the expensive ever sold. Patents have of ViiV, a new joint venture company’s annual report.26, 27 expired in most countries at this point. focusing solely on the R&D and commercialisation of HIV medicines.
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet / capsule / ml of oral solution. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily ViiV Aspen Aurobindo (CF) Cipla (CF) Hetero (CF) Matrix (CF) Micro Labs (CF) Ranbaxy dose
Who can access See annex 2 this price?
AZT 10mg/ml 380 88 66 110 73 20 ml oral solution (0.052/ml) (0.012/ml) (0.009/ml) (0.015/ml) (0.010/ml)
AZT 60mg 115 4 tablet (0.079)
AZT 100mg - (0.185) (0.048) (0.055) capsule
AZT 250mg - (0.301) tablet
AZT 300mg 301 99 88 91 100 88 91 91 2 tablet (0.412) (0.136) (0.121) (0.125) (0.137) (0.121) (0.125) (0.125)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 53 )
ZDV Zidovudine ( AZT or ZDV ) continued or
Evolution of the lowest price quoted AZT for developing countries since 2001: ( As of May 2011, seven generic sources of AZT 300mg tablet were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here. idovudine
Z The originator price increased for the first time this year by 87% compared to 2010, while the 301 generic price has steadily decreased by 54% since 2001. 88
Jun 11
Spotlight on access issues
In 2010, WHO released new In 2011, ViiV clarified their pricing Because of the long-term risks of recommendations for antiretroviral structure (see annex 2), confirming toxicity, particularly lipoatrophy therapy for HIV in adults that their standardised price in children treated with d4T- and adolescents. These new discounts were not in fact available containing regimens, the use of AZT recommendations advise countries to all fully-financed Global Fund or is preferred. Toxicity risks are also to phase out stavudine- (d4T) based PEPFAR programmes, contrary to associated with AZT, with possible regimens because of their long- previous announcements. Global anaemia developing over the first term irreversible side effects and Fund financed programmes in few months of therapy, but the drug remains much better tolerated to move towards zidovudine- middle-income countries have not (AZT) or tenofovir- (TDF) based than d4T.22 WHO guidelines been and will not be eligible for those first-line regimens. recommend a preferential order prices, and will have to negotiate of NRTIs to be used in first-line For many years, the regimen prices on a case-by-case basis. regimens, with AZT preferred over containing d4T has played a Patents ABC, and ABC preferred over d4T. crucial role in ART scale-up in Patents have expired in most resource-limited settings, due As of April 2011, there is one countries at this point. to its availability in a fixed-dose generic version of AZT 60mg combination and most importantly Paediatrics quality-assured by US FDA. its low cost. d4T remains a widely AZT is approved for use and is Generic manufacturers have also used ARV in first-line regimens. 307 widely used in children. In its 2010 been developing both double AZT is also used in second-line guidelines for antiretroviral therapy and triple paediatric fixed-dose treatment as the NRTI backbone for HIV in infants and children, WHO combinations including AZT. – in combination with either recommends AZT as the preferred As of May 2011, four paediatric lamivudine (3TC) or emtricitabine NRTI to be given with 3TC and FDCs containing AZT were (FTC), to which a boosted protease either an NNRTI or a PI in the first- quality-assured by either US FDA inhibitor (PI) should be added – line. AZT can also be part of second- or WHO prequalification. if d4T or AZT have been used line regimens, depending on what in first-line treatment. has been used as a first-line.22
54 Médecins Sans Frontières | July 2011 A
abacavir/ bacavir lamivudine ( ABC/3TC ) /L amivudine GENERAL INFORMATION
• Therapeutic class: Two NRTI in a • First approval by U.S. Food and Drug • World sales of originator product: 2010: double fixed-dose combination. Administration (FDA): August 2004.23 US$ 899 million; 2009: $834 million;
2008: $721 million; 2007: $641 million; (
• WHO guidelines: Indicated for ABC/3TC • WHO Model List of Essential Medicines 2006: $475 million; 2005: first- and second-line for children (EML): Individual medicines included $233 million.163, 25, 27, 28, 29, 30 and as part of triple NRTI drugs in the 17th edition. The WHO Expert under specific conditions in adults, Committee on the Selection and Use • Patents: Most patents on abacavir 6, 22 adolescents and children. of Essential Medicines recommends (ABC) or lamivudine (3TC) also affect
this combination. In addition, GSK ) • Originator company and product brand and endorses the use of fixed-dose applied for patents more specifically name: GlaxoSmithKline (GSK), Kivexa combinations and the development related to the combination.308 The (EU), Epzicom (U.S.). In April 2009, of appropriate new fixed-dose patent expiry dates related to this Pfizer and GSK jointly announced the combinations.24 combination are 2016 in the U.S. creation of ViiV, a new joint venture and 2019 in EU.30 focusing solely on the R&D and commercialisation of HIV medicines.
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily ViiV Aurobindo (CF) Matrix (CF) dose Who can access this price? See annex 2 175 292 ABC/3TC 60/30mg tablet 4 (0.120) (0.200) 388 112 280 ABC/3TC 600/300mg tablet 1 (1.064) (0.308) (0.767)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2006:
As of May 2011, two generic source of ABC/3TC 600/300mg tablet were quality-assured by US FDA or WHO prequalification. The lowest price is shown here.
Since 2006, the originator price has decreased 388 by 43%, while generic prices have dropped by 56%.
112
Dec 10 Jun 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 55 )
Abacavir/Lamivudine ( ABC/3TC ) continued ABC/3TC
(
Spotlight on access issues
This combination is likely to fall the time. This allowed Indian drug Observational Database (TApHOD) out of favour since the latest 2010 manufacturers to develop generic found that ABC was more difficult to amivudine WHO guidelines for adults and versions of each medicine, and of access in Asia and that its relatively /L adolescents recommend treatment the combination of the two. high cost could act as a deterrent to consisting of either AZT or TDF. It wider use.41 This applies particularly However, GSK widely applied remains an important combination in countries where ABC is patented for patents in other developing for the treatment of paediatric and where the generic ABC/3TC bacavir countries where possible. A HIV, however. 60/30mg tablet is not available. Paediatrics In 2011, ViiV clarified their pricing For children who need this structure (see annex 2), confirming In its 2010 guidelines for combination, two generic sources that their standardised price antiretroviral therapy for HIV of ABC/3TC 60/30mg are quality- discounts were not in fact available in infants and children, WHO assured by either US FDA or WHO to all fully-financed Global Fund or recommends ABC/3TC as one of prequalification. However, in PEPFAR programmes, contrary to the possible combinations to be countries where ABC is patented, previous announcements. Global given with either an NNRTI or a PI the generic tablet is not available, Fund financed programmes in in the first-line. ABC/3TC can also and ViiV does not produce a fixed- middle-income countries have not be part of second-line regimens, dose combination of these drugs been and will not be eligible for those depending on what has been used for children – even though the prices, and will have to negotiate as a first-line. WHO guidelines FDCs exist for adults. prices on a case-by-case basis. recommend a preferential order of NRTIs to be used in first-line The Paediatric Antiretroviral In February 2011, Shionogi-ViiV regimens, with AZT preferred over Working Group of WHO considers Healthcare announced the start ABC, and ABC preferred over d4T.22 the development of a scored adult of a phase III trial for a new fixed- fixed-dose combination of ABC/ dose combination including ABC, ABC will nevertheless continue to 3TC 300/150mg tablet, for use lamivudine (3TC)36 and a new be an important drug for HIV/TB in children weighing over 25kg, integrase inhibitor S/GSK1349572 co-infected young children, not to be a high priority.22 (an investigational drug known least because children have limited The Working Group also considers as dolutegravir, now in phase III treatment options – there are the development of a triple fixed- clinical development).37 interactions between TB drugs and dose combination of ABC/3TC/NVP nevirapine (NVP), and the dosage Patents 60/30/50mg tablet to be a high data on efavirenz (EFV) for children GlaxoSmithKline could not apply for priority.22 This formulation does not under three is lacking. basic patents related to ABC or 3TC exist yet although it is needed to in some developing countries such However, a recent survey regarding simplify first-line treatment. as India that did not grant patents paediatric second-line carried out on pharmaceutical products at by the TREAT Asia Paediatric HIV
56 Médecins Sans Frontières | July 2011 L
lamivudine/ amivudine stavudine ( 3TC/d4T ) /S
GENERAL INFORMATION tavudine
• Therapeutic class: Two NRTI in a • Originator company and product brand and endorses the use of fixed-dose double fixed-dose combination. name: No originator product exists. combinations and the development of appropriate new fixed-dose ( • WHO guidelines: Indicated for first-line • First approval by U.S. Food and Drug 24
combinations. 3TC/ in children WHO 2009 guidelines also Administration (FDA): not applicable. recommended to move away from d4T • Patents: Individual patents on 6, 22 • WHO Model List of Essential Medicines first-line in adults and adolescents. lamivudine (3TC) or stavudine (d4T) d WHO updated the 2006 guidelines (EML): Individual medicines included also affect this combination. 4T
to recommend a reduction in dose of in the 17th edition. The WHO Expert ) d4T 40mg to d4T 30mg for all weight Committee on the Selection and Use categories of patients.272 of Essential Medicines recommends
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily Cipla (CF) Hetero (CF) Matrix Ranbaxy (CF) Strides dose
Who can access this price? See annex 2
47 3TC/d4T 30/6mg dispersible tablet 4 (0.032) 40 3TC/d4T 60/12mg dispersible tablet 2 (0.055) 42 46 39 42 41 3TC/d4T 150/30mg tablet 2 (0.058) (0.063) (0.054) (0.058) (0.056)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2003:
As of May 2011, seven generic sources of 3TC/ d4T 150/30mg tablet were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here. 128
As there is no originator fixed-dose combination or co-pack, the price shown for the originator product is the sum of the two individual originator products. 39 Since 2003, the sum of the originator prices has decreased by 30%, while generic prices have Dec Jun dropped by 69%. 10 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 57 )
4T d Lamivudine/Stavudine ( 3TC/d4T ) continued 3TC/
(
Spotlight on access issues
In 2010, WHO released new (available in co-pack). While the AZT/3TC/NVP). With both of these tavudine recommendations for antiretroviral price today is still higher than a d4T- regimens, there is a need to start /S therapy for HIV in adults based regimen, there is a need to NVP at a lower dose for the first two and adolescents. These new generate greater demand which will, weeks to minimise the side effects. recommendations advise countries in turn, increase the competition Quality-assured double fixed-dose to phase out d4T-based regimens and the economies of scale needed combinations are therefore of because of their long-term irreversible to further decrease prices.7 great value in allowing children
amivudine side effects and to move towards to be safely and accurately dosed L We can therefore expect to see zidovudine- (AZT) or tenofovir-based while starting treatment. In their a decrease in the use of this (TDF) first-line regimens.7 absence, the alternative is to use formulation in the future. two different syrups, which can be For many years, the stavudine- Patents difficult to administer. (d4T) containing regimen played Generic companies in certain a crucial role in ART scale-up in Because of the long-term risks of developing countries were able resource-limited settings, due toxicity, particularly lipoatrophy to develop these fixed-dose to its availability in a fixed-dose in children treated with d4T- combinations because patents on combination and, most importantly, containing regimens, the use of AZT the individual products did not exist. its low cost. d4T remains a widely is preferred. Toxicity risks are also used ARV in first-line regimens. The fixed-dose combination is not associated with AZT, with possible available in developed countries anaemia developing over the first During the review of the marketing or in countries such as China, few months of therapy, but the authorisation of this medicine however, where one or both drug remains much better tolerated in February 2011, the European 22 medicines are under patent. than d4T. WHO guidelines Medicines Agency (EMA) decided recommend a preferential order to severely restrict its use in both Paediatrics of NRTIs to be used in first-line adults and children, recommending In its 2010 guidelines for antiretroviral regimens, with AZT preferred over that in view of its long-term therapy for HIV in infants and children, ABC, and ABC preferred over d4T. toxicities, d4T be used for as short WHO recommends 3TC/d4T as one of a time as possible and only when the possible combinations to be given As of May 2011, two generic no appropriate alternatives 8 exist. with either an NNRTI or a PI in the dispersible formulations were first-line.22 quality-assured by either US FDA It is time for countries to invest in a or WHO prequalification. more robust, TDF-containing first- 3TC/d4T, when used with NVP, line regimen, such as TDF/3TC/EFV is part of one of the two most or TDF/FTC/EFV, which are both one commonly used first-line regimens pill, once a day or TDF/3TC + NVP for children today (the other being
58 Médecins Sans Frontières | July 2011 L
lamivudine/stavudine/ amivudine nevirapine ( 3TC/d4T/NVP ) /S
GENERAL INFORMATION tavudine
• Therapeutic class: Two NRTI and • Originator company and product brand • Patents: Individual patents on one NNRTI in a triple fixed-dose name: No originator product exists. lamivudine (3TC), stavudine (d4T)
combination. or nevirapine (NVP) also affect this /N • First approval by U.S. Food and Drug combination. Cipla first developed • WHO guidelines: Indicated for first-line Administration (FDA): Not applicable. evirapine the FDC and applied for patents in for children. WHO 2009 guidelines also • WHO Model List of Essential Medicines several African countries. recommended to move away from d4T (EML): Included in the 17th edition – first-line in adults and adolescents.6, 22 only the d4T 30mg presentation.24 WHO updated the 2006 guidelines The WHO Expert Committee on
to recommend a reduction in dose of the Selection and Use of Essential (
d4T 40mg to d4T 30mg for all weight Medicines recommends and endorses 3TC/ categories of patients.272 the use of fixed-dose combinations and the development of appropriate 24 d
new fixed-dose combinations. 4T/NVP
Price INFORMATION
Developing country prices in US$ per patient per year, as quoted by companies. ) The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily dose Cipla (CF) Hetero (CF) Ranbaxy (CF) Strides Varichem
Who can access this price? See annex 2
3TC/d4T/NVP 30/6/50mg 55 4 dispersible tablet (0.038)
3TC/d4T/NVP 60/12/100mg 53 2 dispersible tablet (0.072)
3TC/d4T/NVP 150/30/200mg 64 67 70 66 61 2 tablet (0.088) (0.092) (0.096) (0.090) (0.083)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2002:
As of May 2011, ten generic sources of 3TC/ d4T/NVP 150/30/200mg tablet were quality- assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
As there is no originator fixed-dose combination 347 or co-pack, the price shown for the originator product is the sum of the three individual originator products.
Since 2002, the sum of the originator prices has 61 decreased by 44%, while generic prices have Jun dropped by 78%. 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 59 )
Lamivudine/Stavudine/Nevirapine ( 3TC/d4T/NVP ) continued 4T/NVP d 3TC/ Spotlight on access issues (
In 2010, WHO released new We can therefore expect to see However, together with AZT/3TC/ recommendations for antiretroviral a decrease in the use of this NVP, 3TC/d4T/NVP is one of the therapy for HIV in adults formulation in the future. two most commonly used first-line
evirapine and adolescents. These new regimens for children today. With Patents recommendations advise countries both of these regimens, there is a /N Cipla was able to develop this to phase out d4T-based regimens need to start NVP at a lower dose combination because none of because of their long-term irreversible for the first two weeks to minimise the individual components were side effects and to move towards the side effects, and therefore patented in India. Many generic zidovudine- (AZT) or tenofovir-based the 3TC/d4T double fixed-dose
7 manufacturers have followed suit in tavudine (TDF) first-line regimens. combinations is of great value in other developing countries, such as
/S allowing children to be safely and For many years, the stavudine- Thailand, where the medicines were accurately dosed while starting (d4T) containing regimen played not patented. treatment. In their absence, the a crucial role in ART scale-up in Extensive competition from alternative is to use two different resource-limited settings, due numerous generic manufacturers syrups, which can be difficult to to its availability in a fixed-dose has made this combination administer. amivudine combination and, most importantly, L the most affordable triple ARV its low cost. d4T remains a widely The Paediatric Working Group at combination treatment to date. used ARV in first-line regimens. WHO has released clear guidance Paediatrics on the ideal strength of each of the During the review of the marketing In its 2010 guidelines for antiretroviral individual ARVs in these fixed-dose authorisation of this medicine therapy for HIV in infants and children, combinations. in February 2011, the European WHO recommends 3TC/d4T as one of Medicines Agency (EMA) decided As of May 2011, two dispersible the possible combinations to be given to severely restrict its use in both formulations were quality-assured with either an NNRTI or a PI in the adults and children, recommending by either US FDA or WHO first-line.22 that in view of its long-term prequalification.43 toxicities, d4T be used for as short Because of the long-term risks of HIV/TB co-infected young children a time as possible and only when toxicity, particularly lipoatrophy cannot be given NVP because of no appropriate alternatives 8 exist. in children treated with d4T- interactions between NVP and TB containing regimens, the use of AZT It is time for countries to invest in a drugs. As there is still no established is preferred. Toxicity risks are also more robust, TDF-containing first- dosing of EFV, the standard associated with AZT, with possible line regimen, such as TDF/3TC/EFV alternative to NVP, for children less anaemia developing over the first or TDF/FTC/EFV, which are both one than three years of age, there is an few months of therapy, but the pill, once a day or TDF/3TC + NVP urgent need to establish the dosing drug remains much better tolerated (available in co-pack). While the of EFV for this age group. than d4T.22 WHO guidelines price today is still higher than a d4T- recommend a preferential order based regimen, there is a need to of NRTIs to be used in first-line generate greater demand which will, regimens, with AZT preferred over in turn, increase the competition ABC, and ABC preferred over d4T. and the economies of scale needed to further decrease prices.7
60 Médecins Sans Frontières | July 2011 L
lamivudine/stavudine + amivudine efavirenz ( 3TC/d4T + EFV ) /S
GENERAL INFORMATION tavudine
• Therapeutic class: Two NRTI (in a • Originator company and product brand combinations and the development fixed-dose combination) + one NNRTI name: No originator product exists. of appropriate new fixed-dose in a co-pack. combinations.24 • First approval by U.S. Food and Drug + E + • WHO guidelines: Indicated for first-line Administration (FDA): Not applicable. • Patents: Individual patents on for children. WHO 2009 guidelines also lamivudine (3TC), stavudine (d4T) favirenz • WHO Model List of Essential Medicines recommended to move away from d4T or efavirenz (EFV) also affect this 6, 22 (EML): Individual medicines included first-line in adults and adolescents. combination. WHO updated the 2006 guidelines to in the 17th edition. The WHO Expert recommend a reduction in dose of Committee on the Selection and Use
d4T 40mg to d4T 30mg for all weight of Essential Medicines recommends (
categories of patients.272 and endorses the use of fixed-dose 3TC/ d 4T + EFV + 4T
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies.
) The price in brackets corresponds to the price of one kit of 3 tablets. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily dose Ranbaxy Strides
Who can access this price? See annex 2
3TC/d4T + EFV 150/30 + 600mg 1 kit 152 106 tablets (co-pack) (3 tablets) (0.417) (0.290)
Evolution of the lowest price quoted for developing countries since 2006:
As of May 2011, one generic source of 3TC/d4T + EFV 150/30 + 600mg co-pack was quality-assured by US FDA or WHO prequalification. Its price is 365 shown here.
As there is no originator co-pack, the price shown for the originator product is the sum of the three individual originator products.
Since 2006, the sum of the originator prices 150 152 has decreased by 7%, while generic prices have 100 dropped by 45%. Jun 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 61 )
Lamivudine/Stavudine + Efavirenz ( 3TC/d4T + EFV ) continued 4T + EFV d
3TC/ Spotlight on access issues
(
In 2010, WHO released new We can therefore expect to see a As there is still no established dosing recommendations for antiretroviral decrease in the use of this formulation of EFV for children less than three therapy for HIV in adults in the future. years of age, there is an urgent need and adolescents. These new
favirenz to establish the dosing of EFV for this Patents recommendations advise countries age group for children with HIV/TB Generic companies in certain + E to phase out d4T-based regimens co-infection. because of their long-term irreversible developing countries were side effects and to move towards able to develop this co-blister In the absence of such data, treatment zidovudine- (AZT) or tenofovir-based because patents on the individual options for children remain limited, (TDF) first-line regimens.7 components contained in the particularly for HIV/TB co-infected
tavudine combination did not exist. young children who cannot be given For many years, the stavudine- /S NVP because of interactions between This product is not available in (d4T) containing regimen played NVP and TB drugs. a crucial role in ART scale-up in developed countries or in China resource-limited settings, due because of various patents on 3TC, Currently a co-pack of d4T/3TC + to its availability in a fixed-dose d4T and/or EFV. EFV for children does not exist. combination and, most importantly, Paediatrics amivudine
L its low cost. d4T remains a widely In its 2010 guidelines for antiretroviral used ARV in first-line regimens. therapy for HIV in infants and children, During the review of the marketing WHO recommends 3TC/d4T as one of authorisation of this medicine the possible combinations to be given in February 2011, the European with either an NNRTI or a PI in the Medicines Agency (EMA) decided to first-line.22 severely restrict its use in both adults Because of the long-term risks of and children, recommending that in toxicity, particularly lipoatrophy view of its long-term toxicities, d4T in children treated with d4T- be used for as short a time as possible containing regimens, the use of AZT and only when no appropriate is preferred. Toxicity risks are also alternatives8 exist. associated with AZT, with possible It is time for countries to invest in a anaemia developing over the first more robust, TDF-containing first- few months of therapy, but the drug line regimen, such as TDF/3TC/EFV remains much better tolerated than or TDF/FTC/EFV, which are both one d4T.22 WHO guidelines recommend pill, once a day or TDF/3TC + NVP a preferential order of NRTIs to be (available in co-pack). While the used in first-line regimens, with price today is still higher than a d4T- AZT preferred over ABC, and ABC based regimen, there is a need to preferred over d4T. generate greater demand which will, in turn, increase the competition and the economies of scale needed to further decrease prices.7
62 Médecins Sans Frontières | July 2011 T
tenofovir disoproxil enofovir fumarate/emtricitabine ( TDF/FTC ) D isopro GENERAL INFORMATION
• Therapeutic class: One NtRTI and • First approval by U.S. Food and Drug • World sales of originator product: 2010: x 23 one NRTI in a double fixed-dose Administration (FDA): August 2004. US$ 2.65 billion; 2009: $2.49 billion; il
combination. 2008: $2.11 billion; 2007: $1.59 billion; F
• WHO Model List of Essential Medicines umarate 2006: $1.19 billion; 2005: $568 million; • WHO guidelines: Indicated for first- (EML): Included in the 17th edition. 2004: $68 million.128, 129, 132 line and second-line for adults and The WHO Expert Committee on adolescents.6 the Selection and Use of Essential • Patents: Most patents related to Medicines recommends and endorses tenofovir (TDF) or to emtricitabine
• Originator company and product /E the use of fixed-dose combinations (FTC) also affect this combination.
brand name: Gilead, Truvada. mtricitabine and the development of appropriate In addition, Gilead applied for new fixed-dose combinations.24 patents specifically related to this combination in 2004, which are due to expire in 2024.120
Price INFORMATION (
Developing country prices in US$ per patient per year, as quoted by companies. TDF/FTC The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Gilead ) Daily Aurobindo (CF) Cipla (CF) Hetero Matrix (CF) dose Category 1 Category 2 countries countries
Who can access this price? See annex 2 & annex 9 See annex 2
315 540 140 134 164 116 TDF/FTC 300/200mg tablet 1 (0.863) (1.479) (0.383) (0.367) (0.450) (0.317)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2005:
As of May 2011, two generic sources of TDF/ FTC 300/200mg tablet were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
Since 2005, the originator price has decreased by 13%, while generic prices have dropped by 58% since 2007. 116
Jun 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 63 )
Tenofovir Disoproxil Fumarate/Emtricitabine ( TDF/FTC ) continued TDF/FTC
(
Spotlight on access issues
This combination is likely to be TDF should then be used as the Gilead’s Phase II trial involving widely used in developing countries NRTI backbone, in combination children (aged between two and as a backbone in first- and second- with either lamivudine (3TC) or 12 years), using an oral powder mtricitabine line regimens. emtricitabine (FTC), to which a formulation is still on-going. /E boosted protease inhibitor (PI) Such data, provided appropriate In 2010, WHO released new should be added. formulations are developed, will recommendations for antiretroviral be crucial to address the urgent therapy for HIV in adults TDF is also active against hepatitis B needs of this paediatric population. and adolescents. These new Virus (HBV) and therefore plays an
umarate Having safety and efficacy data recommendations advise countries important role in co-infected patients. F in paediatric populations would to phase out stavudine- (d4T) based The latest WHO 2010 guidelines il enable children to stay longer on x regimens because of their long-term recommend using TDF with either the same treatment regimen, and irreversible side effects and to move FTC- or 3TC-containing antiretroviral would facilitate harmonisation with towards zidovudine- (AZT) or tenofovir- regimens in all HIV/HBV co-infected adult regimens, as TDF-based first- (TDF) based first-line regimens. individuals needing treatment.22 isopro line regimens are also the preferred
D For many years, the regimen Patents option for adults. containing d4T played a crucial role This combination is produced However, no paediatric fixed-dose in ART scale-up in resource-limited by Indian generic companies combination has been developed settings, due to its availability in because neither of the individual combining these two medicines. a fixed-dose combination and components is patented in India
enofovir There is an urgent need to have this T most importantly its low cost. today. However, Gilead has applied combination developed for HIV and d4T remains a widely used ARV for patents related to TDF, which if hepatitis B co-infected paediatric in first-line regimens. granted will affect the production patients, for whom no treatment of not only TDF but also of this It is time for countries to invest in options currently exist. combination. a more robust, TDF-containing first- line regimen, such as TDF/3TC/EFV For further details on the patent or TDF/FTC/EFV, which are both one status of TDF in India and Brazil, pill, once a day or TDF/3TC + NVP the voluntary licences agreements (available in co-pack). While the signed by Gilead and generic price today is still higher than a d4T- companies, and the Brazilian based regimen, there is a need to initiative for local production, please generate greater demand which will, refer to the tenofovir drug profile. in turn, increase the competition Paediatrics and the economies of scale needed TDF is approved for adolescents to further decrease prices.7 from 12 years old and FTC is TDF is also recommended for approved for use in children, and second-line treatment if d4T or both medicines have the advantage AZT have been used in first-line. of once-daily dosing.
64 Médecins Sans Frontières | July 2011 tenofovir disoproxil T fumarate/emtricitabine/efavirenz enofovir (TDF/FTC/EFV) D isopro GENERAL INFORMATION
• Therapeutic class: One NtRTI + one • WHO Model List of Essential Medicines • Patents: Most patents related to x
NRTI + one NNRTI in a triple fixed- (EML): Included in the 17th edition. tenofovir (TDF), emtricitabine (FTC), il
dose combination. The WHO Expert Committee on TDF/FTC or to efavirenz (EFV) also F
the Selection and Use of Essential affect this combination. In addition, umarate • WHO guidelines: Indicated for first- Medicines recommends and endorses Gilead and BMS jointly applied line for adults and adolescents.6 the use of fixed-dose combinations for patents specifically related to • Originator companies and product and the development of appropriate this combination in 2006,121 which 24 brand name: Gilead/Bristol-Myers new fixed-dose combinations. would last until 2026. Gilead pays Squibb/Merck, Atripla. /E • World sales of originator product: royalties to BMS (and consequently Merck) for the EFV portion, originally mtricitabine • First approval by U.S. Food and Drug 2010: US$ 2.927 billion; 2009: Administration (FDA): July 2006.23 $2.382 billion; 2008: $1.572 billion; owned by Dupont Merck, which was 2007: $903 million; 2006: $164 million subsequently acquired by BMS. (the product entered the market in the third quarter of the year).128, 132 /E
Price INFORMATION favirenz Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold. (
TDF BMS / Gilead / Merck Daily Cipla Hetero Matrix (CF)
dose Category 1 Category 2 /
countries countries FTC/
Who can access this price? See annex 2 & annex 10 See annex 2
613 1033 231 243 219 EFV TDF/FTC/EFV 300/200/600mg tablet 1 (1.680) (2.830) (0.633) (0.667) (0.600)
) (CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2007:
As of May 2011, one generic source of TDF/FTC/ EFV 300/200/600mg tablet was quality-assured by US FDA or WHO prequalification. Its price is shown here.
Since 2007, the originator price has remained stable, while generic prices have dropped by 55%.
Jun 11
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 65 )
EFV
Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz ( TDF/FTC/EFV ) continued FTC/
/
TDF Spotlight on access issues (
This is a one-pill-a-day fixed-dose In addition, efavirenz (EFV) is the Such data, provided appropriate combination, which makes it preferred NNRTI for use in patients formulations are developed, will be well-adapted to resource-poor starting ART while on tuberculosis crucial to address the urgent needs
favirenz settings, although TDF/3TC/EFV treatment. of this paediatric population. Having
/E is more affordable. safety and efficacy data in paediatric Patents populations would enable children In 2010, WHO released new This combination is produced by to stay longer on the same treatment recommendations for antiretroviral Indian generic companies because regimen, and would facilitate therapy for HIV in adults none of the individual components harmonisation with adult regimens, and adolescents. These new is patented in India today. However, as TDF-based first-line regimens are recommendations advise countries 309 310 Gilead and BMS have applied also the preferred option for adults. mtricitabine to phase out stavudine- (d4T) based for patents related to TDF, including
/E regimens because of their long-term the one specifically related to this However, no paediatric fixed-dose irreversible side effects and to move combination.311 If these patents are combination has been developed towards zidovudine- (AZT) or tenofovir- granted in India, generic competition with TDF, FTC and EFV. (TDF) based first-line regimens. for this product may be affected. There is an urgent need to have this
umarate For many years, the regimen For further details on the patent combination developed for HIV and F containing d4T played a crucial role status of TDF in India and Brazil, hepatitis B co-infected paediatric il in ART scale-up in resource-limited patients, for whom no treatment x the voluntary licences agreements settings, due to its availability in signed by Gilead and generic options currently exist, as well as for a fixed-dose combination and companies, and the Brazilian HIV/TB co-infected young children most importantly its low cost. initiative for local production, who cannot be given NVP because isopro d4T remains a widely used ARV please refer to the tenofovir of interactions between NVP D in first-line regimens. drug profile. and TB drugs.
It is time for countries to invest in a Paediatrics As there is still no established dosing of EFV for children less than three more robust, TDF-containing first- TDF is approved for adolescents from line regimen, such as TDF/3TC/EFV years of age, there is an urgent need 12 years old, FTC is approved for enofovir or TDF/FTC/EFV, which are both one to establish the dosing of EFV for this
T use in children, and EFV is approved pill, once a day or TDF/3TC + NVP age group for children with HIV/TB for use in children above three years (available in co-pack). While the co-infection. old. All three medicines have the price today is still higher than a d4T- advantage of once-daily dosing. based regimen, there is a need to generate greater demand which will, Gilead’s Phase II trial involving in turn, increase the competition children (aged between two and and the economies of scale needed 12 years), using an oral powder to further decrease prices.7 formulation is still on-going.
66 Médecins Sans Frontières | July 2011 tenofovir disoproxil tenofovir fumarate/lamivudine ( TDF/3TC )
disopro GENERAL INFORMATION
• Therapeutic class: One NtRTI and • WHO Model List of Essential Medicines • Patents: Most patents related to x
one NRTI in a double fixed-dose (EML): Individual medicines included tenofovir (TDF) or to lamivudine il
combination. in the 17th edition. The WHO Expert (3TC) also affect this combination. fumarate • WHO guidelines: Indicated for first- and Committee on the Selection and Use In addition, other patents may have second-line for adults and adolescents.6 of Essential Medicines recommends been applied for, more specifically and endorses the use of fixed-dose related to the use of these medicines • Originator company and product brand combinations and the development in combination, or to this specific name: No originator product exists. of appropriate new fixed-dose FDC, such as by Cipla.312 / • First approval by U.S. Food and Drug combinations.24 lamivudine Administration (FDA): Not applicable.
Price INFORMATION (
Developing country prices in US$ per patient per year, as quoted by companies. TDF/3TC The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily dose Aurobindo (CF) Cipla (CF) Hetero (CF) Matrix (CF) )
Who can access this price? See annex 2
116 103 116 91 TDF/3TC 300/300mg tablet 1 (0.317) (0.283) (0.317) (0.250)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest quoted price for developing countries since 2006:
As of May 2011, four generic sources of TDF/3TC 300/300mg tablet were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
As there is no originator fixed-dose combination or co-pack, the price shown for the originator product is the sum of the two individual originator products. 284 Since 2006, the sum of the originator prices has increased by 3%, while generic prices have 91 dropped by 91%. The most affordable generic Jun 11 product is 68% less expensive than the sum of the originator products.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 67 )
Tenofovir Disoproxil Fumarate/Lamivudine ( TDF/3TC ) continued TDF/3TC
(
Spotlight on access issues
This combination is likely to be TDF should then be used as the Gilead’s Phase II trial involving widely used in developing countries NRTI backbone, in combination children (aged between two and
lamivudine as a backbone in first- and second- with either lamivudine (3TC) or 12 years), using an oral powder / line regimens. emtricitabine (FTC), to which a formulation is still on-going. boosted protease inhibitor (PI) Such data, provided appropriate In 2010, WHO released new should be added. formulations are developed, will recommendations for antiretroviral be crucial to address the urgent therapy for HIV in adults TDF is also active against hepatitis B needs of this paediatric population. fumarate
and adolescents. These new Virus (HBV) and therefore plays an Having safety and efficacy data il recommendations advise countries important role in co-infected patients.
x in paediatric populations would to phase out stavudine- (d4T) based The latest WHO 2010 guidelines enable children to stay longer on regimens because of their long-term recommend using TDF with either the same treatment regimen, and irreversible side effects and to move FTC- or 3TC-containing antiretroviral would facilitate harmonisation with towards zidovudine- (AZT) or tenofovir- regimens in all HIV/HBV co-infected
disopro adult regimens, as TDF-based first-
(TDF) based first-line regimens. 22 individuals needing treatment. line regimens are also the preferred For many years, the regimen Patents option for adults. containing d4T played a crucial role This combination is produced by However, no paediatric fixed-dose in ART scale-up in resource-limited Indian generic companies because combination has been developed settings, due to its availability in neither of the individual components with TDF and 3TC. tenofovir a fixed-dose combination and is patented in India today. However, most importantly its low cost. There is an urgent need to have this Gilead has applied for patents related d4T remains a widely used ARV combination developed for HIV and to TDF, which if granted will affect in first-line regimens. hepatitis B co-infected paediatric the production of not only TDF but patients, for whom no treatment It is time for countries to invest in a also of this combination. more robust, TDF-containing first- options currently exist. For further details on the patent line regimen, such as TDF/3TC/EFV The Paediatric Antiretroviral status of TDF in India and Brazil, the or TDF/FTC/EFV, which are both one Working Group of WHO considers voluntary licences agreements signed pill, once a day or TDF/3TC + NVP the development of a fixed-dose by Gilead and generic companies, (available in co-pack). While the combination of TDF/3TC 75/75mg and the Brazilian initiative for local price today is still higher than a d4T- tablet and a scored 300/300mg production, please refer to the based regimen, there is a need to tablet to be a high priority.22 generate greater demand which will, tenofovir drug profile. in turn, increase the competition Paediatrics and the economies of scale needed TDF is approved for adolescents to further decrease prices.7 from 12 years old and 3TC is TDF is also recommended for approved for use in children. Both second-line treatment if d4T or medicines have the advantage of AZT have been used in first-line. once-daily dosing.
68 Médecins Sans Frontières | July 2011 tenofovir disoproxil fumarate/ tenofovir lamivudine/efavirenz ( TDF/3TC/EFV )
disopro GENERAL INFORMATION
• Therapeutic class: One NtRTI, one • WHO Model List of Essential Medicines • Patents: Most patents related to x
NRTI and one NNRTI in a triple (EML): Individual medicines included tenofovir (TDF), lamivudine (3TC) il
fixed-dose combination. in 17th edition. The WHO Expert or to efavirenz (EFV) also affect this fumarate • WHO guidelines: Indicated for first- Committee on the Selection and Use combination. In addition, other line for adults and adolescents.6 of Essential Medicines recommends patents may have been applied for and endorses the use of fixed-dose more specifically related to the use • Originator company and product brand combinations and the development of these medicines in combination, name: No originator product exists.
of appropriate new fixed-dose or to this specific FDC. / • First approval by U.S. Food and Drug combinations.24 lamivudine Administration (FDA): Not applicable.
Price INFORMATION /
Developing country prices in US$ per patient per year, as quoted by companies. efavirenz The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily dose Cipla Matrix (CF) (
Who can access this price? See annex 2 TDF/3TC/EFV TDF/3TC/EFV 300/300/600mg 195 173 1 tablet (0.533) (0.475)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
)
Evolution of the lowest quoted price for developing countries since 2007:
As of May 2011, one generic source of TDF/ 3TC/EFV 300/300/600mg tablet was quality- 521 assured by US FDA or WHO prequalification. Its price is shown here.
As there is no originator fixed-dose combination or co-pack, the price shown for the originator product is the sum of the three individual 173 originator products.
Since 2007, the sum of the originator prices has remained practically stable, while generic prices Jun 11 have dropped by 59%.
Continued overleaf
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 69 )
Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz ( TDF/3TC/EFV ) continued TDF/3TC/EFV Spotlight on access issues (
This is a one-pill-a-day fixed-dose Patents However, no paediatric fixed-dose combination, which makes it well- This combination is produced by combination has been developed adapted to resource-poor settings, Indian generic companies because with TDF, 3TC and EFV.
efavirenz and likely to be widely used in none of the individual components
/ There is an urgent need to have this developing countries as first-line is patented in India today. However, combination developed for HIV and regimen. It is also more affordable Gilead has applied for patents hepatitis B co-infected paediatric than TDF/FTC/EFV. related to TDF, which if granted will patients, for whom no treatment affect the production of not only In 2010, WHO released new options currently exist, as well as for TDF but also of this combination. recommendations for antiretroviral HIV/TB co-infected young children
lamivudine therapy for HIV in adults and For further details on the patent who cannot be given NVP because / adolescents. These new status of TDF in India and Brazil, the of interactions between NVP and recommendations advise countries voluntary licences agreements signed TB drugs. to phase out stavudine- (d4T) based by Gilead and generic companies, As there is still no established regimens because of their long-term and the Brazilian initiative for local dosing of EFV for children less irreversible side effects and to move fumarate production, please refer to the than three years of age, there is
towards zidovudine- (AZT) or tenofovir- tenofovir drug profile.
il an urgent need to establish the
x (TDF) based first-line regimens. Paediatrics dosing of EFV for this age group for children with HIV/TB co-infection. For many years, the regimen TDF is approved for adolescents from containing d4T played a crucial role 12 years old, 3TC is approved for in ART scale-up in resource-limited use in children, and EFV is approved disopro settings, due to its availability in a for use in children above three years fixed-dose combination and most old. All three medicines have the importantly its low cost. d4T remains a advantage of once-daily dosing. widely used ARV in first-line regimens. Gilead’s Phase II trial involving It is time for countries to invest in a children (aged between two and tenofovir more robust, TDF-containing first- 12 years), using an oral powder line regimen, such as TDF/3TC/EFV formulation is still on-going. or TDF/FTC/EFV, which are both one Such data, provided appropriate pill, once a day or TDF/3TC + NVP formulations are developed, will (available in co-pack). While the be crucial to address the urgent price today is still higher than a d4T- needs of this paediatric population. based regimen, there is a need to Having safety and efficacy data generate greater demand which will, in paediatric populations would in turn, increase the competition enable children to stay longer on and the economies of scale needed the same treatment regimen, and to further decrease prices.7 would facilitate harmonisation with In addition, EFV is the preferred adult regimens, as TDF-based first- NNRTI for use in patients starting line regimens are also the preferred ART while on tuberculosis treatment. option for adults.
70 Médecins Sans Frontières | July 2011 tenofovir disoproxil fumarate/ tenofovir lamivudine/nevirapine ( TDF/3TC + NVP )
disopro GENERAL INFORMATION
• Therapeutic class: One NtRTI and • First approval by U.S. Food and Drug • Patents: Most patents related to x
one NRTI (in a double fixed-dose Administration (FDA): Not applicable. tenofovir (TDF), lamivudine (3TC) il
combination) + one NNRTI in a or to nevirapine (NVP) also affect fumarate • WHO Model List of Essential Medicines co-pack. this combination. (EML): Individual medicines included • WHO guidelines: Indicated for first- in 17th edition. The WHO Expert line for adults and adolescents.6 Committee on the Selection and Use of Essential Medicines recommends
• Originator company and product brand /
and endorses the use of fixed-dose lamivudine name: No originator product exists. combinations and the development of appropriate new fixed-dose combinations.24
Price INFORMATION /N Developing country prices in US$ per patient per year, as quoted by companies. evirapine The price in brackets corresponds to the price of one kit of three tablets. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily dose Matrix (
Who can access this price? See annex 2 NVP + TDF/3TC
TDF/3TC + NVP 300/300 + 200mg 134 1 kit (3 tablets) (co-pack) (0.367)
Spotlight on access issues )
This co-pack is likely to be widely For many years, the regimen today is still higher than a d4T-based used in developing countries as containing d4T played a crucial role regimen, there is a need to generate first-line regimen. in ART scale-up in resource-limited greater demand which will, in turn, settings, due to its availability in a increase the competition and the In 2010, WHO released new fixed-dose combination and most economies of scale needed to further recommendations for antiretroviral importantly its low cost. d4T remains a decrease prices.7 therapy for HIV in adults widely used ARV in first-line regimens. and adolescents. These new However NVP interacts with one of recommendations advise countries It is time for countries to invest in a the most commonly used TB drugs, to phase out stavudine- (d4T) based more robust, TDF-containing first-line rifampicin, requiring a switch to EFV regimens because of their long-term regimen, such as TDF/3TC/EFV or during the course of TB treatment. irreversible side effects and to move TDF/FTC/EFV, which are both one towards zidovudine- (AZT) or tenofovir- pill, once a day or TDF/3TC + NVP (TDF) based first-line regimens. (available in co-pack). While the price
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 71 ) zidovudine/ 3TC lamivudine ( AZT/3TC ) AZT/
(
GENERAL INFORMATION
• Therapeutic class: Two NRTI in a • First approval by U.S. Food and • World sales of originator product: 2010: double fixed-dose combination. Drug Administration (FDA): US$ 588 million; 2009: $649 million;
23 lamivudine September 1997. 2008: $713 million; 2007: $888 million; / • WHO guidelines: Indicated for first- 2006: $1 billion; 2005: $1.1 billion; and second-line for adults, adolescents • WHO Model List of Essential 2004: $1.1 billion.163, 25, 26, 27, 28, 29, 30 6, 22 and children. Medicines (EML): Included in the • Patents: Most patents related to 17th edition. The WHO Expert • Originator company and product zidovudine (AZT) or to lamivudine Committee on the Selection and Use brand name: GlaxoSmithKline (GSK), (3TC) also affect this combination. Combivir. In April 2009, Pfizer and of Essential Medicines recommends In addition, GSK applied for patents zidovudine GSK jointly announced the creation and endorses the use of fixed-dose specifically related to the use of AZT of ViiV, a new joint venture combinations and the development and 3TC in combination,313 and for focusing solely on the R&D and of appropriate new fixed-dose the tablet formulation of the FDC,314 commercialisation of HIV medicines. combinations.24 which are due to expire in 2012 and 2017, respectively. Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily ViiV Aurobindo (CF) Cipla (CF) Hetero (CF) Matrix (CF) Micro Labs (CF) Ranbaxy (CF) Strides Varichem dose Who can access See annex 2 this price?
AZT/3TC 92 73 88 60/30mg 4 (0.063) (0.050) (0.060) tablet
AZT/3TC 231 107 104 110 101 112 110 123 107 300/150mg 2 (0.316) (0.147) (0.142) (0.150) (0.138) (0.154) (0.150) (0.169) (0.147) tablet
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2001:
As of May 2011, 11 generic sources of AZT/3TC 300/150mg tablet were quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
Since 2001, the originator price has decreased by 68%, while generic prices have dropped by 63%. 231
101
Jun 11
72 Médecins Sans Frontières | July 2011 zidovudine / lamivudine Spotlight on access issues
In 2010, WHO released new Patents for children today (the other being recommendations for antiretroviral This combination was produced by d4T/3TC/NVP). With both of these therapy for HIV in adults Indian generic companies because regimens, there is a need to start
and adolescents. These new none of the individual components NVP at a lower dose for the first two (
recommendations advise countries was patented in India. However, weeks to minimise the side effects. AZT/ to phase out stavudine- (d4T) based these generic versions came under Quality-assured double fixed-dose
threat when India began granting combinations are therefore of
regimens because of their long-term 3TC irreversible side effects and to move patents on pharmaceuticals in great value in allowing children
2005, as GSK had applied for a towards zidovudine- (AZT) or tenofovir- to be safely and accurately dosed ) (TDF) based first-line regimens. patent on the combination.315, 316 while starting treatment. In their absence, the alternative is to use For many years, the regimen Civil society organisations in India two different syrups, which can be containing d4T played a crucial role opposed the patent application in difficult to administer. in ART scale-up in resource-limited March 2006,317 which resulted in settings, due to its availability in GSK communicating in August 2006 Because of the long-term risks of a fixed-dose combination and that patents specifically related to toxicity, particularly lipoatrophy most importantly its low cost. the fixed-dose combination were in children treated with d4T- 318 d4T remains a widely used ARV being withdrawn in all countries. containing regimens, the use of AZT is preferred. Toxicity risks are also in first-line regimens. Yet in some countries, generic associated with AZT, with possible AZT is also recommended for versions of the FDC are not anaemia developing over the first second-line treatment if tenofovir available because of GSK patent few months of therapy, but the has been used in first-line. AZT rights. In China, for example, GSK’s drug remains much better tolerated exclusive rights on 3TC alone should then be used as the 22 than d4T. WHO guidelines NRTI backbone, in combination have led to the fact that only the recommend a preferential order with either lamivudine (3TC) or originator product is available at $1,839 per patient per year. of NRTIs to be used in first-line emtricitabine (FTC), to which a regimens, with AZT preferred over boosted protease inhibitor (PI) Paediatrics ABC, and ABC preferred over d4T. should be added. In its 2010 guidelines for antiretroviral therapy for HIV As of May 2011, two paediatric In 2011, ViiV clarified their pricing in infants and children, WHO AZT/3TC fixed-dose combination structure (see annex 2), confirming recommends AZT/3TC as one of the tablets were quality-assured that their standardised price possible combinations to be given by either US FDA or WHO discounts were not in fact available with either an NNRTI or a PI in the prequalification. to all fully-financed Global Fund or first-line. The combination can also PEPFAR programmes, contrary to be part of second-line regimens, previous announcements. Global depending on what has been used Fund financed programmes in as a first-line.22 middle-income countries have not been and will not be eligible for those AZT/3TC, when used with NVP, prices, and will have to negotiate is part of one of the two most prices on a case-by-case basis. commonly used first-line regimens
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 73 ) zidovudine/lamivudine/ abacavir ( AZT/3TC/ABC ) AZT/3TC/ABC GENERAL INFORMATION (
• Therapeutic class: Three NRTI in • First approval by U.S. Food and Drug • World sales of originator product: 2010: a triple fixed-dose combination. Administration (FDA): November 2000.23 US$ 233 million; 2009: $307 million; 2008: $350 million; 2007: $455 million; • WHO guidelines: Indicated under • WHO Model List of Essential Medicines
abacavir 2006: $529 million; 2005: $598 million;
/ specific conditions in adults, (EML): Individual medicines included 2004: $635 million.163, 25, 26, 27, 28, 29, 30 adolescents and children.6, 22 in 17th edition.The WHO Expert Committee on the Selection and Use • Patents: Most patents on zidovudine • Originator company and product of Essential Medicines recommends (AZT), lamivudine (3TC), AZT/3TC brand name: GlaxoSmithKline (GSK), and endorses the use of fixed-dose or abacavir (ABC) also affect this Trizivir. In April 2009, Pfizer and combinations and the development combination. In addition, GSK applied GSK jointly announced the creation of appropriate new fixed-dose for patents more specifically related lamivudine of ViiV, a new joint venture 24 308 / combinations. to the triple combination. focusing solely on the R&D and commercialisation of HIV medicines.
Price INFORMATION zidovudine Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold.
Daily ViiV Matrix Ranbaxy dose
Who can access this price? See annex 2
AZT/3TC/ABC 244 4 60/30/60 mg tablet (0.167) AZT/3TC/ABC 645 365 548 2 300/150/300 mg tablet (0.884) (0.500) (0.750)
Evolution of the lowest price quoted for developing countries since 2001:
As of May 2011, two generic source of AZT/ 3TC/ABC 300/150/300mg tablet were quality- assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
Since 2002, the originator price has decreased by 73%, while generic prices have dropped by 78%. 645
365
Jun 11
74 Médecins Sans Frontières | July 2011 zidovudine / lamivudine Spotlight on access issues
This FDC is the only triple NRTI Patents Paediatrics formulation available, and is no GSK could not apply for basic In its 2010 guidelines for longer a preferred regimen in the patents related to ABC, AZT or antiretroviral therapy for HIV developed world,320 where its use is / 3TC in some developing countries in infants and children, WHO abacavir limited to individuals with contra- such as India, which did not grant recommends AZT/3TC/ABC as indication to NNRTI-based regimens patents on pharmaceuticals at the an option for TB/HIV co-infected or who are unable to tolerate them. time. This allowed Indian generic patients.22 This is crucial for a small This applies particularly to people companies to develop generic cohort of patients below three years
co-infected with TB/HIV, pregnant versions of each medicine, and of age, for whom dosing studies for (
women, patients with chronic viral of the combination. EFV do not exist. AZT/3TC/ABC hepatitis and those with HIV-2 However, GSK widely applied A generic paediatric formulation of infection.22 for patents in other developing AZT/3TC/ABC has been developed In 2011, ViiV clarified their pricing countries, where possible. and quality-assured by WHO structure (see annex 2), confirming prequalification. However, this In India, GSK had applied for that their standardised price product is not commercially available
patents more specifically related ) discounts were not in fact available yet because of insufficient demand. to the fixed-dose combination. to all fully-financed Global Fund or The company withdrew the patent PEPFAR programmes, contrary to application after a pre-grant previous announcements. Global opposition was filed by civil Fund financed programmes in society in 2006.321 middle-income countries have not been and will not be eligible for those prices, and will have to negotiate prices on a case-by-case basis.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 75 ) zidovudine/lamivudine/ NVP nevirapine ( AZT/3TC/NVP ) 3TC/
AZT/ GENERAL INFORMATION (
• Therapeutic class: Two NRTI + one NNRTI • First approval by U.S. Food and Drug • Patents: Most patents related to in a triple fixed-dose combination. Administration (FDA): Not applicable. zidovudine (AZT), lamivudine (3TC), AZT/3TC or to nevirapine (NVP) also • WHO guidelines: Indicated for • WHO Model List of Essential Medicines affect this combination. first-line for adults, adolescents and (EML): Included in the 17th edition. 6, 22 nevirapine children. The WHO Expert Committee on / the Selection and Use of Essential • Originator company and product brand Medicines recommends and endorses name: No originator product exists. the use of fixed-dose combinations and the development of appropriate new fixed-dose combinations.24 lamivudine / Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one tablet. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold. zidovudine Daily Aurobindo (CF) Cipla (CF) Hetero (CF) Matrix (CF) Ranbaxy (CF) Strides dose Who can access this price? See annex 2
AZT/3TC/NVP 101 183 4 60/30/50mg tablet (0.069) (0.125) AZT/3TC/NVP 144 137 143 134 140 141 2 300/150/200mg tablet (0.197) (0.188) (0.196) (0.183) (0.192) (0.193)
(CF) The Clinton Foundation has negotiated with this manufacturer for reduced prices on some formulations for countries in their consortium. See annex 13 for details.
Evolution of the lowest price quoted for developing countries since 2001:
As of May 2011, six generic sources of AZT/3TC/ NVP 300/150/200mg tablet were quality- assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
As there is no originator fixed-dose combination or co-pack, the price shown for the originator 600 product is the sum of the three individual originator products. 134 Since 2002, the sum of the originator price has decreased by 56%, while generic prices have Jun dropped by 68%. 11
76 Médecins Sans Frontières | July 2011 zidovudine / lamivudine Spotlight on access issues
In 2010, WHO released new In early 2004, MSF made Because of the long-term risks of recommendations for antiretroviral the original request for the toxicity, particularly lipoatrophy therapy for HIV in adults development of this FDC to Apotex, in children treated with d4T-
and adolescents. These new as no generic versions of the FDC containing regimens, the use of AZT / nevirapine recommendations advise countries were available at the time.296 is preferred. Toxicity risks are also to phase out stavudine- (d4T) based associated with AZT, with possible MSF, however, ultimately ended regimens because of their long- anaemia developing over the first up procuring the FDC from term irreversible side effects and few months of therapy, but the manufacturers in India, which reached to move towards zidovudine- drug remains much better tolerated the market earlier because the Indian 22
(AZT) or tenofovir- (TDF) based than d4T. WHO guidelines ( manufacturers were not hampered
first-line regimens. recommend a preferential order AZT/ by the excessively bureaucratic of NRTIs to be used in first-line For many years, the regimen procedural requirements of the
regimens, with AZT preferred over containing d4T has played a new WTO rules on CL for export. 3TC/ ABC, and ABC preferred over d4T. crucial role in ART scale-up in Paediatrics
resource-limited settings, due HIV/TB co-infected young children In its 2010 guidelines for NVP to its availability in a fixed-dose antiretroviral therapy for HIV cannot be given NVP because of
combination and most importantly interactions between NVP and TB in infants and children, WHO ) its low cost. d4T remains a widely recommends AZT/3TC as one of the drugs. As there is still no established used ARV in first-line regimens. possible combinations to be given dosing of EFV, the standard alternative to NVP, for children less Patents with either an NNRTI or a PI in the 22 than three years of age, there is an The Canadian generic company first-line. urgent need to establish the dosing Apotex manufactures an AZT/3TC/ Together with d4T/3TC/NVP, AZT/ of EFV for this age group. NVP fixed-dose combination for 3TC/NVP is one of the two most export to developing countries commonly used first-line regimens As of May 2011, there was only under the 30 August 2003 World for children today. With both of one generic paediatric fixed-dose Trade Organization decision. The these regimens, there is a need to combination quality-assured by US purpose of the August 30 Decision start NVP at a lower dose for the FDA or WHO prequalification. is to find an ‘expeditious solution’ first two weeks to minimise the side to the problems of developing effects, and therefore the AZT/3TC countries with no or insufficient double fixed-dose combinations is manufacturing capacity and who of great value in allowing children therefore would rely on importing to be safely and accurately dosed medicines produced in and while starting treatment. In their exported from other countries, absence, the alternative is to use under compulsory licence.275 two different syrups, which can be difficult to administer.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 77 ) zidovudine/lamivudine + efavirenz ( AZT/3TC + EFV )
AZT/3TC + EFV GENERAL INFORMATION
(
• Therapeutic class: Two NRTI • WHO Model List of Essential Medicines • Patents: Most patents related to (in a fixed-dose combination) + (EML): Individual medicines included zidovudine (AZT), lamivudine (3TC), one NNRTI in a co-pack. in 17th edition. The WHO Expert AZT/3TC or to efavirenz (EFV) also Committee on the Selection and Use affect this combination. In addition, • WHO guidelines: Indicated for first-line
efavirenz of Essential Medicines recommends Cipla applied for patents specifically for adults, adolescents and children.6, 22
+ and endorses the use of fixed-dose related to the use of AZT, 3TC and • Originator company and product brand combinations and the development EFV in combination.319 name: No originator product exists. of appropriate new fixed-dose combinations.24 • First approval by U.S. Food and Drug Administration (FDA): Not applicable. lamivudine /
Price INFORMATION Developing country prices in US$ per patient per year, as quoted by companies. The price in brackets corresponds to the price of one kit of three tablets. Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold. zidovudine
Daily dose Aurobindo Ranbaxy Strides
Who can access this price? See annex 2
AZT/3TC + EFV 300/150 + 1 kit 216 292 225 600mg tablets (co-pack) (3 tablets) (0.593) (0.800) (0.617)
Evolution of the lowest quoted price for developing countries since 2006:
As of May 2011, three generic sources of AZT/3TC + EFV 300/150 + 600mg tablets (co-pack) were 468 quality-assured by US FDA or WHO prequalification. The one with the lowest price is shown here.
As there is no originator co-pack, the price shown for the originator product is the sum of the two 216 individual originator products.
Since 2006, the sum of the originator prices has decreased by 16%, while the generic prices have dropped by 52%. Jun 11
78 Médecins Sans Frontières | July 2011 zidovudine / lamivudine Spotlight on access issues
In 2010, WHO released new Patents few months of therapy, but the recommendations for antiretroviral Basic patents related to AZT, 3TC drug remains much better tolerated therapy for HIV in adults or EFV could not be obtained in than d4T.22 WHO guidelines and adolescents. These new some developing countries such as recommend a preferential order +
recommendations advise countries India, which did not grant product of NRTIs to be used in first-line efavirenz to phase out stavudine- (d4T) based patents on pharmaceuticals at the regimens, with AZT preferred over regimens because of their long- time. This allowed Indian drug ABC, and ABC preferred over d4T. term irreversible side effects and to companies to manufacture generic As there is still no established move towards zidovudine- (AZT) versions of the medicines and dosing of EFV for children less or tenofovir- (TDF) based first-line to develop this product. (
than three years of age, there is EFV + AZT/3TC regimens. However, GlaxoSmithKline and an urgent need to establish the For many years, the regimen Merck may hold patents in other dosing of EFV for this age group for containing d4T played a crucial role developing countries, which could children with HIV/TB co-infection. prevent the importation and use in ART scale-up in resource-limited In the absence of such data, treatment of this co-pack combination. settings, due to its availability in options for children remain limited, a fixed-dose combination and Paediatrics particularly for HIV/TB co-infected
most importantly its low cost. In its 2010 guidelines for antiretroviral young children who cannot be ) d4T remains a widely used ARV therapy for HIV in infants and children, given NVP because of interactions in first-line regimens. WHO recommends AZT/3TC as one between NVP and TB drugs. AZT is also recommended for of the possible combinations to be second-line treatment if tenofovir given with either an NNRTI or a PI in the first-line.22 has been used in first-line. AZT should then be used as the Currently a co-pack of AZT/3TC + NRTI backbone, in combination EFV for children does not exist. with either lamivudine (3TC) or Because of the long-term risks of emtricitabine (FTC), to which a toxicity, particularly lipoatrophy boosted protease inhibitor (PI) in children treated with d4T- should be added. containing regimens, the use of AZT In addition, efavirenz (EFV) is the is preferred. Toxicity risks are also preferred NNRTI for use in patients associated with AZT, with possible starting ART while on TB treatment.7 anaemia developing over the first
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 79 Annex 1: Summary table of all prices
Developing country prices in US$ per patient per year, as quoted by companies. prices
The price in brackets corresponds to the price of one unit (tablet, capsule, etc.). Products quality-assured by US FDA or WHO prequalification (as of May 2011) are in bold. all
of ARVs in Daily
Originator company Generic companies alphabetical order dose
Abacavir (ABC) ViiV Aspen Aurobindo Cipla Hetero Matrix Ranbaxy Strides
347 153 212 139
table 20mg/ml oral solution 10 ml (0.095/ml) (0.042/ml) (0.058/ml) (0.038/ml)
y 146 158 134 60mg tablet 4 (0.100) (0.108) (0.092)
382 195 231 231 183 261 292 300mg tablet 2 (0.523) (0.267) (0.317) (0.317) (0.250) (0.358) (0.400)
ummar BMS Atazanavir (ATV)* Emcure Matrix Category 1 Category 2 countries countries x 1: S 100mg capsule 3 (0.267)
412 547 268 426
nne 150mg capsule 2 (0.565) (0.749) (0.367) (0.583) A 200mg capsule xx (0.677) (0.942) (0.483)
268 250 300mg capsule 1 (0.733) (0.686)
Darunavir (DRV)* Tibotec
1095 300mg tablet 4 (0.750)
BMS Didanosine (ddI) Aurobindo Cipla Matrix Ranbaxy Category 1 Category 2 countries countries
2g powder for 276 reconstitution (final 12 ml (12.590/2g) concentration 10mg/ml)
256 138 252 25mg tablet 6 (0.117) (0.063) (0.115)
50mg tablet xx (0.159) (0.079) (0.125)
100mg tablet xx (0.213) (0.133) (0.129) (0.166)
125mg enteric-coated 110 119 1 capsule (0.300) (0.325)
150mg tablet xx (0.225) (0.167)
200mg tablet xx (0.267) (0.257)
200mg enteric-coated xx (0.383) (0.489) capsule
250mg enteric-coated 223 316 170 103 172 134 1 capsule (0.612) (0.866) (0.467) (0.283) (0.467) (0.367)
400mg enteric-coated 288 408 256 132 268 183 1 capsule (0.789) (1.118) (0.700) (0.363) (0.733) (0.500)
Merck Efavirenz (EFV) Aspen Aurobindo Cipla Emcure Hetero Matrix Micro Labs Ranbaxy Strides Category 1 Category 2 countries countries
30mg/ml suspension xx (0.094/ml)
50mg capsule xx (0.083) (0.047)
50mg tablet xx (0.120) (0.050)
100mg capsule xx (0.042)
100mg tablet xx (0.117) (0.150)
116 134 152 80 97 200mg capsule 3 (0.106) (0.122) (0.139) (0.073) (0.089)
394 183 113 200mg tablet 3 (0.360) (0.167) (0.103)
237 62 73 79 61 67 55 58 72 52 600mg tablet 1 (0.650) (0.170) (0.200) (0.217) (0.167) (0.183) (0.150) (0.158) (0.197) (0.143)
*The required addition of RTV as a booster must also be considered in the final cost of this drug.
80 Médecins Sans Frontières | July 2011 A
ARVs in Daily nne Originator company Generic companies alphabetical order dose
Emtricitabine (FTC) Aurobindo Cipla S 1: x
61 97 200mg capsule 1 (0.167) (0.267)
Etravirine (ETV) Tibotec ummar
913 100mg tablet 4 (0.625)
Fosamprenavir (FPV)* ViiV y y 837 50mg/ml suspension 12ml table (0.191/ml)
1131 700mg tablet 2 (1.549)
Merck of Indinavir (IDV)* Category 1 Category 2 Aurobindo Cipla Hetero
countries countries all
394 292 422 406 400mg capsule 4 (0.270) (0.200) (0.289) (0.278)
prices Micro Lamivudine (3TC) ViiV Alkem Aspen Aurobindo Cipla Hetero Matrix Ranbaxy Strides Labs
10mg/ml 212 33 29 55 37 10ml oral solution (0.058/ml) (0.009/ml) (0.008/ml) (0.015/ml) (0.010/ml)
80 42 29 34 33 33 31 31 34 29 150mg tablet 2 (0.109) (0.058) (0.040) (0.047) (0.045) (0.045) (0.042) (0.042) (0.047) (0.040)
24 41 38 26 300mg tablet 1 (0.067) (0.113) (0.103) (0.071)
Abbott Lopinavir/ Aurobindo Cipla Hetero Matrix ritonavir (LPV/r) Category 1 Category 2 countries countries
80/20mg/ml 164 400 256 4ml oral solution (0.112/ml) (0.274/ml) (0.175/ml)
100/25mg tablet 153 376 175 164 3 (heat-stable) (0.140) (0.343) (0.160) (0.150)
133/33mg soft-gel 500 1000 633 6 capsule (non heat-stable) (0.228) (0.457) (0.289)
200/50mg tablet 410 1000 438 499 493 402 4 (heat-stable) (0.281) (0.457) (0.300) (0.342) (0.338) (0.275)
Maraviroc (MVC) ViiV
1584 150mg tablet 4 (1.085)
Roche Nelfinavir (NFV) Category 1 Category 2 countries countries
2742 3171 50mg/g oral powder 24g (0.313/g) (0.362/g)
2018 3132 250mg tablet 10 (0.553) (0.858)
Boehringer Ingelheim Nevirapine (NVP) Aspen Aurobindo Cipla Hetero Matrix Ranbaxy Strides Category 1 Category 2 countries countries
380 533 58 110 10mg/ml suspension 20ml (0.052/ml) (0.073/ml) (0.008/ml) (0.015/ml)
219 438 37 37 39 37 31 37 32 200mg tablet 2 (0.300) (0.600) (0.051) (0.050) (0.054) (0.050) (0.043) (0.050) (0.044)
Merck Raltegravir (RAL) Category 1 Category 2 countries countries
675 400mg tablet 2 (0.925)
*The required addition of RTV as a booster must also be considered in the final cost of this drug.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 81 ARVs in Daily Originator company Generic companies alphabetical order dose
Abbott
prices Ritonavir (RTV) Matrix Category 1 Category 2 countries countries
all 80mg/ml oral solution xx (0.093/ml)
100mg soft-gel capsule 83
of 2**
(non heat-stable) (0.114)
100mg heat-stable 83 183 2** tablet (0.114) (0.250)
Roche table Saquinavir (SQV)* Category 1 Category 2 y countries countries
1566 3132 200mg hard capsule 10 (0.429) (0.858)
1435 3130 500mg tablet 4 ummar (0.983) (2.144)
BMS Stavudine (d4T) Aspen Aurobindo Cipla Hetero Ranbaxy Strides Category 1 Category 2 x 1: S countries countries
1mg/ml powder for 58 58 51 20 ml
nne oral solution (0.008/ml) (0.008/ml) (0.007/ml) A 15mg capsule xx (0.083) (0.118) (0.027) (0.024) (0.025)
20mg capsule xx (0.094) (0.118) (0.031) (0.025) (0.028)
48 86 20 21 24 22 30mg capsule 2 (0.066) (0.118) (0.027) (0.029) (0.033) (0.030)
Gilead
Tenofovir (TDF) Category 1 Category 2 Aspen Aurobindo Cipla Hetero Matrix Ranbaxy Strides countries countries
204 360 87 88 83 103 76 97 79 300mg tablet 1 (0.559) (0.986) (0.237) (0.242) (0.227) (0.283) (0.208) (0.267) (0.217)
Zidovudine (AZT) ViiV Aspen Aurobindo Cipla Hetero Matrix Micro Labs Ranbaxy
380 88 66 110 73 10mg/ml oral solution 20 ml (0.052/ml) (0.012/ml) (0.009/ml) (0.015/ml) (0.010/ml)
115 60mg tablet 4 (0.079/ml)
100mg capsule xx (0.185) (0.048) (0.055)
250mg capsule xx (0.301)
301 99 88 91 100 88 91 91 300mg tablet 2 (0.412) (0.136) (0.121) (0.125) (0.137) (0.121) (0.125) (0.125)
ABC/3TC ViiV Aurobindo Matrix
175 292 60/30mg tablet 4 (0.120) (0.200)
388 112 280 600/300mg tablet 1 (1.064) (0.308) (0.767)
3TC/d4T Cipla Hetero Matrix Ranbaxy Strides
30/6mg dispersible 47 4 tablet (0.032)
60/12mg dispersible 40 2 tablet (0.055)
42 46 39 42 41 150/30mg tablet 2 (0.058) (0.063) (0.054) (0.058) (0.056)
3TC/d4T/NVP Cipla Hetero Ranbaxy Strides Varichem
30/6/50mg dispersible 55 4 tablet (0.038)
60/12/100mg 53 2 dispersible tablet (0.072)
64 67 70 66 61 150/30/200mg tablet 2 (0.088) (0.092) (0.096) (0.090) (0.083)
*The required addition of RTV as a booster must also be considered in the final cost of this drug. **Dosing frequency depends on which drug RTV is used with as a booster.
82 Médecins Sans Frontières | July 2011 A
ARVs in Daily nne Originator company Generic companies alphabetical order dose
3TC/d4T + EFV Ranbaxy Strides S 1: x (co-pack)
150/30 + 600mg tablets 1 kit 152 106 (co-pack) (3 tablets) (0.417) (0.290) ummar Gilead TDF/FTC Aurobindo Cipla Hetero Matrix Category 1 Category 2 countries countries
315 540 140 134 164 116 300/200mg tablet 1 y (0.863) (1.479) (0.383) (0.367) (0.450) (0.317) table BMS / Gilead / Merck
TDF/FTC/EFV Category 1 Category 2 Cipla Hetero Matrix countries countries
613 1033 231 243 219 of 300/200/600mg tablet 1 (1.680) (2.830) (0.633) (0.667) (0.600)
TDF/3TC Aurobindo Cipla Hetero Matrix all
116 103 116 91
300/300mg tablet 1
(0.317) (0.283) (0.317) (0.250) prices
TDF/3TC/EFV Cipla Matrix
195 173 300/300/600mg tablet 1 (0.533) (0.475)
TDF/3TC + NVP Matrix (co-pack)
300 / 300 + 200mg 1 kit 134 tablets (co-pack) (3 tablets) (0.367)
AZT/3TC ViiV Aurobindo Cipla Hetero Matrix Micro Labs Ranbaxy Strides Varichem
92 73 88 60/30mg tablet 4 (0.063) (0.050) (0.060)
231 107 104 110 101 112 110 123 107 300/150mg tablet 2 (0.316) (0.147) (0.142) (0.150) (0.138) (0.154) (0.150) (0.169) (0.147)
AZT/3TC/ABC ViiV Matrix Ranbaxy
60/30/60mg 244 4 tablet (0.167)
645 365 548 300/150/300mg tablet 2 (0.884) (0.500) (0.750)
AZT/3TC/NVP Aurobindo Cipla Hetero Matrix Ranbaxy Strides
60/30/50mg 101 183 4 dispersible tablet (0.069) (0.125)
300/150/200mg 144 137 143 134 140 141 2 tablet (0.197) (0.188) (0.196) (0.183) (0.192) (0.193)
AZT/3TC + EFV Aurobindo Ranbaxy Strides (co-pack)
300/150 + 600mg 1 kit 216 292 225 tablets (co-pack) (3 tablets) (0.593) (0.800) (0.617)
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 83 y Annex 2: Conditions of offer by company
compan Company Eligibility (countries) Eligibility (bodies) Additional comments Delivery of goods y b
Abbott Category 1 countries: Governments and FOB. All African countries and programmes fully funded all United Nations defined by governments, UN least-developed countries systems organisations, NGOs offer outside Africa. and other not-for-profit institutional providers in low of Category 2 countries: and lower middle-income See Annex 8 for more details. countries.
Alkem No restrictions. No restrictions. FCA Mumbai. onditions
x 2: C Aspen South Africa public South Africa public Ex-works. sector only. sector only. nne A Aurobindo No reported restrictions. NGOs and governmental Prices available for above Payment by letter of credit. organisations. 300,000 units for tablet FOB Hyderabad (India). packs and above 5,000 packs for oral solutions. Delivery of goods 10-12 weeks from the date of confirmed orders.
Boehringer Category 1: Governments, NGOs CIF. Ingelheim All LDCs, all low-income and other partners who countries and all of Africa. can guarantee that the programme is run in a Category 2: responsible manner. All middle-income countries not covered under category 1.
Bristol-Myers Category 1 countries: Both private and public Category 1 countries CIP. Squibb Sub-Saharan African sector organisations that are invoiced in US$. countries (except southern are able to provide effective, Category 2 countries African countries) plus sustainable and medically- are invoiced in countries classified as low- sound care and treatment South African Rand. income by the World Bank of HIV/AIDS. (except Korea, Kyrgyzstan, Moldova and Uzbekistan). Category 2 countries: Southern African countries See annex 7 for more details. For other developing countries, prices are negotiated on a case-by- case basis with BMS local representatives.
Cipla No reported restrictions No restrictions. No quantity-related FOB Mumbai (India) or CIF. but higher prices have been conditions. Prices for larger The actual freight is negotiated separately for quantities are negotiable. charged separately. 10 Latin American countries.
84 Médecins Sans Frontières | July 2011 A
Company Eligibility (countries) Eligibility (bodies) Additional comments Delivery of goods nne x 2: C 2: x Emcure Only atazanavir is restricted No restrictions. Ex-works. to sales in India and sub-Saharan Africa. onditions No restrictions for others.
Gilead There are 130 eligible Organisations that provide The programme is Shipping terms vary by countries, including all HIV treatment in 130 managed through Gilead’s local distributor. African states and additional countries are covered by the International Access
countries classified as low- Gilead Access Programme. Operations and Gilead’s of or lower middle-income local distribution partners.
based on a country’s Please note that local taxes, offer economic status measure by tariffs, and limited distributor gross national income (GNI) mark-ups may be added and HIV prevalence. See to the ex-factory prices.
Annex 9 for more details. b
For other countries, prices y
are negotiated on a case- compan by-case basis.
Hetero No reported restrictions. Private sector, public sector Prices may be negotiated FOB Mumbai (India). and NGOs. on individual basis according y to commercial terms.
Matrix No reported restrictions No restrictions. Minimum order – One full Ex-works Nashik, India or except: Cuba, Iran, North shipper / carton packs. as specified by customers. Korea, Syria, Sudan, Belarus, Myanmar, Democratic Republic of Congo & Liberia for which prior approval from Mylan is required.
Merck All countries in sub-Saharan Governments and Additional costs may include DDU, CIP or CPT airport Africa and low- income programmes fully funded freight, insurance, customs of destination basis. countries based on World by governments and / or by handling, taxes and duties. (Incoterms, 2000). Bank country classification. multi- and bi-lateral donors (i.e., Global Fund, PEPFAR, Countries classified as lower- or UNITAID), UN System middle and upper-middle Organisations, NGOs and income by the World Bank other non-commercial will be eligible for prices providers of HIV treatment. that are discounted from the prices in the developed high income countries. These prices will vary based on country income, disease burden, and will be negotiated with each government. Please refer to Annex 10 for the individual drug country eligibility.
Micro Labs All countries except India. All organisations / bodies Prices are subject to change Ex-works. except India. due to fluctuation in active pharmaceutical ingredient price and exchange rate.
Ranbaxy No reported restrictions, NGOs and governments Confirmed letter of credit or FCA Delhi (India). but higher prices were or programmes supported advance payment preferred negotiated separately for by them. for new customers. 10 Latin American countries.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 85 y Company Eligibility (countries) Eligibility (bodies) Additional comments Delivery of goods
Roche Category 1 countries: Governments, non-profit CAD (Cash Against FCA Basel airport All countries in sub-Saharan institutional providers of Documents) 30 days at (Switzerland) or CIP compan Africa and all countries HIV care, NGOs. sight. Minimum order airport of destination. y classified as least-developed and delivery amount per b (Incoterms, 2000). countries by the United shipment is CHF 10,000. Nations. Category 2 countries:
offer Low-income countries and lower middle-income
of countries, as classified by the World Bank.
Strides No reported restrictions. Governments, non-profit Payment by signed letter FOB Bangalore (India). Arcolab institutional providers of of credit. HIV treatment, NGOs. onditions
Tibotec Sub-Saharan Africa and No restrictions. Questions regarding prices FOB.
x 2: C least-developed countries applied in the related (LDCs). countries need to be addressed to Aspen. nne For other low- and middle-
A income countries, public sector prices are negotiated on a case-by-case basis.
Varichem No restrictions. No restrictions. Prices are dependent on FOB (Harare). quantities being ordered.
ViiV Least-developed countries, Governments, aid Supply Agreement required All NFP prices are quoted low-income countries and organisations, charities, (for NGOs requiring fewer ex-factory. Cost of delivery sub-Saharan Africa. UN agencies, other not- than ten patient packs per will be added to the for-profit organisations and month, this requirement ex-factory price. All Country Coordination international procurement may be waived). Mechanisms (CCM) projects agencies. in low-income countries, All organisations must least-developed countries In sub-Saharan Africa, supply the preferentially and countries in sub-Saharan employers offering HIV/AIDS priced products on a Africa fully financed by the care and treatment directly not-for-profit basis. Global Fund to Fight AIDS, to their uninsured staff TB and Malaria, as well as through workplace clinics projects funded by PEPFAR. or similar arrangements. For middle-income countries, public sector prices are negotiated on a case-by- case basis, either bilaterally or through the Accelerating Access Initiative.
Notes: The conditions detailed in the table above were those quoted directly by the companies. Definitions of eligibility vary from company to company. Each originator company establishes different restrictions to their offer of reduced prices, and classifies countries according to different categories. Some companies resort to least-developed country (LDC) criteria developed by the United Nations, others to the UN Development Programme’s Human Development Index (UNDP HDI), and others still to World Bank classifications concerning country income.
For complete details please refer to annexes 3-10.
86 Médecins Sans Frontières | July 2011 A
Annex 3: Mongolia; Morocco; Namibia; Lower middle-income economies: nne Least-Developed Nicaragua; Pakistan; Paraguay; Angola; Armenia; Belize; Bhutan;
Countries (LDCs) Philippines; Solomon Islands; South Bolivia; Cameroon; Cape Verde; 3 x Africa; Sri Lanka; Suriname; Swaziland; China; Congo (Rep); Côte d’Ivoire;
Source: United Nations /A Syria; São Tomé and Príncipe; Tajikistan; Djibouti; Ecuador; Egypt; El Salvador; http://www.un.org/special-rep/ohrlls/ Thailand; Timor-Leste; Turkmenistan; Georgia; Guatemala; Guyana; nne ldc/list.htm Uzbekistan; Vietnam. Honduras; India; Indonesia; Iraq; Jordan; Kiribati; Kosovo; Lesotho; 4 x 48 countries are currently designated Annex 5: Sub-Saharan Maldives; Marshall Islands; Micronesia; by the United Nations as least-developed /A Moldova; Mongolia; Morocco; countries (LDCs). countries Nicaragua; Nigeria; Pakistan; Papua nne Source: World Bank country classification Afghanistan; Angola; Bangladesh; New Guinea; Paraguay; Philippines; Benin; Bhutan; Burkina Faso; Burundi; http://web.worldbank.org/WBSITE/ Samoa; São Tomé and Principe; 5 x EXTERNAL/DATASTATISTICS/ Senegal; Sri Lanka; Sudan; Swaziland; Cambodia; Central African Republic; /A Chad; Comoros; Congo (Democratic 0,,contentMDK:20421402~pagePK:64 Syria; Thailand; Timor-Leste; Tonga; nne Republic); Djibouti; Equatorial Guinea; 133150~piPK:64133175~theSitePK:23 Tunisia; Turkmenistan; Tuvalu; Ukraine; 9419,00.html#Sub_Saharan_Africa Uzbekistan; Vanuatu; Vietnam; West
Eritrea; Ethiopia; Gambia; Guinea; 6 x Bank and Gaza; Yemen. Guinea-Bissau; Haiti; Kiribati; Laos; Angola; Benin; Botswana; Burkina
Lesotho; Liberia; Madagascar; Malawi; Faso; Burundi; Cameroon; Cape Upper middle-income economies: /A Mali; Mauritania; Mozambique; Verde; Central African Republic; Chad; Albania; Algeria; American Samoa; nne Myanmar; Nepal; Niger; Rwanda; Comoros; Congo; Congo (Democratic Antigua and Barbuda; Argentina; Samoa; São Tomé and Principe; Republic); Côte d’Ivoire; Eritrea; Azerbaijan; Belarus; Bosnia and 7 x Senegal; Sierra Leone; Solomon Islands; Ethiopia; Gabon; Gambia; Ghana; Herzegovina; Botswana; Brazil; Bulgaria; Somalia; Sudan; Tanzania; Timor-Leste; Guinea; Guinea-Bissau; Kenya; Lesotho; Chile; Colombia; Costa Rica; Cuba; Togo; Tuvalu; Uganda; Vanuatu; Liberia; Madagascar; Malawi; Mali; Dominica; Dominican Republic; Yemen; Zambia. Mauritania; Mauritius; Mozambique; Fiji; Gabon; Grenada; Iran; Jamaica; Kazakhstan; Lebanon; Libya; Lithuania; Annex 4: Namibia; Niger; Nigeria; Rwanda; São Tomé and Principe; Senegal; Seychelles; Macedonia; Malaysia; Mauritius; Mexico; Human Development Montenegro; Namibia; Palau; Panama; Sierra Leone; Somalia; South Africa; Index (HDI) Peru; Romania; Russia; Serbia; Seychelles; Sudan; Swaziland; Tanzania; Togo; Source: United Nations Development South Africa; St. Kitts and Nevis; St. Lucia; Uganda; Zambia; Zimbabwe. Programme (UNDP) 2010 rankings St. Vincent and the Grenadines; http://hdr.undp.org/en/statistics/ Annex 6: World Bank Suriname; Turkey; Uruguay; Venezuela. classification of The Human Development Index is Annex 7: Bristol- economies published annually as a part of UNDP’s Myers Squibb eligible annual Human Development Report. Source: World Bank countries Category 1 Countries: Low human development: http://web.worldbank.org/WBSITE/ EXTERNAL/DATASTATISTICS/ Afghanistan; Angola; Bangladesh; Afghanistan; Angola; Bangladesh; 0,,contentMDK:20421402~pagePK:64 Benin; Bhutan; Burkina Faso; Burundi; Benin; Burkina Faso; Burundi; 133150~piPK:64133175~theSitePK:23 Cambodia; Cameroon; Cape Verde; Cameroon; Central African Republic; 9419,00.html Central African Republic; Chad; Comoros; Chad; Comoros; Congo (Democratic Congo; Congo (Democratic Republic); Republic); Côte d’Ivoire; Djibouti; The list is updated every year on 1 July. Côte d’Ivoire; Djibouti; Equatorial Guinea; Ethiopia; Gambia; Ghana; Guinea; This version is effective from 1 July 2010. Eritrea; Ethiopia; Gabon; Gambia; Ghana; Guinea-Bissau; Haiti; Kenya; Lesotho; Low-income economies: Guinea; Guinea-Bissau; Haiti; Kenya; Laos; Liberia; Madagascar; Malawi; Mali; Liberia; Madagascar; Mali; Mauritania; Afghanistan; Bangladesh; Benin; Mauritania; Mozambique; Myanmar; Mauritius; Mongolia; Myanmar; Nepal; Burkina Faso; Burundi; Cambodia; Nepal; Niger; Nigeria; Papua New Nicaragua; Niger; Nigeria; Pakistan; Central African Republic; Chad; Guinea; Rwanda; Senegal; Sierra Leone; Papua New Guinea; Rwanda; São Tomé Comoros; Congo (Democratic Sudan; Tanzania; Togo; Uganda; and Principe; Senegal; Seychelles; Sierra Republic); Eritrea; Ethiopia; Gambia; Yemen; Zambia; Zimbabwe. Leone; Solomon Islands; Somalia; South Ghana; Guinea; Guinea-Bissau; Sudan; Tanzania; Timor-Leste; Togo; Medium human development: Haiti; Kenya; Korea (Democratic Tuvalu; Uganda; Vietnam; Yemen. Bolivia; Botswana; Cambodia; Cape Republic); Kyrgyzstan; Laos; Liberia; Verde; China; Congo; Dominican Madagascar; Malawi; Mali; Mauritania; Category 2 Countries: Republic; Egypt; El Salvador; Equatorial Mozambique; Myanmar; Nepal; Southern African countries: Guinea; Fiji; Gabon; Guatemala; Guyana; Niger; Rwanda; Sierra Leone; Solomon Botswana; Lesotho; Malawi; Honduras; India; Indonesia; Kyrgyzstan; Islands; Somalia; Tajikistan; Tanzania; Mozambique; Namibia; South Africa; Laos; Maldives; Micronesia; Moldova; Togo; Uganda; Zambia; Zimbabwe. Swaziland; Zambia; Zimbabwe.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 87 Annex 8: Abbott Annex 9: Gilead Annex 10: Merck eligible countries eligible countries eligible countries x 10 Source: Abbott’s Access to HIV Source: Gilead Access Program Source: The following lists and notes
nne Care Program http://www.gilead.com/ are from correspondence with Merck. /A Category 1 countries: enabling_access Merck’s pricing policy efavirenz, indinavir and raltegravir x 9 Africa and Least-developed Category 1 countries: countries: All countries in sub-Saharan Africa and Low-income pricing tier nne Afghanistan; Algeria; Angola; Low-Income Countries based on World Afghanistan; Algeria; Angola; Anguilla; /A Bangladesh; Benin; Bhutan; Botswana; Bank country classification. Antigua and Barbuda; Bahamas; Burkina Faso; Burundi; Cambodia; Afghanistan; Angola; Bangladesh; x 8 Cameroon; Cape Verde; Central African Bangladesh; Barbados; Belize; Benin; Benin; Botswana; Burkina Faso; Burundi; Republic; Chad; Comoros; Congo- Bhutan; Bolivia; Botswana; British nne Virgin Islands; Burkina Faso; Burundi; Cambodia; Cameroon; Cape Verde;
A Brazzaville; Côte d’Ivoire; Congo Central African Republic; Chad; Comoros; (Democratic Republic); Djibouti; East Cambodia; Cameroon; Cape Verde; Congo; Congo (Democratic Republic); Timor; Egypt; Equatorial Guinea; Central African Republic; Chad; Cote d’Ivoire; Equatorial Guinea; Eritrea; Eritrea; Ethiopia; Gabon; Gambia; Comoros; Congo; Congo (Democratic Ethiopia; Gabon; Gambia, The; Ghana; Ghana; Guinea; Guinea-Bissau; Haiti; Republic); Côte d’Ivoire; Cuba; Djibouti; Kiribati; Kenya; Laos; Lesotho; Liberia; Dominica; Dominican Republic; Egypt; Guinea; Guinea-Bissau; Haiti; Kenya; Libya; Madagascar; Malawi; Maldives; Equatorial Guinea; Eritrea; Ethiopia; Korea Democratic Republic; Kyrgyzstan; Mali; Mauritania; Mauritius; Morocco; Gabon; Gambia; Ghana; Grenada; Laos; Lesotho; Liberia; Madagascar; Mozambique; Myanmar; Namibia; Guatemala; Guinea; Guinea-Bissau; Malawi; Mali; Mauritania; Mauritius; Nepal; Niger; Nigeria; Rwanda; Samoa; Guyana; Haiti; Honduras; India; Mozambique; Myanmar; Namibia; Nepal; São Tomé and Principe; Senegal; Indonesia; Jamaica; Kenya; Kiribati; Niger; Nigeria; Rwanda; São Tomé and Seychelles; Sierra Leone; Solomon Kyrgyzstan; Laos; Lesotho; Liberia; Principe; Senegal; Seychelles; Sierra Islands; Somalia; South Africa; Sudan; Libya; Madagascar; Malawi; Maldives; Leone; Solomon Islands; Somalia; Swaziland; Tanzania; Togo; Tunisia; Mali; Mauritania; Mauritius; Moldova; South Africa; Sudan; Swaziland; Tuvalu; Uganda; Vanuatu; Yemen; Mongolia; Montserrat; Morocco; Tajikistan; Tanzania; Togo; Uganda; Zambia; Zimbabwe. Mozambique; Myanmar; Namibia; Zambia; Zimbabwe. Category 2 countries: Nauru; Nepal; Nicaragua; Niger; Merck’s pricing policy for TDF/FTC/EFV Nigeria; Pakistan; Palau; Papua New Low-income economies (excluding Category 1 countries: Guinea; Rwanda; St. Kitts and Nevis; Africa and the LDCs as defined Afghanistan; Angola; Antigua and St. Lucia; St. Vincent and the Grenadines; by the UN) Barbuda; Bangladesh; Belize; Benin; Samoa; São Tomé and Principe; India; Kyrgyzstan; Mongolia; Pakistan; Bhutan; Botswana; Burkina Faso; Burundi; Senegal; Seychelles; Sierra Leone; Papua New Guinea; Tajikistan; Cambodia; Cameroon; Cape Verde; Solomon Islands; Somalia; South Africa; Central African Republic; Chad; Comoros; Uzbekistan; Vietnam. Sudan; Suriname; Swaziland; Syria; Congo; Congo (Democratic Republic); Lower middle-income economies Tajikistan; Tanzania; Timor-Leste; Togo; Côte d’Ivoire; Djibouti; Dominica; (excluding Africa and the LDCs Trinidad and Tobago; Tunisia; Turks Dominican Republic; Equatorial Guinea; as defined by the UN) and Caicos; Tuvalu; Uganda; Ukraine; Eritrea; Ethiopia; Gabon; Gambia; Albania; Armenia; Azerbaijan; Belarus; Uzbekistan; Vanuatu; Vietnam; Yemen; Ghana; Grenada; Guatemala; Guinea- Bissau; Guinea; Guyana; Haiti; Honduras; Bolivia; Bosnia and Herzegovina; Zambia; Zimbabwe. Jamaica; Kenya; Kiribati; Laos; Lesotho; Brazil; China; Colombia, Dominican Category 2 countries: Liberia; Madagascar; Malawi; Maldives; Republic; Ecuador; El Salvador; Lower middle-income pricing tier Mali; Mauritania; Moldova; Mozambique; Fiji; Georgia; Guatemala; Guyana; Myanmar; Namibia; Nepal; Niger; Honduras; Indonesia; Jamaica; Albania; Armenia; Azerbaijan; Belarus; Nigeria; Pakistan; Panama; Papua New Jordan; Kazakhstan; FYR-Macedonia; Bosnia and Herzegovina; China; Guinea; Rwanda; São Tomé and Principe; Ecuador; El Salvador; Fiji; Georgia; Marshall Islands; Micronesia; Moldova; Senegal; Sierra Leone; Solomon Islands; Iran; Iraq; Jordan; Kazakhstan; Kosovo; Montenegro; Nicaragua; Paraguay ; Somalia; South Africa; St. Kitts and Nevis; Peru; Philippines; Serbia; Sri Lanka; Montenegro; Panama; Paraguay; St. Lucia; St. Vincent and the Grenadines; Suriname; Syria; Thailand; Tonga; Peru; Philippines; Sri Lanka; Thailand; Sudan; Suriname; Swaziland; Tanzania; Turkmenistan; Ukraine. Tonga; Turkmenistan. Timor-Leste; Togo; Trinidad and Tobago; Tuvalu; Uganda; Ukraine; Vanuatu; Western Samoa; Yemen; Zambia; Zimbabwe. Category 2 countries: Bolivia; Indonesia; Kyrgyzstan; Mauritius; Mongolia; Nicaragua; Seychelles; Syria; Tajikistan; Uzbekistan; Vietnam.
88 Médecins Sans Frontières | July 2011 A
Annex 11: Suggested Chapter 2 and Annex B. World UNICEF Procurement of HIV/AIDS nne resources for Bank, Washington, DC, 2004 Related Supplies. September 2007 further information: http://siteresources.worldbank. http://www.unicef.org/supply/files/ S 11: x org/INTPROCUREMENT/Resources/ Procurement_of_HA_supplies(1).pdf For documentation on prices Technical-Guide-HIV-AIDS.pdf quoted by companies: Biotechnology/Pharmaceuticals
“Drug patents under the spotlight. HIV/AIDS Industry Report – April 2005 uggested Untangling the Web can also be found Sharing practical knowledge about http://www.aethlonmedical.com/pdfs/ online at utw.msfaccess.org pharmaceutical patents” MSF, June IndustryReport.pdf Back issues of Untangling the Web of 2004. http://www.who.int/3by5/en/ Clinton Health Access Initative Price Reductions: A pricing guide for patents_2003.pdf Antiretroviral Ceiling Price List
the purchase of ARVs for developing resources Knowledge Ecology International http://www.clintonfoundation.org/ countries, can be found at: http://www.keionline.org, or files/chai_arv_ceilingPriceList_201105_ http://utw.msfaccess.org/downloads http://www.cptech.org/ip/health/ english.pdf Sources and Prices of Selected The Patent Status Database Medicines and Diagnostics for People for Selective HIV Medicines.
Living with HIV/AIDS (June 2005) Medecines Patent Pool [Online]. MSF Campaign for Access to for http://www.who.int/medicines/ 2011. Available from: http://www. Essential Medicines website
areas/access/med_prices_hiv_aids/en/
medicinespatentpool.org/LICENSING/ http://www.msfaccess.org further index.html Patent-Status-of-ARVs Global HIV/Aids Epidemic Selection For documentation on quality: of Antiretroviral Medications Provided under U.S. Emergency Plan Is Limited, Prequalification Programme managed by
January 2005: http://pdf.dec.org/pdf_ the World Health Organization (WHO) information docs/Pcaab266.pdf http://mednet3.who.int/prequal/ US Food and Drug Administration For documentation on prices (FDA) Tentative Approvals http:// reported by countries: www.fda.gov/cder/ogd/approvals/ WHO Global Price Reporting Mechanism http://www.who.int/3by5/ Other useful websites referenced amds/price/hdd/ in this document: The Global Fund Price Reporting International Dispensary Association Mechanism http://www.theglobalfund. (IDA) Price Indicator http://www. org/en/funds_raised/price_reporting/ idafoundation.org/documents/ida_hiv_ aids_aug_07_zondersnijlijnen.pdf default.asp US Food and Drug Administration Orange Management Sciences for Health Book http://www.fda.gov/cder/ob/ (MSH) International Drug Price Indicator Guide http://erc.msh.org/ Catalogue of US Food and Drug mainpage.cfm?file=1.0.htm&id=1&te Administration Approved Drug mptitle=Introduction&module=DMP&l Products http://www.accessdata.fda. anguage=English#top gov/scripts/cder/drugsatfda/ WHO AFRO Region Essential Medicines WHO Registration http://ftp.who.int/ Price Indicator http://www.who.int/ htm/AMDS/drugsdatabase.pdf medicines/publications/afro-essential_ WHO Antiretroviral Therapy for HIV med_price_indicator_nocover.pdf Infection in Adults and Adolescents: For documentation on patents: Recommendations for a public http://www.who.int/hiv/pub/ “Determining the patent status of guidelines/artadultguidelines.pdf essential medicines in developing countries”, Health Economies Antiretroviral Therapy for HIV Infection and Drugs, EDM Series No. 17, in Infants and Children:Towards UNAIDS/WHO/MSF, 2004. http:// Universal Access: Recommendations for mednet2.who.int/sourcesprices/ a public health approach 2007. DeterminingEssMedPatentStatusW_ http://www.who.int/hiv/pub/ Depliant.pdf guidelines/paediatric020907.pdf HIV/AIDS medicines and related supplies: Contemporary context and procurement. Technical guide.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 89 Annex 12: Bristol-Myers Squibb: Matrix: Company contacts All countries with the exception Arvind Kanda of Southern Africa: Associate Vice President, Business Abbott: Mrs Marie-Astrid Mercier, Development Rob Dintruff Associate Director, ACCESS & Idis Matrix Laboratories Limited contacts HIV / Access Department BMS office: Paris Plot No. 564/A/22, Road No.92, y Abbott Laboratories, Abbott Place Tel: +33 1 58 83 60 72 Jubilee Hills, Hyderabad – 500 033 219 Golf Club Terrace E-mail: [email protected] Andhra Pradesh, India Constantia Kloof 1719, Tel: +91 40 2770 0363
ompan Johannesburg, South Africa Southern Africa: Fax: +91 99591 14370 Tel: +27 11 858 2000 BMS office: Johannesburg E-mail: [email protected] Mr Archie Smuts Pavan Elisetty Kumar Global Access Program Manager Assistant Manager – Business x 12: C Alkem: Tel: +27 11 456 65 27 Development Sunil Nakhawa E-mail: [email protected] Matrix Laboratories Limited nne DGM – Int’l Busines
A Plot No. 564/A/22, Road No.92, Alkem Laboratories Ltd. Cipla: Jubilee Hills, Hyderabad – 500 033 Alkem House, Senapati Bapat Marg, Mr. Prashant Sisodia Andhra Pradesh, India Lower Parel, Mumbai – 400013, India Exports Manager – Cipla Limited Tel: +91 40 2770 0363 or Tel: +91 22 3982 9999 Tel: +91 22 23025557 (Direct) +91 40 3086 6267 E-mail: [email protected] Fax: +91 22 23070013 / 23070393 / Fax: +91 40 6633 6401 23070385 Aspen: E-mail: [email protected], Merck: Stavros Nicolaou [email protected] Margalit Edelman Senior Executive, Strategic Trade Manager, Global Public Policy Development, Aspen Pharmacare Emcure: Merck & Co. Inc. Tel: +27 (0) 11 239 6200, U. Devbalaji WS2A-65, One Merck Drive, P.O. Box 100 +27 (0) 11 239 6798 (Direct) Director – Global HIV / AIDS Initiatives Whitehouse Station, NJ 08889-0100 Fax: +27 (0) 11 239 6018 Emcure Pharmaceuticals Ltd. Tel: (908) 423 3112 E-mail: [email protected] 255/2, Rajiv Gandhi IT Park, E-mail: [email protected] Hinjwadi, Pune 411 057 Aurobindo: Tel: +91 20 3982 1004 Micro Labs: Sharadd Jain E-mail: [email protected] N.K. Kothari Sr. GM International Sales Executive Vice President International (Formulation) & ARVs Gilead: Micro Labs Ltd. Aurobindo Pharma Limited For organisations in Africa enquiries No. 11 Bank Street, Kilpauk, Survey #313, Bachupally should be directed to: Chennai 600010, India Qutubullapur Mandal Graeme Robertson Tel: +91 44 4285 7705 Hyderabad-500072, India Phone Number: +44 20 8587 2229 E-mail: [email protected] Tel: +91 40 2304 4060 Ext 515 (Office) E-mail: [email protected] E-mail: [email protected] All other enquiries should be directed to: Ranbaxy: Phone Number: +1 650 522 5101 Shailesh Pednekar Boehringer Ingelheim: E-mail: [email protected] General Manager – Global Therapy Philipp Baum Website: http://www.gilead.com/ Management and ARV Business CD Communications access_developing_world Plot No 90 Sector 32, Tel: +49 6132 77 2459 Gurgaon 122001, India Fax: +49 6132 77 3829 Hetero: Tel: +91 124 41 85 911(DIR), E-mail: philipp.baum@ing. Bhavesh Shah +91 41 35 000 ext 5911, boehringer-ingelheim.com Hetero Drugs Limited Fax: +91 124 41 66 035 607/608 Matharu Arcard, Plot No.32, Dr. Michael Rabbow E-mail: [email protected] Corp Comms Corporate Affairs Subhash Road, Vile Parle (E), Tel: +49 (6132) 77 92701 Mumbai – 400 057, India Roche: Fax: +49 (6132) 77 6601 Tel: +91 22 6691 0809 (Office) Sandra Torriani E-mail: michael.rabbow@ Fax: +91 22 2684 5709 Demand Manager boehringer-ingelheim.com Mobile: +91 98210 44912 PTBFPMI E-mail: [email protected] F. Hoffmann-La Roche Ltd Web: www.heterodrugs.com Building 237/2.31 CH-4070 Basel, Switzerland Tel: +41 61 688 9390 E-mail: sandra.torriani_cazzato@ roche.com
90 Médecins Sans Frontières | July 2011 A
Strides: nne Dr. Rajiv Alex
Vice – President – AT&M C 12: x Strides Arcolab Ltd. Bannerghatta Road, Bangalore 560076, India ompan Tel: +91 80 6658 0103 Mobile: +91 96329 25925 Fax: +91 80 6658 0800 E-mail: [email protected] y contacts Mr. Vinod Nair Head – marketing AT&M Strides Arcolab Ltd. Bannerghatta Road, Bangalore 560076, India Tel: +91 80 6658 0720 Mobile: +91 99005 90534 Fax: +91 80 6658 0800 E-mail: [email protected]
Tibotec: Luc Denys Senior Director Worldwide Access Programs, Virology Tibotec- Virco Comm. Va Tel: +32 (0) 14 64 10 18 E-mail: [email protected]
Varichem: T. H. Zidyah (Mrs.) Sales & Marketing Manager Varichem Pharmaceuticals (Pvt) Ltd, 194 Gleneagles Road, Willowvale, Harare, Zimbabwe Tel: +263 4 620 181… to 7 E-mail: [email protected]
ViiV: Scott Purdon Director Access and Government Affairs ViiV Healthcare 980 Great West Road Brentford Middlesex, TW8 9GS UK Tel: +44 20 8380 6228 E-mail: scott.d.purdon@ viivhealthcare.com
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 91 Annex 13: The Clinton Health Access initiative ANTIRETROVIRAL (ARV) PRICE LIST (As of May 2011)
The Clinton Health Access Initiative (CHAI) supports national governments to expand high-quality care and treatment to people living with HIV/AIDS. CHAI offers reduced prices for antiretrovirals (ARVs) to members of its Procurement Consortium.
SUPPLIERS & PRODUCTS Access to CHAI prices assumes prompt QUALITY CHAI has agreements with eight payment following the shipment of CHAI is committed to the sustainable manufacturers of ARV formulations, orders. Purchasers issuing requests for supply of high-quality ARVs, consistent active pharmaceutical ingredients price quotes and/or tenders to which with the specifications of dossiers and/or pharmaceutical intermediates: CHAI partner suppliers are invited to approved by the World Health ANTIRETROVIRAL (ARV) PRICE LIST Aurobindo Pharma, Cipla Ltd., Emcure respond should reference membership Organization (WHO), U.S. Food and Pharmaceuticals, Hetero Drugs, Matrix in the CHAI Procurement Consortium, Drug Administration (U.S. FDA), Laboratories, Micro Labs Ltd., Ranbaxy but requests and tenders need not be or a stringent regulatory authority Laboratories and Strides Arcolabs. restricted to CHAI partner suppliers. (SRA) as defined by the International The ARVs included in CHAI’s pricing Conference on Harmonization (ICH). nitiative PRICES I agreements are: abacavir (ABC), In the list below, footnotes specify the CHAI ceiling prices represent the atazanavir (ATV), efavirenz (EFV), applicable quality assurance status for maximum levels at which indicated emtricitabine (FTC), lamivudine (3TC), each formulation: (1) Approved by
ccess suppliers may price their products lopinavir/ritonavir (LPV/r), nevirapine the WHO Prequalification Programme;
A when selling or communicating price (NVP), ritonavir (RTV), stavudine (d4T), (2) Approved by the U.S. FDA or other quotes to members of the CHAI tenofovir (TDF) and zidovudine (AZT). SRA; (3) Submitted to the WHO, Procurement Consortium. CHAI notes U.S. FDA or other SRA for review
ealth TERMS & CONDITIONS that there may be, in several cases, and recommended for procurement
H opportunities to obtain lower prices Prices listed below are available to by Expert Review Panel (ERP) of as a result of higher volumes, greater countries participating in the CHAI The Global Fund; (4) Submitted to the competition, and other market factors. Procurement Consortium, which WHO, U.S. FDA or other SRA for review currently includes over 70 nations. We encourage Consortium members
linton but not yet recommended by ERP. These prices apply to procurements to seek and take advantage of such C by national governments that are opportunities and to base treatment he members of the CHAI Procurement decisions on observed market prices, Consortium, or organizations with ceiling prices indicating the upper procuring on behalf of member bounds of treatment costs. Prices listed
x 13: T governments, to support public care below are FCA Airport from the point and treatment programs. Products of export. Annual treatment costs for
nne should be purchased directly pediatric formulations are determined A from partner suppliers or through based on the recommended daily procurement agents representing dosing for a 10 kg child (unless a the aforementioned programs. formulation is not recommended for For TDF products offered by suppliers a 10kg child, in which case the annual under a voluntary licence from Gilead, price is calculated based on dosing indicated pricing is available only to for an applicable weight band). countries covered under the voluntary licence. Please contact Neeraj Mohan at [email protected] with any questions related to this issue.
92 Médecins Sans Frontières | July 2011 A
The Clinton Health Access Initiative — Antiretroviral (ARV) nne Price List x 13: T 13: x
ADULT PRODUCTS CEILING PRICE (USD) SUPPLIER he
Name and strength Packaging Per Year Per Pack Per Unit Aurobindo Cipla Emcure Hetero Matrix Ranbaxy Micro C linton HDPE bottle 3TC (150mg) $32 $2.6 $0.044 2 1 1,2 1,2 4 60 tablets a a a a a HDPE bottle ABC (300mg) $210 $17.5 $0.292 2 1,2 1,2 60 tablets a a a H HDPE bottle 2 1,2 1,2 1,2 1 AZT (300mg) $89 $7.4 $0.123 ealth 60 tablets a a a a a AZT (300mg) + HDPE bottle $105 $8.8 $0.146 2 1,2 1,2 1,2 1 1 3TC (150mg) 60 tablets a a a a a a A AZT (300mg) +
HDPE bottle ccess 3TC (150mg) + $134 $11.2 $0.186 2 1,2 1,2 1,2 1 60 tablets a a a a a NVP (200mg) HDPE bottle ATV (300mg)* $265 $22.1 $0.736 2 1,2 30 capsules a a I nitiative HDPE bottle d4T (30mg) $24 $2.0 $0.033 2 60 capsules a d4T (30mg) + HDPE bottle $45 $3.8 $0.063 1,2 2 1 3TC (150mg) 60 tablets a a a
d4T (30mg) + HDPE bottle LIST PRICE (ARV) ANTIRETROVIRAL 3TC (150mg) + $79 $6.6 $0.110 1,2 1,2 1 60 tablets a a a NVP (200mg) HDPE bottle EFV (600mg) $60 $5.0 $0.167 2 1,2 30 tablets a a HDPE bottle LPV/r (200/50mg) $399 $33.3 $0.277 2 2 1,2 120 tablets a a a HDPE bottle NVP (200mg) $36 $3.0 $0.050 2 1,2 1,2 1,2 60 tablets a a a a RTV (100mg) HDPE bottle $90 $7.5 $0.250 1 heat stable* 30 tablets a HDPE bottle TDF (300mg) $78 $6.5 $0.217 2 1,2 2 1,2 1 30 tablets a a a a a TDF + 3TC HDPE bottle $99 $8.3 $0.275 2 2 2 1,2 (300/300mg)* 30 tablets a a a a
TDF + FTC HDPE bottle $126 $10.5 $0.350 2 3 1,2 (300/200mg) 30 tablets a a a
TDF + 3TC + EFV HDPE bottle $169 $14.1 $0.469 1,2 (300/300/600mg) 30 tablets a
TDF + FTC + EFV HDPE bottle $194 $16.2 $0.539 1,2 (300/200/600mg) 30 tablets a
ATV (300mg) + Blister Pack of 30 tablets each RTV 100mg + TDF $395 $32.9 4 of ATV + RTV a /3TC (300/300mg) + TDF/3TC
* Abbott, the originator for the heat-stable formulation of RTV, has an access pricing policy of its own and has not joined CHAI’s ceiling price agreement. The company supplies the drug at a reduced price of $42 per person per year to its Category 1 countries, which includes countries in sub-Saharan Africa and all other Least-Developed Countries. Thus, when the individual components are purchased separately from different suppliers, the TDF+3TC+ATV+RTV regimen is available at less than $410 per person per year.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 93 The Clinton Health Access Initiative — Antiretroviral (ARV) Price List
PAEDIATRIC PRODUCT CEILING PRICE (USD) SUPPLIER
Name and strength Packaging Per Year Per Pack Per Unit Aurobindo Cipla Matrix Strides
HDPE bottle 3TC (50mg/5ml)* $28 $1.85 $0.008 2 240ml a HDPE bottle ABC (20mg/ml)* $203 $13.50 $0.056 2 1 240ml a a HDPE bottle ABC 60mg $125 $5.20 $0.087 2 1,2 60 tablets a a HDPE bottle ABC (60mg) + 3TC (30mg) $151 $6.30 $0.105 2 1 60 tablets a a HDPE bottle AZT (50mg/5ml)* $63 $2.10 $0.009 2 240ml a ANTIRETROVIRAL (ARV) PRICE LIST HDPE bottle AZT (100mg) $34 $4.75 $0.048 2 1,2 100 capsules a a HDPE bottle AZT (60mg) + 3TC (30mg) $78 $3.25 $0.054 2 1 60 tablets a a AZT (60mg) + 3TC (30mg) HDPE bottle nitiative $102 $4.25 $0.071 a1,2 I + NVP (50mg) 60 tablets HDPE bottle d4T (1mg/ml)* $47 $1.30 $0.007 2 200ml a
ccess HDPE bottle d4T (15mg) $16 $1.35 $0.023 a2 A 60 capsules HDPE bottle d4T (20mg) $8 $1.40 $0.023 2 60 capsules a HDPE bottle ealth d4T (6mg) + 3TC (30mg) $46 $1.90 $0.032 2 60 tablets a H HDPE bottle d4T (12mg) + 3TC (60mg) $40 $3.30 $0.055 2 60 tablets a d4T (6mg) + 3TC (30mg) HDPE bottle $55 $2.30 $0.038 1,2 + NVP (50mg) 60 tablets a linton
C d4T (12mg) + 3TC (60mg) HDPE bottle $52 $4.30 $0.072 1,2 + NVP (100mg) 60 tablets a he HDPE bottle EFV (50mg) $27 $2.24 $0.075 2 2 30 tablets a a HDPE bottle EFV (200mg) $34 $8.55 $0.095 2 2 x 13: T 90 capsules a a HDPE bottle EFV (200mg) $38 $9.60 $0.107 a1,2 nne 90 scored tablets A HDPE bottle LPV/r (100/25mg) $214 $17.85 $0.149 2 1 120 tablets a a HDPE bottle LPV/r (80 +20 mg/ml)* $240 $48.00 $0.160 3 300ml a HDPE bottle NVP (50mg/5ml)* $59 $1.95 $0.008 2 240ml a
* Price includes a measuring device such as a syringe, which was not included in the prior ceiling price list.
94 Médecins Sans Frontières | July 2011 R References eferences
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Rejection order of Patent Application patients infected with retrovirus. EP0273277 dos EUA (Government Will produce AIDS No. 2076/DEL/1997 [Online] 2009 July 30 (A2) [Online]. 1988 Jul 7 [cited 2010 May 22]. drug that used to be imported from the US) [cited 2011 June 18] Available from: Indian Available from: European Patent Office: esp@ Correio Braziliense 2011 Feb 10. Available Patent Officehttp://ipindiaonline.gov. cenet: http://v3.espacenet.com/textdoc?DB= from: http://www.correiobraziliense.com. in/decision/2076-DEL-1997-344/2076-del- EPODOC&IDX=EP0273277&F=8 br/app/noticia/brasil/2011/02/10/interna_ 1997%20cipla.pdf brasil,237010/governo-passara-a-fabricar- 275. WTO: TRIPS and public health [Online] 286. Rejection order of Patent Application remedio-contra-aids-que-era-importado-dos- [cited 2010 May 23]. 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104 Médecins Sans Frontières | July 2011 País (Company refrains from launching and R 297. Department of Health and Human 314. Pharmaceutical compositions eferences Services. Letter to Dara Wambach, Regulatory anti-AIDS drug because it disagrees with the containing lamivudine and zidovudine. Affairs, Gilead Sciences. Supplement Approval. patent law of the country). Estado de São WO9818477 (A2) [Online]. 1998 May [Letter]. 2010 Mar 24. Available from: http:// Paulo 2008 Jan 19. Available from: http:// 7 [cited 2010 May 23]. Available from: www.accessdata.fda.gov/drugsatfda_docs/ www.abin.gov.br/modules/articles/article. European Patent Office: esp@cenet:http:// php?id=1806 appletter/2010/021356s033ltr.pdf v3.espacenet.com/origdoc?DB=EPODOC&ID 298. U.S. Food and Drug Administration. 307. Highlights of prescribing information X=WO9818477&F=0&QPN=WO9818477 FDA application search orphan drug – Retrovir (zidovudine) [Online] US Food 315. 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DevelopingProductsforRareDiseases Ltd, Bangalore, (KS) in respect of application com/1RuvPUO Conditions/HowtoapplyforOrphanProduct No 896/Del/2002 and hearing held on Designation/ucm135125.htm 18/09/2008. 2009 Jul 30 [cited 2010 May 317. Pre Grant Opposition by PLHIV Networks 23]. Available from: http://www.i-mak.org/ to Patent Application No. 2044/CAL/1997 300. Pyranone compounds useful to treat storage/896.DEL.2002_Intermed%20Labs.PDF [Online] [Cited 2011 June 20] Available from: retroviral infections. WO9530670 (A2) http://indianpatentoppositions.blogspot. [Online] 1995 Nov 16 [cited 2010 May 22]. 309. 9527/DELNP/2007. Indian com/2011/06/azt3tc-opposition.html Available from: European Patent Office: esp@ Patent Information Retrieval System. cenet: http://v3.espacenet.com/origdoc?DB= Office of Controller General of Patents 318. Open Letter from GSK promising EPODOC&IDX=WO9530670&F=0&QPN=W Designs, and Trademarks. [Online] withdrawal of AZT/3TC FDC [Online] 2006 O9530670 India, 2011, June [cited 2011, June 22] August 9 [Cited 2011 June 20] Available from: Available from: http://124.124.220.66/ 301. Self-emulsifying formulation for lipophilic http://indianpatentoppositions.blogspot. patentpublishedsearch/publishApplication compounds. WO9906043 (A1) [Online]. 1999 com/2011/06/azt3tc-opposition.html Number.aspx?application_number=9527/ Feb 11 [cited 2010 May 23]. Available from: DELNP/2007 319. Pharmaceutical combinations European Patent Office: esp@cenet: http:// comprising lamivudine, zidovudine and v3.espacenet.com/origdoc?DB=EPODOC&IDX 310. 9661/DELNP/2007. Indian efavirenz for treating viral infections. =WO9906043&QPN=WO9906043 Patent Information Retrieval System. WO2004089382 (A1) [Online]. 2004 Oct 21 Office of Controller General of Patents 302. Pharmaceutical composition for acidic [cited 2010 May 23]. Available from: European Designs, and Trademarks. [Online] lipophilic compounds in a form of a self- India, 2011, June [cited 2011, June 22] Patent Office: esp@cenet:http://v3.espacenet. emulsifying formulation. WO9906044 (A1) Available from: http://124.124.220.66/ com/origdoc?DB=EPODOC&IDX=WO200408 [Online]. 1999 Nov 11 [cited 2010 May 22]. patentpublishedsearch/publishApplication 9382&F=8&QPN=WO2004089382 Available from: European Patent Office: esp@ Number.aspx?application_number=9661/ cenet: http://v3.espacenet.com/origdoc?DB 320. Panel on Antiretroviral Guidelines for DELNP/2007 =EPODOC&IDX=WO9906044&QPN=WO9 Adults and Adolescents. Guidelines for the 906044 311. Application Number 9661/ use of antiretroviral agents in HIV-1-infected DELNP/2007. Stable Fixed-Dose Unitary adults and adolescents. Department of Health 303. Brazil. Agencia Nacional de Vigilancia Formulations Containing tenofovir, a and Human Services. December 1, 2009; Sanitaria. Anuência prévia a produtos e surfactant, efavirenz and emtricitabine. processos farmacêuticos: situação dos 49. [cited 2010 May 20]. Available from: [Online]. 2007 Dec 13. [cited 2010 May 22]. processos atualizado até 30/11/2009. Patent http://www.aidsinfo.nih.gov/ContentFiles/ Intellectual Property India. Office of Controller application no. PI 9507615-8. Available from: AdultandAdolescentGL.pdf General of Patent, Designs and Trademarks. http://www.anvisa.gov.br/medicamentos/ Available from: http://124.124.220.66/ 321. Unnikrishnan C.H. GSK withdraws intelectual/situacao_processos.pdf patentpublishedsearch/publishApplication trizivir patent application ‘in public 304. Novos medicamentos: alternativas Number.aspx?application_number=9661/ interest’. livemint.com and The Wall Street para a falência terapêutica (New Medicines: DELNP/2007 Journal 2007 Oct 10 [cited 2010 May alternatives for therapeutic failure). Cadernos 23]. Available from: http://www.livemint. 312. Pharmaceutical combination. pela vidda – Aids, tratamento e ativismo. WO2007068934 (A2) [Online]. 2007 Jun com/2007/10/10005826/GSK-withdraws- 2007 Apr;44:4-7. Available from: http://www. 21 [cited 2010 May 22]. Available from: Trizivir-patent.html aids.org.br/media/File/cadernos/CPV_n44.pdf European Patent Office: esp@cenet:http:// 322. Apotex. About Apo-Triavir [Online] 305. Vieira, M. Empresas transnacionais v3.espacenet.com/origdoc?DB=EPODOC&I [cited 2010 May 23]. Available from: http:// européias na América Latina: Estudo de caso DX=WO2007068934&F=0&QPN=WO2007 www.apotex.com/apotriavir/default.asp de transnacionais farmacêuticas no Brasil. 068934 (Transnational European companies at Latin 323. IN240930 – Prodrugs of Aspartyl 313. Antiviral combinations containing America: Case study of pharmaceutical nucleoside analogs. WO9220344 (A1) protease inhibitors [online] [cited 2011, transnational in Brazil) GTPI/REBRIP – ABIA [Online]. 1992 Nov 26[cited 2010 May 23]. 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Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 105 Glossary and Abbreviations bbreviations A 3TC: lamivudine; nucleoside analogue CHF: Swiss franc. of clinical trials) for the purpose of reverse transcriptase inhibitor. obtaining marketing approval may and CIF: ‘Cost Insurance and Freight’.
y not be used for a specified period by ABC: abacavir; nucleoside analogue A commercial term (incoterm 2000) regulatory authorities to grant approval reverse transcriptase inhibitor. meaning that the seller delivers once to a generic product.1 the goods pass the ship’s rail in the AIDS: Acquired Immune Deficiency
lossar Syndrome. port of shipment. The seller must pay d4T: stavudine; nucleoside analogue G the costs and freight necessary to reverse transcriptase inhibitor. API: active pharmaceutical ingredient. bring the goods to the named port ddl: didanosine; nucleoside analogue ARIPO: African Regional Intellectual of destination BUT the risk of loss reverse transcriptase inhibitor. Property Organisation. There are or damage to the goods, as well as any additional costs due to events currently seventeen states which are Differential pricing: The practice of occurring after the time of delivery, are party to the Lusaka Agreement and setting different prices for different transferred from the seller to the buyer. therefore members of ARIPO. These markets, typically higher prices in are: Botswana, Gambia, Ghana, Kenya, CIP: ‘Carriage and Insurance paid to...’. richer markets and lower prices in Lesotho, Liberia, Malawi, Mozambique, A commercial term (incoterm 2000) poorer markets.1 Companies sometimes Namibia, Sierra Leone, Somalia, Sudan, meaning that the seller delivers the offer standardised price discounts Swaziland, Tanzania, Uganda, Zambia goods to the carrier nominated by him, - whereby all countries in a certain and Zimbabwe. but the seller must in addition pay the income bracket or geographical area ARV: Antiretroviral medicine to treat cost of carriage necessary to bring the are eligible for one standardised price. HIV/AIDS. goods to the named destination. This Other companies offer differential prices means that the buyer bears all the risks ATV: atazanavir, protease inhibitor. that are negotiated on a case-by-case and any additional costs occurring basis and are often unpublished. AZT: zidovudine (also abbreviated after the goods have been delivered. to ZDV), nucleoside analogue reverse However, in CIP the seller also has to DDU: ‘Delivered duty unpaid’. transcriptase inhibitor. procure insurance against the buyer’s A commercial term (incoterm 2000) meaning that the seller delivers the BI: Boehringer Ingelheim. risk of loss of or damage to the goods during carriage. Consequently, the goods to the buyer, not cleared for BMS: Bristol-Myers Squibb. seller contracts for insurance and pays import, and not unloaded from any arriving means of transport at the Category 1: In this document, the insurance premium. named place of destination. The seller ‘Category 1’ is used to describe those CL: see compulsory licence. countries that are eligible for the most has to bear the costs and risks involved discounted price offered by a company. Compulsory licence: A licence to in shipping the goods, other than, exploit a patented invention granted where applicable, any ‘duty’ (which Category 2: In this document, by the state upon request of a includes the responsibility for the risks ‘Category 2’ is used to describe those third party.1 of the carrying out of the customs countries that are not eligible for the formalities, and the payment of lowest prices reserved for category 1 Counterfeit drugs: Drugs which formalities, customs duties, taxes countries, but are nevertheless offered are deliberately and fraudulently and other charges) for import in the a discount by companies. Crucially, this mislabelled with respect to identity or country of destination. Such ‘duty’ has discount is usually considerably smaller source. Counterfeiting can apply to than the discount offered to category 1 both branded and generic products. to be borne by the buyer as well as any countries. Counterfeit products may include costs and risks caused by his failure to clear the goods for the import time. CCR5: chemokine coreceptor 5. products with the correct ingredients or the wrong ingredients, without Divisional patent: A type of patent CHAI: Clinton Health Access Initiative. active ingredients, with insufficient application which contains matter Since 2002, the Clinton Health Access active ingredient or with fake from a previously filed application. Initiative has assisted countries in packaging.1 implementing large-scale, integrated DRV: darunavir, protease inhibitor. care, treatment and prevention Data exclusivity: A legal provision programmes. that data collected (e.g. the results EC: enteric-coated.
106 Médecins Sans Frontières | July 2011 G
EFV: efavirenz; non-nucleoside damage to the goods from that point. NVP: nevirapine; non-nucleoside lossar analogue reverse transcriptase inhibitor. The FOB term requires the seller to analogue reverse transcriptase inhibitor. Also abbreviated to EFZ. clear the goods for export. OAPI: Organisation Africaine de
EMA: European Medicines Agency. FPV: fosamprenavir; protease inhibitor. la Propriété Intellectuelle, African y
Formerly European Agency for the Intellectual Property Organisation, and FTC: emtricitabine; nucleoside analogue Evaluation of Medicinal Products. whose member states are Benin, reverse transcriptase inhibitor. A Essential medicines list (EML): First Burkina Faso, Cameroon, Central Generic drug: According to WHO, bbreviations published by WHO in 1977, it serves to African Republic, Chad, Congo, Côte a pharmaceutical product usually identify a list of medicines, which provide d’Ivoire, Gabon, Guinea, Guinea-Bissau, safe and effective treatment for infectious intended to be interchangeable with Equatorial Guinea, Mali, Mauritania, and chronic diseases affecting the vast the originator product, which is usually Niger, Senegal, Togo. majority of the world’s population. The manufactured without a licence from Patent: An exclusive right awarded 17th edition of the adult list and the the originator company. to an inventor to prevent others 3rd edition of the children’s list were GPRM: WHO Global Price Reporting from making, selling, distributing, published in March 2011. Mechanism. A database containing importing or using the invention, ETV: Etravirine, non-nucleoside reverse prices paid by UNICEF, the International without licence or authorisation, for a transcriptase inhibitor. Dispensary Association (IDA), fixed period of time. There are usually Management Sciences for Health three requirements for patentability: EU: European Union. (MSH)/Deliver, and the Global Fund to novelty (new characteristics which Evergreening: A term popularly used Fight AIDS, Tuberculosis and Malaria. are not ‘prior art’); inventive step or to describe patenting strategies that GSK: GlaxoSmithKline. non-obviousness (knowledge not are intended to extend the patent term obvious to one skilled in the field); on the same compound.1 HDI: Human Development Index. and industrial applicability or utility.1 A summary composite index, compile Expert review panel: An independent by UNDP, that measures a country’s Patent Cooperation Treaty: technical body composed of external average achievements in three basic An international patent law treaty, technical experts, hosted by the WHO aspects of human development: concluded in 1970 that provides a Department of Essential Medicines and longevity (or life expectancy at birth), unified procedure for filing patent Pharmaceutical Policies. Their purpose knowledge (or adult literacy rate and applications to protect inventions in is to review the potential quality risk of enrolment in education), and a decent each of its contracting states. A patent using antiretroviral, anti-tuberculosis standard of living (gross domestic application filed under the PCT is and antimalarial products which are product per capita). called an international application, not yet WHO prequalified or authorised or PCT application. by a stringent regulatory authority, HIV: Human Immunodeficiency Virus. and to give advice to the Global Fund Patent pool: A patent pool for IDV: indinavir; protease inhibitor. whether procurement of such products medicines has the potential to can be authorised. LDCs: Least-Developed Countries, increase access to patented medicines according to United Nations classification. for people living with HIV in the EXW: ‘Ex-works’. A commercial term developing world, by creating a (incoterm 2000) meaning that the LPV/r: lopinavir/ritonavir; boosted structure for patent holders to share seller delivers when he places the protease inhibitor. their HIV drug patents and receive goods at the disposal of the buyer at royalties in return. Drug companies the seller’s premises or another named MSF: Médecins Sans Frontières, can then access these patents to place (i.e. works, factory, warehouse Doctors Without Borders. produce more affordable versions of etc.) not cleared for export and not MVC: maraviroc; entry inhibitor. loaded on any collecting vehicle. the patented medicines. Companies NFV: nelfinavir; protease inhibitor. are financially rewarded, and patients FDC: fixed-dose combination – multiple benefit from access to more affordable NGO: Non-Governmental Organisation. drugs combined in a single pill. medicines. The Medicines Patent Pool First-line drugs: The drugs used as a NIH: National Institutes of Health. was formally established in July 2010. first resort to treat a disease. NNRTI: Non-Nucleoside Reverse PCT: See Patent Cooperation Treaty. Transcriptase Inhibitor. FOB: ‘Free on board’. A commercial PEPFAR: President’s Emergency (incoterm 2000) term meaning that NRTI: Nucleoside Analogue Reverse Plan for AIDS Relief, a United States the seller delivers when the goods pass Transcriptase Inhibitor. programme to fight HIV/AIDS in the ship’s rail at the named port of developing countries. shipment. This means that the buyer NtRTI: Nucleotide Reverse has to bear all costs and risks of loss or Transcriptase Inhibitor. PI: Protease Inhibitor.
Untangling the Web of ARV Price Reductions | Please check utw.msfaccess.org 107 PMTCT: Prevention of Mother-to-Child UNAIDS: United Nations Joint Transmission. Cosponsored Programme on HIV/AIDS. Created in 1996, to lead, strengthen ppy: per patient per year. and support an expanded response to r: low-dose ritonavir, used as a booster. the HIV/AIDS epidemic. The six original cosponsors are UNICEF, UNDP, UNFPA, R&D: research and development.
bbreviations UNESCO, WHO and the World Bank.
A UNDCP joined in April 1999. RAL: raltegravir; integrase inhibitor. UNDP: United Nations Development
and RTV: ritonavir; protease inhibitor. Programme. y Second-line drugs: Second-line drugs UNITAID: is an international drug are used when the first-line drugs are purchase facility that was established in no longer effective. 2006 by Brazil, Chile, France, Norway lossar
G Standardised price discounts: and the United Kingdom and now See differential pricing. includes 27 countries to provide new sources of funding to fight HIV/AIDS, Stringent regulatory authority: malaria and tuberculosis. A medicines regulatory authority which US FDA: United States Food and Drug ‘is (a) a member of the International Administration. Conference of Harmonization (ICH); a (b) an ICH observer, being the European VL: voluntary licence. Free Trade Association as represented WHO: World Health Organization. by Swiss Medic, Health Canada and World Health Organization; or (c) a WHO Prequalification: A project regulatory authority associated with originally intended to give United an ICH member through a legally Nations procurement agencies, such binding mutual recognition agreement as Unicef, a choice of products including Australia, Norway, Iceland and meeting various standards as certified by WHO. With time, other agencies Liechtenstein (as may be updated from and governments have found this time to time).’2 a useful service.1 SQV: saquinavir; protease inhibitor. WTO: World Trade Organization. TB: tuberculosis. ZDV: zidovudine (also abbreviated TDF: tenofovir disoproxil fumarate; to AZT); nucleoside analogue reverse nucleotide reverse transcriptase transcriptase inhibitor. inhibitor.
Tentative FDA approval: Is awarded 1 Public Health innovation and intellectual by the US FDA to a drug product that property rights – Report of the Commission on Intellectual Property Rights, Innovation and has met all required quality, safety and Public Health, World Health Organization.
efficacy standards, but is not eligible 2 http://www.theglobalfund.org/documents/ for marketing in the US because of psm/List_of_Countries_SRA.pdf existing patent protection. Tentative approval does make the product eligible for purchase outside of the US under the PEPFAR programme.
TMC 207: Rilpivirine, non-nucleoside reverse transcriptase inhibitor.
TPV: tipranavir; protease inhibitor.
TRIPS: Trade-related Aspects of Intellectual Property Rights.
UN: United Nations.
108 Médecins Sans Frontières | July 2011 Acknowledgements:
Front and back cover photos: © Sven Torfinn
Design/artwork/print: ACW Ltd +44 (0)20 8392 4330 www.acw.uk.com
Disclaimer: “Untangling the Web of Price Reductions” is a pricing guide and cannot be regarded as a company price list nor as a clinical guideline. It is crucial that any purchaser verify prices and availability as well as quality status directly with the supplier before procurement. Médecins Sans Frontières has made every effort to ensure the accuracy of prices and other information presented in this report, but MSF makes no representations or warranties, either expressed or implied, as to their accuracy, completeness or fitness for a particular purpose. Inclusion of a product in this document does not indicate MSF purchases or uses the product. Information on patent status of the products mentioned in this guide is indicative only and not exhaustive, and should be verified with relevant national patent offices when used for other than reasons of general information. Clinical decisions should not be made based on this document.
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