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THE MSF CAMPAIGN FOR ACCESS TO ESSENTIAL MEDICINES In 1999, in the wake of Médecins Sans Frontières (MSF) being awarded the Nobel Peace Prize, 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.

THE INTERNATIONAL UNION AGAINST TUBERCULOSIS AND LUNG DISEASE The mission of the International Union Against Tuberculosis and Lung Disease (The Union) is to bring innovation, expertise, solutions and support to address health challenges in low- and middle-income populations. With nearly 10,000 members and subscribers from 152 countries, The Union has its headquarters in Paris and offices serving the Africa, Asia Pacific, Europe, Latin America, Middle East, North America and South-East Asia regions. Its scientific departments focus on tuberculosis and HIV, lung health and non-communicable diseases, tobacco control and research.

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TABLE OF CONTENTS

14 Introduction

16 The problems that plague DR-TB medicines 17 Limited number of quality sources 19 Limited affordability 10 The neglect of children, and people living with HIV/AIDS 12 Conclusions: Breaking the vicious circle

14 Drug Profiles

Group Two: Injectables 14 Kanamycin 16 Amikacin 18 Capreomycin

Group Three: Fluoroquinolones 20 Moxifloxacin 22 Levofloxacin 24 Ofloxacin

Group Four: Oral bacteriostatic second-line agents 26 Ethionamide 28 Prothionamide 30 Cycloserine 32 Terizidone 34 PAS

Group Five: Agents with unclear efficacy 36 Clofazimine 38 Linezolid

Annexes 40 Methodology 41 Glossary and Abbreviations 43 References 45 Company contacts 47 Disclaimer

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Introduction

Tuberculosis (TB) is a curable disease perspective: treatment is individualised, medicines. For many DR-TB medicines, that continues to kill nearly 1.4 million tailored according to which drugs a the sustainability of drug supply is people1 across the globe each year, patient is resistant to. It is long and constantly under threat and therefore and is the main cause of death in taxing, requiring people to take a extremely vulnerable to disruption. For people living with HIV/AIDS2. Of the course of antibiotics for up to two some medicines, there is only one 9.4 million new tuberculosis cases each years and endure often intolerable side quality-assured source, while for others year, 440,000 are forms of the disease effects. Partly as a result of the there may be several but they all rely that are multi-drug-resistant3, meaning complexities of treatment, on a single source of the active they can not be treated with the two programmes must devote considerable pharmaceutical ingredient required to primary antibiotics used to treat TB. resources to adherence counselling, the make the drug. Over the last decade, roughly five management of side effects and million people developed drug- psychosocial care, all of which place Some of the DR-TB drugs come at resistant TB, but less than 1% had large demands on human resources. In extremely high prices, with the result access to appropriate treatment, and some countries, the lack of political will that one patient's treatment can cost 1.5 million died4. to appropriately address DR-TB is a almost $9,000 - nearly 475 times more major barrier. than a $19 treatment course for drug- That such an appallingly low sensitive TB. Alarmingly, in recent years proportion of patients should access Another factor that hampers scale-up prices have actually been increasing as appropriate treatment is due to a of treatment - and the focus of this some manufacturers put an end to number of factors. Treating DR-TB is report - is the limited availability and subsidies that have kept prices lower. complicated from a programmatic high cost of quality-assured second-line

DR, MDR, XDR, PDR: the many faces of resistant TB Drug-resistant tuberculosis (DR-TB) is used to describe strains of TB that show resistance to one or more first-line drugs. Multidrug-resistant tuberculosis (MDR-TB) is defined by TB that is resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. Extensively drug-resistant tuberculosis (XDR-TB) is caused by strains of MDR-TB that are also resistant to second-line drugs, including at least one from the class of fluoroquinolones, and at least one of three injectable second-line drugs (capreomycin, kanamycin and amikacin). All forms of resistance to more than one of the first-line antibiotics, and which are neither MDR-TB nor XDR-TB, are defined as polydrug-resistant TB (PDR-TB).

THE UNION AND TB MSF AND TB The International Union Against Tuberculosis and Lung Disease In 2010, MSF treated close to 30,000 people (The Union) has been the leading international TB control and for tuberculosis, of which 3,300 were prevention agency since 1920. Each year The Union works in children under the age of 15. MSF - often more than 70 countries, providing technical assistance at the working alongside national health authorities request of national tuberculosis control programmes; conducting - treats patients for TB in 29 countries in a operational research and clinical trials; organising conferences wide variety of settings, ranging from urban and courses; and publishing both a peer-reviewed journal and a slums to rural areas, prisons or refugee range of technical guides. In addition, The Union regularly camps. monitors MDR-TB project sites and provides technical assistance on all aspects of MDR-TB management in Africa, Asia, Latin In recent years, MSF has worked to increase America and the Middle East. Its clinical trial of a shortened the numbers of people it treats with drug- standardised MDR-TB treatment regimen will begin enrolling resistant tuberculosis from 11 patients in patients in 2011 and has the potential to revolutionise the 2001 to around 1,000 people across 15 management of MDR-TB. countries in 2010.

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“Was it possible that I could live?” - The story of Happiness

DR-TB can be cured, but treatment Photo © Krisanne Johnson requires people to take a course of up to six different antibiotics – as many as 20 pills per day for up to two years, plus, for the first six months, a daily painful injection. Patients often endure intolerable side effects. These can include nausea, severe vomiting, depression, aggressive behaviour, hallucinations, vertigo, hearing loss, diarrhoea and lethargy. Patients may need to take additional medication to mitigate these side effects. Treatment needs to be tailored to the precise drugs that will be effective for a patient, depending on their drug-resistance profile. People's lives are interrupted by DR-TB treatment, and many find adhering to it too arduous to bear. Happiness Dlamini from Swaziland shares what life is like on DR-TB treatment. Happiness Dlamini lies with her daughter Nokwenza outside her home in Swaziland. She keeps her distance so she does not spread MDR-TB to her child. Happiness Dlamini lives with her eleven year-old son and four-year old daughter in the village of Emhlabeni - four hours drive from MDR-TB. She started treatment within 30 minutes to make sure I'm Mbabane, the capital of through MSF's community care not defaulting on my treatment.” Swaziland. Before getting sick, she MDR-TB programme in Shiselweni worked as a housekeeper. She is Region, after she was diagnosed in Every day, Happiness struggles not living with HIV and is also infected December 2010. When she started only with the burdens of treatment, with multidrug-resistant treatment, she had to take 18 and a but with the stress of not being able tuberculosis, which is all too half tablets every day, in addition to to provide for her family. And common in the small southern receiving a painful injection from a keeping her distance from her African country. One third of those health worker who comes to her children to make sure they don't newly diagnosed with TB in home. Now, over three months later get infected is affecting her Swaziland have DR-TB12. her daily routine still consists of an relationship with her four-year-old injection and 15 and a half pills. daughter in particular - little “I had been coughing for a long Nokwenza has now become closer time, so after discussion with my The side-effects the medicines cause to her grandmother. family, we felt I should go get are harsh - she can barely list all of tested for TB,” she says. “I was them - and have made her feel Happiness has responded well to very scared when they told me I mentally unstable and physically ill. treatment so far and has been had MDR-TB. To me, it meant the determined to stay the course. But end of my life, because everyone “It was like I was losing my mind - I she does not find it easy to be in my community that I knew had had hallucinations and found myself optimistic. MDR-TB had died.” banging against things at night,” she says. “I have sore feet and my “I have to be honest that when it Happiness learned that if she was legs cramp up. I have diarrhoea and comes to my future, I am very able to stick to her treatment, she I often vomit after taking the pills, so unsure,” Happiness says. “I really had a good chance at surviving I have to take them again if it was don't know what will happen.”

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The problems that plague DR-TB medicines

This report provides an overview of available DR-TB medicines, providing GROUPING DRUGS relevant information for each product, including its sources, quality status and Group 1 - First-line oral agents isoniazid*, rifampicin*, price, that can aid treatment providers, ethambutol*, pyrazinamide*, treatment programmes and national rifabutin* procurement centres in making procurement decisions. Transparency Group 2 - Injectable agents kanamycin, amikacin, capreomycin, of price and quality information is one streptomycin* problem that this document also aims to help overcome. In providing this Group 3 - Fluoroquinolones moxifloxacin, levofloxacin, overview, a number of important ofloxacin problems that hamper access to medicines are brought to light. Group 4 - Oral bacteriostatic ethionamide, prothionamide, second-line agents cycloserine, terizidone, p- The medicines examined in this report aminosalicylic acid (PAS) are those DR-TB drugs classified in groups 2-5 of the World Health Group 5 - Agents with unclear clofazimine, linezolid, Organization's 2008 Guidelines for the efficacy amoxicillin/clavulanate*, Programmatic Management of Drug- thioacetazone*, resistant Tuberculosis. Certain problems imipenem/cilastatin*, high-dose are more relevant to some drug classes isoniazid*, clarithromycin* than others. * this report does not include first-line oral agents, first-line injectable agents, or certain group 5 agents

How countries procure DR-TB drugs

In response to a growing need for From 2000 to end 2010, a programmes, compared to an DR-TB treatment - and to prevent cumulative total of 105,140 patients estimated 440,000 new cases and further drug resistance from were approved for treatment 150,000 deaths3. developing through improper use through the GLC - although less of DR-TB drugs - the World Health than half of these (under 30,000 Many programmes continue to use Organization, together with MSF, patients) had actually been started DR-TB drugs from outside the GLC and other partners, created the on treatment by the end of 200972. process, where drug quality may be 'Green Light Committee' Initiative uncertain, and drug prices may be (GLC) in 20009. The core function Until now, programmes without GLC substantially higher7. This is of the Green Light Committee has approval are not allowed to turn to especially concerning in countries been to provide technical review of the Global Drug Facility to access with the highest disease burden. proposed DR-TB treatment WHO quality-assured medicines. projects, and 'green-light' them if The GLC Initiative has been they meet certain criteria. Not surprisingly, nearly one decade undergoing a reform process since Approved projects then get access on, only 13% of the estimated DR- early 2010 and an intended key to quality-assured drugs at reduced TB drug market is channelled change is to let all programmes prices - since 2002, these have through the Global Drug Facility. In purchase quality-assured medicines been procured through the WHO- 2010, only 12,000 patients were through the GDF13. hosted Global Drug Facility. enrolled in GLC-approved treatment

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Global DR-TB drug market

The global DR-TB market was estimated to be worth $300 million in 2010, with only $125 million procured through the public sector. Of this, only $40 million was channelled through the Global Drug Facility.

The market has been growing by approximately 5% per year, with India and China taking the largest share, at 63% and 17%, respectively17.

1. Limited number of quality sources

Relatively few products for the The example of kanamycin illustrates One welcome step is that the Global treatment of drug-resistant tuberculosis the risks associated with relying on few Drug Facility now has a clear policy, are included on the WHO List of sources for a given medicine. In the sending a signal to manufacturers to Prequalified Medicinal Products or past, several manufacturers had invest in quality, by requiring products approved by a stringent drug kanamycin registered for use in the US, to be either quality assured by the regulatory authority such as the US although all but one subsequently World Health Organization's Food and Drugs Administration. Such ceased production, because of falling prequalification programme, or quality approval is a requirement by demand in wealthy countries. Today, approved by the Expert Review Panel. donors financing MDR programmes only three quality-assured sources are The Panel provides time-limited such as the Global Fund to Fight AIDS, identified. Of those, the first was forced approval for products that have fewer TB and Malaria. to suspend production because of the than three sources approved by either relocation of its supplier of active the WHO Prequalification or a stringent To date, of the DR-TB medicines pharmaceutical ingredient in 2009. regulatory authority. With the covered in this report, only six The second also experienced a supply implementation of the GDF quality- products (for five different drugs) have problem in 2010 and ceased assurance policy, price is no longer the been prequalified by WHO and only production for a period of time, leaving main determinant for purchasing four sources (for two different programmes dependent on a third decisions. medicines) are recommended for manufacturer with limited capacity, so purchase in 2011 by the Expert Review much so that its production is solely Sources of active pharmaceutical Panel14, a joint mechanism of the dedicated to GDF procurement, ingredients are limited. The Global Fund to Fight AIDS, TB, and leaving other DR-TB treatment difficulties faced in trying to increase Malaria and the GDF that gives programmes with no quality-assured the number of quality-assured sources temporary purchase permission for source. for some DR-TB drugs are to a large drugs still under evaluation. extent due to those associated with the For a number of DR-TB medicines, production of the active Few quality-assured sources exist. multiple producers in Russia, India, pharmaceutical ingredient (API). For For many DR-TB drugs, such as China and other countries are known several drugs, such as capreomycin and capreomycin, prothionamide, to manufacture DR-TB drugs, but kanamycin, only one quality-assured terizidone, PAS and clofazimine, only whether they could comply with WHO API source has been identified. In the one quality-assured source exists. For or stringent regulatory authority case of capreomycin, all quality-assured others, including ethionamide*, standards is unknown. Part of the finished products identified in this moxifloxacin and PAS-Sodium, there problem of too few quality-assured document are reliant on a single source are only two quality-assured sources. sources for international supply could of API, again making the entire supply Although there has been some recent be resolved by encouraging of capreomycin extremely vulnerable progress - with a decrease in the manufacturers to improve their to disruption. A recent study for the number of products that had only one compliance with internationally GDF noted that the supply of API was supplier, down from 11 in 2008 to four recognised quality standards and vulnerable for amikacin, kanamycin, in 20115 - for all of these medicines, submit product dossiers for quality prothionamide and clofazimine11. supply is extremely vulnerable to assessment through the WHO disruption. Prequalification Programme or Part of the problem is due to the stringent regulatory authorities. complexity of production. For

* not including the temporary approval by ERP of Cipla's 250mg tablet of ethionamide.

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example, producing the API for the Photo © Bruno de Cock injectables capreomycin and kanamycin requires a fermentation process that is more complex than the synthetic process. The complexity is further increased as the API should be sterile.

Some medicines that are active against DR-TB are not reaching the DR-TB market. Developed for the treatment of infectious diseases, some medicines do not have an approved indication for use in DR-TB, even though they have shown efficacy in in-vitro studies and have been used for many patients and recommended in treatment guidelines. This is particularly the case for the latest group of antibiotics used in DR-TB treatment, the fluoroquinolones (such as moxifloxacin, levofloxacin and ofloxacin).

Although a number of quality-assured manufacturers exist for such medicines - in the case of levofloxacin, for example, there are 13 producers that have secured tentative approval in the US, for moxifloxacin there are two and for ofloxacin three - none of them have applied to participate in the GDF procurement tender. As such, the perspective of higher earnings by targeting more profitable diseases than DR-TB acts as a barrier to increasing the number of quality-assured sources of DR-TB medicines.

Getting medicines into countries: Lead times and regulatory constraints

There are additional barriers faced by treatment providers to getting drugs in countries. One is lead times. GDF is committed to deliver medicines within 90 days15 after order confirmation. However, this commitment is sometimes difficult to respect due to long lead time or difficulty of production at manufacturer level. The GDF has thus decided to put in place a stockpile of DR-TB medicines, with support from UNITAID16.

Delays in drug delivery are also largely due to national regulations, and regulatory issues form a barrier to accessing DR- TB drugs. As they are typically not registered in countries where treatment projects are located, MSF experience suggests that often cumbersome special authorisation is needed to import DR-TB medicines.

For manufacturers of some products that do not have an approved indication for TB, like fluoroquinolones, registration can be difficult. When these products are used as a part of a DR-TB treatment regimen, they are essentially being used “off label” for this indication. This may increase difficulties for manufacturers trying to register their products for the indication of TB in some countries.

Countries should use fast-track registration procedures to facilitate the importation if medicines are quality-assured by WHO or another stringent drug regulatory authority.

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2. Limited affordability

First-line TB treatment costs $19 per quickly with DR-TB, will increase countries introduce additional patient for a six-month treatment demand for more second-line anti- monopoly protection such as data course32. Yet the cost of DR-TB tuberculosis medicines. exclusivity provisions, as for example treatment is considerably more currently demanded by the European expensive, and this acts as a barrier to The price of four medicines in Union as a part of the EU-India Free treatment scale up. For both drug- particular weigh heavily in the Trade Agreement negotiations. sensitive and drug-resistant TB, to the overall cost of a DR-TB regimen. price of the medicines must be added Overall costs of the DR-TB regimen are Some DR-TB drug prices have significant costs in terms of biological particularly driven by capreomycin, increased considerably between 2001 monitoring, human resources for moxifloxacin, PAS and cycloserine. and 2011, including for the medicines medical and psychosocial care, and procured through the GDF for GLC- treatment to counter side effects. For most DR-TB drugs, patents are approved treatment programmes. The not typically a factor in causing high prices of amikacin, kanamycin, The price of DR-TB treatment varies prices because the medicines were cycloserine and capreomycin have all considerably, as treatment must be developed so long ago that patents on increased substantially in recent years individualised according to a patient's most have long run out. (see table below). drug resistance profile. Drugs procured through the GLC/GDF cost between However, moxifloxacin is one notable For kanamycin, the hike in price is $4,400 and almost $9,000 per patient exception. Until now, Bayer's partly due to GDF turning to Meiji after for a standard 18-24 month treatment monopoly has kept prices high. But supply problems affected the course. For drugs purchased outside of now that there is one WHO production of more affordable versions the GLC/GDF, prices may be even Prequalified generic moxifloxacin made by APPPharma and PanPharma. higher. source available, the situation will For capreomycin and cycloserine, the change, and as the number of generic rise in price can be explained by the These prices are a reflection of sources increases, the price should fall. fact that Eli Lilly has ceased production, insufficient market competition among Although patents claiming and put an end to the subsidised prices multiple producers, both at the level of moxifloxacin as a compound should it was offering the GLC. Since 2003, API production, as well as at finished have expired in most countries, the US company has been actively product level. They are also a subsequent patents could possibly engaged in technology transfer to consequence of limited demand for stand in the way of generic production generic manufacturers, and those who DR-TB drugs, as with low volumes, and/or distribution in countries where now produce charge substantially manufacturers cannot hope to achieve such patents have been granted and higher prices. In fact, the price of economies of scale necessary to bring remain valid. capreomycin is expected to continue prices down. This is one area where a rising, and double in the near future - new diagnostic test, by diagnosing The threat of rising prices still exists for from $4 to $8 per unit - as Eli Lilly's patients more effectively and more off-patent DR-TB drugs if producing existing stock at the GDF eventually

Prices available for GLC - approved programmes, in US$

Products July 2001 March 2011 % Difference (lowest price) 2001/2011

Amikacin 500mg 0.11 1.20 +991% Kanamycin 1g 0.36 2.58 +617% Cycloserine 250mg 0.14 0.59 +321% Capreomycin 1gr 1.02 4.00 +292% Ethionamide 250mg 0.10 0.09 Stable Prothionamide 250mg 0.10 0.10 Stable PAS 4g sachet 1.51 1.57 Stable

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runs out and Akorn's product is used. Photo © Dieter Telemans The impact on the overall cost of a DR- TB regimen is estimated to be around $720.

Prices directly from manufacturers - the overwhelming majority of patients who receive DR-TB treatment are not funnelled through the GLC process. They may receive treatment through national programmes or NGOs or other treatment providers, or more concerning is on the private market. No analysis of the private market was undertaken and is outside the scope of this report. MDR-TB patients in Cambodia. 3. The neglect of children and people living with HIV/AIDS

Until today, there has been very little beyond 14 days of treatment, when a toxicity when used with tenofovir research to even determine the best child with drug-resistant tuberculosis (the backbone of the WHO- use of existing drugs used for MDR-TB. would need to take the medicine for recommended first-line antiretroviral In fact, today's treatment for DR-TB is close to two years. For cycloserine, regimen) is unstudied. The medicines largely based on experience and expert different guidelines give different of the fluoroquinolone class - opinion, not randomised clinical trials, recommendations so there is no clarity moxifloxacin, levofloxacin and with a large number of 'grey areas' regarding the safety and efficacy of the ofloxacin - are thought to interact where expert opinions may be use of this drug in children. with crucial protease inhibitors like conflicting4. ritonavir and atazanavir (both part of Even when a drug is registered for use second-line AIDS regimens). Drug Children are particularly neglected. in children and a paediatric formulation interactions are also predicted At least 10-15% of total TB cases each does exist - for amikacin, for example - between ethionamide and year occur in children and a similar it is not included in the GDF product prothionamide and ARVs such as percentage can be assumed among catalogue, meaning that GLC- nevirapine and efavirenz. There is new DR-TB cases in children48. Yet only approved programmes cannot precious little knowledge about two medicines featured in this report purchase it through the GDF. possible interactions for other (amikacin and levofloxacin) have been medicines, such as terizidone, PAS developed as paediatric formulations, The interactions of DR-TB drugs and cycloserine. and these are not widely available. This with AIDS medicines are also means that treatment providers who largely unknown. There is precious The adaptability of some DR-TB attempt to treat children must do so little information on how DR-TB medicines for use in resource-poor by manipulating adult formulations, drugs interact with antiretroviral settings is also a concern. Many such as breaking or crushing tablets to medicines used to treat HIV/AIDS70 - DR-TB drugs are poorly adapted to approximate the required dose. This this has not been a priority for the constraints of health systems in carries a major risk or over- or under- developers of HIV drugs as co- high-burden settings. PAS requires dosing a child. infection with TB is today uncommon refrigeration, which is an added in wealthy countries. This is logistical burden for programmes, In addition, safety and efficacy data in particularly problematic given that TB particularly in sub-Saharan Africa. The children have not been established for is the biggest killer of people living use of injectable products like the majority of the medicines used in with HIV today2. kanamycin and amikacin also imposes DR-TB treatment. Only three medicines burdens both on the programme, as in this report have been licensed for For many DR-TB medicines the crucial qualified staff will be required for use in children. One of those that is research is lacking. For kanamycin, administration of the product, and on licensed for paediatric use, levofloxacin, amikacin and capreomycin, for the patient, who must undergo six has however not been approved example, the potential for renal months of painful injections.

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R&D for TB: A long story of neglect

The medicines used in DR-TB compounds in the clinical development to be available to allow for the treatment cause often intolerable stage and the intention is that some of selection of optimum regimens and side effects, which can include them will be part of a future single meet the goal of a single therapy nausea, severe vomiting, depression, treatment regimen active against both effective against both drug-sensitive aggressive behaviour, hallucinations, drug-sensitive and all forms of drug- and drug-resistant TB. Thus drug vertigo, hearing loss and diarrhoea. resistant TB18. discovery efforts need to be scaled With such a litany of complaints up in order to have a healthy associated with drug-resistant It is questionable whether this objective pipeline able to deliver an optimal tuberculosis treatment, many look to can be achieved within reasonable treatment regimen. the research and development timelines. In addition, the most urgent (R&D) pipelines for a new regimen priority is to improve treatment of In the immediate term, it is crucial to answer these problems. MDR-TB, given length, toxicity and to make today's DR-TB treatment as limited effectiveness of current tolerable as possible for patients. R&D into TB drugs and diagnostics treatment. This entails conducting studies on were neglected for decades because how to alleviate the worst side the disease primarily affects Among the new drugs, Tibotec's effects caused by existing drugs, by developing countries and therefore TMC20719 and Otsuka's OPC6768320 for example looking at ways to did not represent a lucrative market are in most the advanced stages, and space the intake of drugs, optimise for the pharmaceutical industry. This have recently completed Phase IIb doses, develop alternative, more applies as much to drug-susceptible clinical trials in MDR-TB patients. TMC user-friendly formulations (for the as drug-resistant TB. In the case of 207 is expected to get accelerated injectables) and study their use in second-line TB medicines, however, approval for use in DR-TB treatment as children and people living with HIV. the problem is amplified, as the early as 2012. However, further studies drugs used are of limited will be needed to determine if the Part of these efforts involve effectiveness, with success rates of addition of the new drug will allow exploring new combinations of the current treatment at around 80% some of the older drugs to be existing medicines to reduce the at best. removed from the regimen and how duration of treatment21. A shorter much the treatment regimen can be regimen has already been used in After having been at a virtual shortened. Bangladesh, the results of which standstill for about 40 years, the TB have been recently published. Based drug pipeline has seen encouraging To ensure a range of effective on this experience, The Union will progress in recent years68, with treatment options in the long-term, a conduct a clinical trial of this renewed R&D activities by the Global large number of new drug candidates shortened regimen and will begin Alliance for TB Drug Development with novel mechanisms of action need enrolling patients in 2011.

(the product development Photo © Krisanne Johnson partnership established in 2000 to foster development of new TB drugs) and a few pharmaceutical companies. However, compared to other disease R&D pipelines, TB's remains fairly limited, and no new drug has yet reached the market.

The objective of the TB Alliance, the leading product development partnership in TB drug R&D, is to deliver a new regimen able to treat both drug-sensitive and drug- resistant TB, shorter than current first-line treatment and compatible with HIV treatment69. Currently there are ten new or repurposed MDR-TB patient in Swaziland awaits painful daily injection

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Conclusions: Breaking the vicious circle

Untreated DR-TB kills and further encourages the disease's spread. But with insufficient numbers of patients on treatment, demand for DR-TB drugs is low, and the market for the development and production of DR-TB drugs remains unattractive. This creates a vicious circle because limited drug supplies in turn contribute to hindering the scale up of DR-TB treatment. As demand stays low, not least for WHO quality-assured drugs, there is little incentive either for new producers to enter the market or for existing producers to invest in meeting WHO quality standards or increasing production capacity. Supply insecurity due to delivery delay or interruption - as for kanamycin in 2010 - means that programmes have been cautious rather than ambitious about the number of people they aim to treat - a direct disincentive to treatment scale-up.

Low demand for DR-TB drugs is also caused by the difficulties surrounding diagnosis - only 11% of 440,000 new MDR-TB cases were detected in 2009. Until now, it has taken up to three months to determine a patient's precise drug-resistance profile, and diagnosis of TB is especially complicated in both people living with HIV/AIDS and children.

However, a new diagnostic tool based on molecular technology could help break open the vicious circle by dramatically shortening the time it takes to determine whether someone has TB to 90 minutes49. It can also determine whether a patient is resistant to one of the main first-line drugs to treat TB. Endorsed in December 2010 by the World Health Organization, the test is being rolled out in MSF programmes in 15 countries this year. If the new test is implemented more widely, improved diagnosis could contribute to the level of increased demand needed to make the DR-TB drug market more attractive to drug developers and manufacturers. This, in turn, could lead to additional suppliers entering the market and seeking WHO quality assurance, and prices decreasing.

A number of targeted interventions are also needed to stimulate the MDR-TB drug market. The framework of the Green Light Committee Initiative and the work of the Global Drug Facility may have made an important contribution but have not yet been able to overcome supply problems and decrease prices. The GLC Initiative and the GDF have been undergoing a reform process since early 2010 - what is needed is for GDF to take a clear break from its previous short-term approach and limited focus on risk minimising strategies. The GDF can and should play a stronger market shaping role, guided and supported by users and donors.

The Global Drug Facility: ■ Should publish prices of medicines procured on its website in order to improve transparency. ■ Should no longer restrict sale of quality-assured medicines to GLC-approved programmes. All treatment programmes should be able to buy quality-assured medicines, as currently envisioned as part of the GLC reform; ■ Should further develop and pursue the activities outlined as a part of its 'Roadmap for MDR-TB Scale Up', which lists a number of market interventions to attract new suppliers. This roadmap includes: ■ giving manufacturers long-term contracts to ensure increased production volumes; ■ a strategic revolving fund to provide manufacturers a financial guarantee while countries await fund disbursement; ■ providing manufacturers with reliable demand forecasting per country, both in the short and in the longer term; ■ the expansion of the existing rotating stockpile to decrease the time it takes for countries to receive medicines. ■ a transparent market share allocation mechanism to manufacturers to provide incentives to manufacturers to participate in GDF procurement.

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Manufacturers and drug developers:

■ Should agree to provide information on prices and pricing conditions in order to improve the transparency on the price of DR-TB medicines ■ Should broadly register their products in endemic countries ■ Should invest in production and WHO prequalification of existing DR-TB drugs, and develop paediatric formulations adapted to resource limited settings, anticipating an international treatment scale up; ■ Drug developers currently investing in the development of new TB drugs should trial their compounds in DR-TB patient populations. Efforts should be undertaken to make new drugs available as quickly as possible via compassionate use and expanded access programmes. ■ Drug developers should study the safety and efficacy of existing and new medicines in paediatric formulations and for possible drug interactions with antiretrovirals.

Countries affected by TB: ■ Should ensure that first-line treatment is continuously available for TB patients to prevent generating new MDR-TB cases; ■ Should invest in the scale up of DR-TB treatment including investment in increased diagnostic and programmatic capacity to enrol progressively more patients on treatment. Innovative models for community-based treatment that allow to reach more patients and better are showing good results and should be supported; ■ Should commit to purchase only quality-assured medicines. This will benefit patients and act against further resistance development but will also help to create increased economies of scale for quality-assured products; ■ High-level support is needed in many high-burden countries to ensure fast track registration of DR-TB medicines or easier mechanisms for importation; ■ Good in-country drug management systems are needed to ensure continued drug supply at programme level and input into reliable international drug forecasting.

Donors: ■ Have an important role to play to guide and support financially the market interventions outlined in the GDF's Roadmap, as these are needed to improve international DR-TB drug supply and reduce prices; ■ Donors' support will be critical to ensure international treatment scale-up, although many DR-TB high-burden countries have contributed and need to continue contributing significant resources to MDR-TB programmes. It has been

estimated that $16.2 billion are Photo © Ivan Sigal needed between 2010-2015 to support treatment in the 27 high- burden countries; and ■ Donors should support research to define a better and shorter DR-TB treatment regimen with the inclusion of newer drugs.

MDR-TB patient receives care through MSF in Uzbekistan

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KANAMYCIN (Km)

General Information

• Therapeutic Class: • Presentations available: solution • Approved indication in the US: Aminoglycoside antibiotic for injection: 1g/4ml, 500mg/2ml, Kanamycin is indicated in the 1g/3ml. As powder for injection: 1g short-term treatment of serious • ATC Code: J01GB0422 infections caused by susceptible • First approved by U.S. Food • Included in the WHO strains of microorganisms44 and Drug Administration Guidelines as Group 2 injectable (FDA): The date of the original agent23 New Drug Application (NDA) is not • Included in the 16th edition of publically available on the US FDA the WHO Model List of Essential website. The first Abbreviated New Medicines24 and in the 2nd edition Drug Application (ANDA) was of the WHO Model List of Essential approved on 13 February 1973. Medicines for Children25 The only registered product in the US today was approved on 17 November 2002

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Meiji Panpharma Macleods APP Pharma GDF pooled procurement price

Quality status Approved by SRA Approved by SRA Under evaluation Approved by SRA GDF Quality Assurance Policy

1g powder for xx 0.84* No price xx No price injection information given information given 1g/4ml solution No price xx xx xx 2.58 for injection information given (Meiji) 1g/3ml solution xx xx xx Not currently in xx for injection production

* Price received in Euro and converted to US$ on 7 March 2011

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There is no clinical difference between and the price is considerably more assured alternative. The Panpharma kanamycin and amikacin. They have than the Panpharma product. The price offered to this report is still more similar side effect profiles and show supply is also reserved for GDF leaving than double the 2001 price, but due cross reactivity and therefore almost other treatment providers with no to capacity issues this source is not identical resistance23. The choice of a alternative quality-assured sources. assured. National TB Programme or treatment provider will also therefore depend on This is a good example of the Adaptability other factors including price, vulnerability of supply with limited Kanamycin, like the other availability and adaptability of the sources. Additional manufacturers may aminoglycosides and capreomycin formulation. exist in China, India, the former Soviet cannot be administered orally. This Union, and other countries, but imposes burdens both on the Number of quality sources whether they comply with WHO programme, as qualified staff will be In the past, kanamycin formulations quality standards is unknown. required for administration of the from several different manufacturers product, and on the patient, who were registered in the US. Today, Active Pharmaceutical must undergo six months of painful however, only three kanamycin Ingredient injections. products approved by a stringent Increasing the number of quality- regulatory authority were identified in assured sources for the finished Kanamycin is available in both a this report. No sources of kanamycin product is to a large extent tributary of powder and a fully liquid formulation; are approved through WHO the difficulties associated with the the latter is more adaptable to Prequalification, although one production of the active resource-limited settings as manufacturer (Macleods) has pharmaceutical ingredient (API). reconstitution of the powder is not submitted a dossier to WHO required. Prequalification and has been accepted Kanamycin API is manufactured by a for evaluation. process of fermentation. This is a Paediatrics specialised process, and there are not The safety and effectiveness in children Despite this, the supply of kanamycin many manufacturers globally who has not been established. While there remains vulnerable to disruption. have the capacity to produce quality- are dosages published in several Today, only one company (APP assured API produced through the guidelines, there is an urgent need for Pharma) has an active registration in fermentation process - the complexity further research (pharmacokinetics, the US - but they have not had any is further increased as the API should pharmacodynamics, safety data), into production since February 2009 due to be sterile. In today's regulatory the use of this drug in the younger the relocation of the API environment, the quality assurance of populations, in particular children manufacturer26. In the EU, there is only the API is critical in the approval aged under five, so that dosages can one approved manufacturer process of the finished product be clarified and child adapted (Panpharma) but in 2010 they had a through WHO Prequalification or a formulations developed to be able to problem with the API resulting in an stringent regulatory authority. deliver these dosages to children. interruption in supply. As this was the only quality-assured source available to Evolution in price HIV co-infection GDF at the time, this resulted in a In 2001, Green Light Committee- There have been no studies significant problem for GLC-approved approved programmes were able to performed, but based on programmes and other treatment access kanamycin for US$ 0.36 per pharmacokinetic profiles, the potential providers. The problem has been vial27. Since then the price has slowly for drug interactions are low. There is rectified but capacity issues remain. increased and today the most however potential for additive affordable price available through the toxicities in particular with In reaction to the potential shortage of GDF, for a fully liquid ampoule, is antiretrovirals which may cause renal quality-assured kanamycin, GDF more than seven times the price toxicity like tenofovir28. Further studies identified an alternative source in offered to the GLC in 2001. The are required to confirm this. Japan (Meiji). While this helped to reason for this is not clear, but partially ensure continual supply while this is related to the unavailability of Panpharma was not in production, the Panpharma product in 2010, and Meiji has limited production capacity the identification of Meiji as a quality-

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AMIKACIN (Am)

General Information

• Therapeutic Class: • Presentations available: • Approved indication in the US: Aminoglycoside antibiotic solution for injection: 500mg/2ml; Amikacin is indicated in the short- 100mg/2ml. As powder for term treatment of serious infections • ATC Code: J01GB0622 injection: 100mg, 500mg & 1g due to susceptible strains of Gram- • Included in the WHO negative bacteria, including • First approved by U.S. Food Guidelines as a Group 2 bacterial septicemia (including and Drug Administration injectable agent23 neoatal sepsis), serious infections of (FDA): The date of the original the respiratory tract, bones and • Included in the 16th edition of New Drug Application (NDA) is not joints, central nervous system the WHO Model List of Essential publically available on the US FDA (including meningitis) and skin and Medicines24 and in the 2nd edition website. The first Abbreviated New soft tissue; intra-abdominal of the WHO Model List of Essential Drug Application (ANDA) was infections (including peritonitis); Medicines for Children25 approved on 22 January 198145 burns and postoperative infections (including postvascular surgery)46

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Medochemie Cipla Help SA GDF pooled procurement price

Quality status Approved by SRA Approved by WHO Approved by SRA GDF Quality PQ Assurance Policy

500mg/2ml 1.06* No price 1.54* 1.20* solution for information given (Medochemie) injection

* Price received in Euro and converted to US$ on 7 March 2011

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There is no clinical difference Evolution in price Paediatrics between kanamycin and amikacin. In 2001, Green Light Committee- Amikacin is licensed for use in They have similar side effect profiles approved programmes were able to neonates, infants and children31. and show cross reactivity and access amikacin for US$ 0.11 per vial There is a smaller dosage 23 therefore almost identical resistance . or ampoule27. Since then, the price (100mg/2ml) available which allows The choice of a National TB has slowly increased and today the for more accurate dosing in Programme or treatment provider will most affordable price available children. therefore depend on other factors through the GDF is $1.20 per vial or including price, availability and ampoule. This is an increase of close No prices were offered for this adaptability of the formulation. to 1000% since 2001, the reasons for product for this report. In addition, which are unclear. the GDF does not include this Number of quality sources formulation in its product catalogue, Several companies have amikacin Nevertheless this remains considerably meaning that GLC-approved approved by stringent regulatory more affordable than prices paid in programmes cannot order this authorities. In addition, in January rich countries - the British National product for children through the 2011, the first generic amikacin from Formulary lists a price of $16.49 per GDF32. Cipla was prequalified by WHO. A vial29,30. further Indian manufacturer (Micro HIV co-infection Labs) is expected to submit a dossier Adaptability There have been no studies to WHO Prequalification during the Amikacin, like the other performed, but based on course of 2011. aminoglycosides and capreomycin pharmacokinetic profiles, the cannot be administered orally. This potential for drug interactions are There are multiple sources of quality- imposes burdens both on the low. There is however potential for assured amikacin, possibly because programme, as qualified staff will be additive toxicities in particular with other approved indications of use required for administration of the antiretrovirals which may cause exist for the drug. The supply of product, and on the patient, who renal toxicity like tenofovir28. Further amikacin is therefore secure. must undergo six months of painful studies are required to confirm this. injections.

Amikacin is available in both a powder and a fully liquid formulation; the latter is more adaptable to resource- limited settings as reconstitution of the powder is not required.

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CAPREOMYCIN (Cm)

General Information • Therapeutic Class: • Presentations available: • Approved indication in the US: polypeptide antibiotic 1g powder for injection Capreomycin is to be used

22 concomitantly with other • ATC Code: J01GB06 • First approved by U.S. Food appropriate anti-tuberculosis and Drug Administration • Included in the WHO agents, is indicated in pulmonary (FDA): 2 June 197133 Guidelines as a Group 2 infections caused by capreomycin- injectable agent23 susceptible strains of M. tuberculosis • Included in the 16th edition of when the primary agents the WHO Model List of Essential (isoniazid, rifampicin, ethambutol, Medicines24 and in the 2nd edition aminosalicylic acid, and of the WHO Model List of Essential streptomycin) have been ineffective Medicines for Children25 or cannot be used because of toxicity or the presence of resistant tubercle bacilli33 Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Akorn Macleods GDF pooled procurement price Quality status Approved by SRA Under evaluation GDF Quality Assurance Policy 1g powder for 8.00 No price 4.00* injection information given (Eli Lilly)

* In future, the price will change as the Akorn product replaces Eli Lilly's.

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Spotlight on access issues GROUP 2

Number of quality sources environment, the quality assurance of see a further price increase in the Eli Lilly filed the initial application to the API is critical in the approval future as GDF turns to Akorn for the US FDA in 1971. Since 2003, the process of the finished product supplies. If the price Akorn charges for company has been actively engaged in through WHO Prequalification or a GDF remains the same as the one the technology transfer to three generic stringent regulatory authority. manufacturer provided for this manufacturers (Aspen, Hisun and SIA document ($8), the impact on the International) and today has ceased Eli Lilly transferred the technology for overall cost of a drug-resistant production of capreomycin in the US. capreomycin API to only one tuberculosis treatment containing None of these manufacturers has yet manufacturer - the Chinese generic capreomycin will be an increase of received regulatory approval by a SRA producer Hisun in 2003. Although this around $720. or WHO PQ. has been a success, with the Hisun API being approved by the US FDA in June Nevertheless the Akorn price remains Today, there are no sources of 2006, all manufacturers of quality- considerably more affordable than capreomycin approved through WHO assured capreomycin are reliant on this prices paid in rich countries - the British PQ. In the US, Eli Lilly's license was sold one source. National Formulary lists a price of to Akorn, which today is the only $40.95 per vial29,30. quality-assured source available to GDF. Although other API manufacturers An additional manufacturer (Macleods) exist, none of them has yet been Adaptability has submitted a dossier to WHO approved by a stringent regulatory Capreomycin, like DR-TB medicines Prequalification and has been accepted authority or by the WHO from the aminoglycosides class, cannot for evaluation, and Aspen is expected Prequalification Programme. be administered orally. This imposes to submit during the course of 2011. burdens both on the programme, as Evolution in price qualified staff will be required for The supply of quality-assured In 2001, Green Light Committee- administration of the product, and on capreomycin therefore remains approved programmes were able to the patient, who must undergo six vulnerable to disruption. Additional access capreomycin for US$ 1.02 per months of painful injections. manufacturers may exist in China, vial27. Since this time, the price has India, the former Soviet Union, and increased, with prices reported in the Paediatrics other countries, but whether they Global Fund Price and Quality The safety and effectiveness in children comply with WHO quality standards is Reporting (PQR) Tool between 2007 has not been established. While there unknown. and today ranging between $3.21 and are dosages published in several $3.64 per vial.64 guidelines, there is an urgent need for Active Pharmaceutical further research (pharmacokinetics, Ingredient For a number of years, Eli Lilly pharmacodynamics, safety data), into Increasing the number of quality- subsidised the price of the the use of this drug in the younger assured sources for the finished capreomycin for programmes populations, in particular children aged product is to a large extent tributary of approved by the Green Light under five, so that dosages can be the difficulties associated with the Committee. Since transferring the clarified and child adapted production of the active technology to other manufacturers, formulations developed to be able to pharmaceutical ingredient (API). however, the price of capreomycin has deliver these dosages to children. increased by almost 300%. Now that Capreomycin API is manufactured by a Eli Lilly has ceased production for this HIV co-infection process of fermentation. This is a market, the price will not be subsidised There have been no studies performed, specialised process, and there are not anymore and we will see a further but based on pharmacokinetic profiles, many manufacturers globally who have increase in prices. the potential for drug interactions are the capacity to produce quality-assured low. There is however potential for API produced through the The price currently quoted by GDF for additive toxicities in particular with fermentation process - the complexity this report corresponds to the Eli Lilly antiretrovirals which may cause renal is further increased as the API should subsidised price as stock is still toxicity like tenofovir28. Further studies be sterile. In today's regulatory available. We can therefore expect to are required to confirm this.

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MOXIFLOXACIN (Mfx)

General Information • Therapeutic Class: • Presentations available: • Approved indication in the US: Fluoroquinolone 400mg tablet Moxifloxacin was initially approved

22 for the indications of bacterial • ATC Code: J01MA14 • First approved by U.S. Food sinusitis and community acquired and Drug Administration • Included in the WHO pneumonia. This was further (FDA): 12 October 199971 Guidelines as a Group 3 expanded to include acute Fluoroquinolones23 bacterial exacerbation of chronic • Not included in the 16th edition bronchitis, uncomplicated and of the WHO Model List of Essential complicated skin and skin structure Medicines24 nor in the 2nd edition infection and complicated intra- 35 of the WHO Model List of Essential abdominal infections Medicines for Children25

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Macleods Cipla Bayer GDF pooled procurement price

Quality status Under evaluation Approved by WHO Approved by SRA GDF Quality PQ Assurance Policy 400mg tablet No price No price No price 1.70 information given information given information given (Cipla)

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Number of quality sources Approved Indication are dosages published in several For many years, Bayer was the only While moxifloxacin has been shown to guidelines, there is an urgent need for quality-assured source of moxifloxacin be effective against Mycobacterium further research (pharmacokinetics, available. In November 2010, the first Tuberculosis (Mtb)36 and has been pharmacodynamics, safety data), into moxifloxacin was prequalified by WHO included in many guidelines for use in the use of this drug in the younger (Cipla) and a second manufacturer DR-TB, it does not have an indication populations, in particular children aged (Macleods) has submitted a dossier approved by any stringent regulatory under five, so that dosages can be that has been accepted for evaluation. authority. When moxifloxacin is used as clarified and child adapted formulations The supply of moxifloxacin will a part of a DR-TB treatment regimen, it developed to be able to deliver these therefore be relatively secure in the is therefore essentially being used “off dosages to children. As there is no near future (although price remains a label” for this indication. This may paediatric formulation available today, barrier). increase complexities for manufacturers paediatric doses are obtained by trying to register their products for the manipulating adult formulations to In addition, we can expect to see indication of TB in some countries. achieve target doses. Today the only further sources of quality-assured quality-assured adult source available moxifloxacin, because other approved In August 2005, Bayer and TB Alliance through the GDF does not have a break indications of use exist for the drug. signed an agreement to conduct a line to allow for accurate fractioning of Indeed, there are two generic global clinical development the dose. manufacturers (Dr Reddy's and Teva) programme, aiming to register that have US FDA tentative approval, moxifloxacin for a first-line TB One alternative is to use an waiting to enter the US market when indication. Three Phase II trials have extemporaneously prepared the patent expires. been completed, and a Phase III trial is moxifloxacin oral suspension, the ongoing. subject of a stability study published in 38 Additional manufacturers may exist in 2009 . This suspension allows for a China, India, the former Soviet Union Other actors, including The Union, are more accurate way to measure and and other countries, but whether they currently involved in clinical trials administer a dose to a child. However, comply with WHO quality standards is looking at the use of moxifloxacin in a preparing this formulation requires a unknown. regimen to shorten the treatment of certain level of training, supervision and MDR-TB21. resources, which may not be available Evolution in price in many settings where DR-TB is With the entry of a quality-assured Patents prevalent. This solution is far from ideal generic into the market the price has Although patents covering the and there is therefore a need for a reduced considerably. Prior to this the moxifloxacin molecule have now commercially available paediatric only option available was Bayer and expired in most countries, subsequent formulation. prices for this product reported in the patents claiming a crystal monohydrate HIV co-infection Global Fund Price and Quality form of moxifloxacin appear to stand No interaction studies have been Reporting (PQR) Tool between 2009 in the way of generic production. Such performed, but based on the and today range between US$ 3.97 patents, due to run until 2016, have knowledge of the metabolism of and $5.03 per tablet.64 been granted in several countries moxifloxacin, levels of the drug may be including China, Russia, South Africa reduced by ritonavir and increased by This shows that some developing and Ukraine. atazanavir. Further research is needed countries are therefore paying prices to assess this. higher than those paid in rich countries In India, where this patent was - the British National Formulary lists a withdrawn by Bayer, additional patents Protease inhibitors and efavirenz may price of $4.03 per tablet29,30. With more on other pharmaceutical forms have prolong QT interval so concomitant use generic manufacturers expected to been granted but do not appear to be with moxifloxacin should be cautious, enter the market, we could expect to blocking generic manufacture. with electrocardiogram monitoring. see this price continue to fall. Oral absorption of fluoroquinolones are Paediatrics reduced by buffered drugs, so doses The safety and effectiveness in children should be separated from didanosine- has not been established. While there buffered tablets28.

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LEVOFLOXACIN (Lfx)

General Information • Therapeutic Class: • Presentations available: • Approved indication in the US: Fluoroquinolone 250mg, 500mg and 750mg Levofloxacin was initially approved • ATC Code: J01MA1222 tablets, 25mg/ml oral solution for the indications of acute maxillary sinusitis, acute bacterial • First approved by U.S. Food • Included in the WHO exacerbations of chronic bronchitis, and Drug Administration Guidelines as a Group 3 community-acquired pneumonia, 23 (FDA): 20 December 1996. The Fluoroquinolones uncomplicated skin and skin paediatric formulation (25mg/ml structure infections, complicated • Included in the 16th edition of oral solution) was approved on 21 urinary tract infections (UTI), and the WHO Model List of Essential October 200440 Medicines24 and in 2nd edition of acute pyelonephritis. This was the WHO Model List of Essential further expanded to include Medicines for Children25. uncomplicated UTI, chronic Levofloxacin is considered a better bacterial prostatitis, and treatment alternative to ofloxacin based on of inhalational anthrax (post- 40 availability and programme exposure) considerations

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Cipla Macleods GDF pooled procurement price Quality status Under evaluation Under evaluation GDF Quality Assurance Policy 250mg tablet No price No price 0.05 information given information given (Macleods) 500mg tablet No price No price 0.08 information given information given (Macleods)

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Number of quality sources DR-TB, it does not have an indication twice a day dosing for children between Two manufacturers have dossiers approved by any stringent regulatory six months and 17 years. Other submitted and accepted for evaluation authority. When levofloxacin is used as a publications suggest twice a day dosing by WHO Prequalification. These Cipla part of a DR-TB treatment regimen, it is for under five years, while the WHO (250mg) and Macleods (250mg and therefore essentially being used “off guidelines suggest a once a day dosing. 500mg) sources have already been license” for this indication. This may This can be confusing to National TB assessed by the Expert Review Panel for create problems for manufacturers Programmes and dangerous for children. the GDF and the Global Fund and are trying to register their products for the There is a need for a further clarification currently listed as purchasable in 2011 indication of TB in some countries. and a consensus on the dosing of small with Global Fund money. children. Patents An additional manufacturer (Micro Patents claiming levofloxacin were While there is paediatric formulation Labs) is expected to submit to WHO originally filed in 198165 and 198666 by (25mg/ml oral solution) available in the Prequalification during the course of Daiichi Seiyaku, now a subsidiary of US, this is not widely available elsewhere. 2011. The supply of levofloxacin is Daiichi Sankyo, and licensed to Janssen. There has been a study published therefore relatively secure. Although 20-year patents expired in looking at the stability of an 2001 and 2006 respectively, patent extemporaneously prepared levofloxacin In addition, there are multiple sources of protection has been extended until June oral suspension39. This suspension allows quality-assured levofloxacin, because 2011 in several European countries and for a more accurate way to measure and other approved indications of use exist the US. administer a dose to a child. However, for the drug. Indeed, a further 13 preparing this formulation requires a manufacturers have obtained US FDA As the patent will expire soon, certain level of training, supervision and tentative approval for levofloxacin, manufacturers are already registering resources, which may not be available in waiting to enter the US market when their product in the US and the EU. many settings where DR-TB is prevalent. the patent expires in the US in June Those manufacturers should be 2011. However, none of these contacted by GDF to see if they could be The reality today is adult formulations producers have applied for WHO interested, once the patent has expired, are manipulated in order to achieve Prequalification, nor have made their in also supplying GLC-approved target doses. Today the only quality- products available to GDF. programmes. assured source available through GDF does not have a break line to allow for Evolution in price Paediatrics accurate fractioning of the dose. Both of The prices reported in the Global Fund Levofloxacin has been approved in the these solutions are far from ideal and Price and Quality Reporting (PQR) tool US for children aged over six months, there is therefore a need for the between 2007 and today has remained but only for use in children for acute paediatric formulation to be made more at US$ 0.05 per 250mg tablet, and has infections. The safety in paediatric widely available. varied between $0.05 and $0.10 per patients treated for more than 14 days 500mg tablet34. has not been studied. Because children HIV co-infection with DR-TB may be treated with this No interaction studies have been This remains considerably more drug up for up to two years, there is performed, but based on the knowledge affordable than prices paid in rich therefore a need for more safety data on of the metabolism of levofloxacin, no countries - the British National the use of levofloxacin for extended interactions are predicted. Further Formulary lists a price of $2.36 per periods of time in children. research is needed to assess this. 250mg tablet and $4.21 per 500mg Protease inhibitors and efavirenz may tablet29,30. The price of levofloxacin does Children metabolise levofloxacin faster prolong QT interval so concomitant use not appear to be an issue. than adults and smaller children need to with levofloxacin should be cautious, receive doses twice a day rather than with electrocardiogram monitoring. Approved Indication daily as recommended for adults. This Oral absorption of fluoroquinolones is While levofloxacin has been shown to can be difficult to implement reduced by buffered drugs, so doses be effective against Mycobacterium programmatically if strict directly should be separated from didanosine- Tuberculosis (Mtb)36 and has been observed therapy is followed. The US- buffered tablets28. included in many guidelines for use in approved product information suggests

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OFLOXACIN (Ofx)

General Information • Therapeutic Class: • Presentations available: • Approved indication in the US: Fluoroquinolone 200mg, 300mg, 400mg tablet Ofloxacin is approved for the

22 indications of acute bacterial • ATC Code: JJ01MA01 • First approved by U.S. Food exacerbations of chronic bronchitis, and Drug Administration • Included in the WHO acute uncomplicated uretheral and (FDA): 28 December 199071 Guidelines as a Group 3 cervical gonorrhea, non- Fluoroquinolones23 gonococcal urethritis and cervicitis, • Included in the 16th edition acute pelvic inflammatory disease of the WHO Model List of Essential and uncomplicated skin and skin 41 Medicines24 nor in the 2nd edition structure infections of the WHO Model List of Essential Medicines for Children25

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Cipla Macleods GDF pooled procurement price

Quality status Under evaluation Under evaluation GDF Quality Assurance Policy

200mg tablet No price No price 0.06 information given information given (Macleods) 400mg tablet No price No price 0.06 information given information given (Macleods)

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Number of quality sources Approved Indication HIV co-infection Today there is no ofloxacin approved While ofloxacin has been shown to be No interaction studies have been by WHO PQ, but three manufacturers effective against Mycobacterium performed, and based on the (including Cipla and Macleods) have Tuberculosis (Mtb)36 and has been metabolism of ofloxacin, interactions dossiers submitted and accepted for included in many guidelines for use in are not predicted. However one evaluation, and an additional DR-TB, it does not have this indication source suggests there may be a manufacturer (Micro Labs) is expected approved by any stringent regulatory potential interaction with atazanavir to submit during the course of 2011. authority. When ofloxacin is used as a and lopinavir. There is an urgent need The supply of ofloxacin will therefore part of a DR-TB treatment regimen, it for further research to clarify these be relatively secure in the near future. is therefore essentially being used “off inconsistencies regarding drug license” for this indication. This may interactions to guide clinicians on In addition, there are multiple sources create problems for manufacturers drug dosing51. of quality-assured ofloxacin, because trying to register their products for other approved indications of use the indication of TB in some countries. Protease inhibitors and efavirenz may exist for the drug. As the patent for prolong QT interval so concomitant ofloxacin has now expired, there are Paediatrics use with ofloxacin should be cautious, three generic manufacturers (Ranbaxy, The safety and effectiveness in with electrocardiogram monitoring. Teva, and Dr. Reddy's) that have children has not been established. products available on the US market While there are dosages published in Oral absorption of fluoroquinolones and several others on the EU market, several guidelines, there is an urgent are reduced by buffered drugs, so but none of them have made their need for further research doses should be separated from products available to GDF. (pharmacokinetics, didanosine-buffered tablets28. pharmacodynamics, safety data), into Evolution in price the use of this drug in the younger In 2001, Green Light Committee- populations, in particular children approved programmes were able to aged under five, so that dosages can access ofloxacin for US$ 0.33 per be clarified and child adapted tablet27. Since then, the price has formulations developed to be able to decreased dramatically with prices deliver these dosages to children. reported in the Global Fund Price and Quality Reporting (PQR) Tool between As there is no paediatric formulation 2007 and today ranging between available today, children's doses are $0.03 and $0.06 per 200mg tablet obtained by manipulating adult and between $0.05 and $0.07 per formulations to achieve target doses. 400mg tablet64. These prices remain Today the only quality-assured source considerably more affordable than available through GDF does not have prices paid in rich countries - the a break line to allow for accurate British National Formulary lists a price fractioning of the dose. of $1.09 per 200mg tablet and $0.89 per 400mg tablet29,30.

The price of ofloxacin does not appear to be an issue.

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ETHIONAMIDE (Eto)

General Information

• Therapeutic Class: • Included in the 16th edition of • First approved by U.S. Food carbothionamides group, derivative the WHO Model List of Essential and Drug Administration of isonicotinic acid23 Medicines24 and in 2nd edition of (FDA): 30 April 196571 the WHO Model List of Essential • ATC Code: J04AD0322 • Approved indication in the US: Medicines for Children25 ethionamide is primarily indicated • Included in the WHO • Presentations available: 250mg for the treatment of active Guidelines as a Group 4 oral tablet tuberculosis in patients with bacteriostatic second-line agent23 M. tuberculosis resistant to isoniazid or rifampicin, or when there is intolerance on the part of the patient to other drugs42 Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Lupin Cipla Macleods Pfizer GDF pooled procurement price

Quality status Under evaluation Under evaluation Approved by WHO Approved by SRA GDF Quality PQ Assurance Policy

250mg tablet 0.09 No price No price 3.50 0.09 information given information given (Macleods)

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The situation is likely to improve as a Paediatrics further two manufacturers (Lupin, The safety and effectiveness in Cipla) have submitted dossiers to children has not been established. WHO Prequalification and have been While there are dosages published in accepted for evaluation. The Cipla several guidelines, there is an urgent product has already been assessed by need for further research the Expert Review Panel for the GDF (pharmacokinetics, and the Global Fund and is currently pharmacodynamics, safety data), into listed as purchasable in 2011 with the use of this drug in the younger Global Fund money. An additional populations, in particular children manufacturer (Micro Labs) is expected aged under five, so that dosages can to submit during the course of 2011. be clarified and child adapted formulations developed to be able to Additional manufacturers may exist in deliver these dosages to children. China, India, the former Soviet Union and other countries, but whether they As there are no paediatric comply with WHO quality standards is formulations commercially available unknown. today, dosages for children are obtained by manipulation of adult formulations. The one quality-assured source available today is a film-coated tablet that is not breakable, which means that fractioning the tablet is not accurate.

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PROTHIONAMIDE (Pto)

General Information

• Therapeutic Class: • Presentations available: 250mg • Approved indication in carbothionamides group, derivative tablet Germany: Treatment of all forms of isonicotinic acid23 and stages of pulmonary and • First approved by German extra-pulmonary tuberculosis as • ATC Code: J04AD0122 Federal Institute for Drugs second-line drug in the case of and Medical Devices (BfArM): • Included in the WHO proven multidrug-resistance of the First marketed in Germany in the Guidelines as a Group 4 oral pathogens against first-line drugs; 1970s but registered in the bacteriostatic second-line agent23 treatment of diseases caused by so- framework of posterior registration called ubiquitous (atypical) • Not included in the 16th edition process in Germany on 14 June mycobacteria; treatment of leprosy of the WHO Model List of Essential 200550 in the context of modified therapy Medicines24 nor in the 2nd edition regimens52 of the WHO Model List of Essential Medicines for Children25

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Lupin Fatol GDF pooled procurement price Quality status Under evaluation Approved by SRA GDF Quality Assurance Policy 250mg tablet 0.08 0.14* 0.14* (Fatol)

* Price received in Euro and converted to US$ on 7 March 2011

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Spotlight on access issues GROUP 4

Prothionamide is the propyl analog of Evolution in price HIV co-infection ethionamide. There is complete cross The current price available directly There have been no studies resistance between ethionamide and through manufacturers or through the performed, but based on prothionamide and the two are used GDF shows little evolution over the pharmacokinetic profiles, drug interchangeably43. past ten years. In 2001, Green Light interactions are predicted. There are Committee-approved programmes potentially interactions with some Number of quality sources were able to access prothionamide for classes of antiretrovirals and there is Today there is only one US$0.10 per tablet - the price today is an urgent need for further studies to prothionamide product approved by almost identical27. The price of confirm this. There is also potential for a stringent regulatory authority (Fatol prothionamide does not appear to be additive toxicities in particular with product in Germany) and none is an issue. antiretrovirals which may cause prequalified by WHO. Such a limited hepatotoxicity including efavirenz and number of quality-approved sources Paediatrics nevirapine28. means this product is relatively The safety and effectiveness in vulnerable to supply disruption. children has not been established. While there are dosages published in The situation is likely to improve as a several guidelines, there is an urgent further manufacturer (Lupin) has need for further research submitted a dossier to WHO (pharmacokinetics, Prequalification and has been pharmacodynamics, safety data), into accepted for evaluation, and an the use of this drug in the younger additional producer (Micro Labs) is populations, in particular children expected to submit during the course aged under five, so that dosages can of 2011. be clarified and child adapted formulations developed to be able to Additional manufacturers may exist in deliver these dosages to children. China, India, the former Soviet Union and other countries, but whether they As there are no paediatric comply with WHO quality standards is formulations commercially available unknown. today, dosages for children are obtained by manipulation of adult formulations. The only quality-assured source available today does have a break line, which facilitates breaking the tablet in half. However prothionamide has a very unpleasant taste and breaking the tablet is not ideal. There is a need for a paediatric formulation to be made available.

29 MSF TB print 3/22/11 5:27 PM Page 30

CYCLOSERINE (Cs)

General Information

• Therapeutic Class: • Presentations available: 250mg • Approved indication in the US: analog of D-alanine23 capsule Cycloserine is indicated in the treatment of active pulmonary and • ATC Code: J04AB0122 • First approved by U.S. Food extra-pulmonary tuberculosis and Drug Administration • Included in the WHO (including renal disease) when the (FDA): 29 June 196471 Guidelines as a Group 4 oral causative organisms are susceptible bacteriostatic second-line agent23 to this drug and when treatment with the primary medications • Included in the 16th edition of (streptomycin, isoniazid, rifampicin the WHO Model List of Essential and ethambutol) has proved Medicines24 and in 2nd edition of inadequate53 the WHO Model List of Essential Medicines for Children25

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Lupin Aspen Macleods Purdue GMP GDF pooled procurement price

Quality status Under evaluation Approved by WHO Approved by WHO Approved by SRA GDF Quality PQ PQ Assurance Policy

250mg capsule 0.60 0.78 No price No price 0.59 and 0.78 information given information given (Macleods and Aspen)

30 MSF TB print 3/22/11 5:27 PM Page 31

Spotlight on access issues GROUP 4

Number of quality sources Evolution in price Paediatrics Eli Lilly filed the initial application to In 2001, Green Light Committee- The British National Formulary the US FDA in 1964. Since 2003, the approved programmes were able to provides doses for children aged 2 to company has been actively engaged access cycloserine for US$ 0.14 per 18 while the US FDA states that the in technology transfer to three capsule27. Since this time the price has safety and effectiveness in children generic manufacturers (Aspen, Purdue slowly increased, with prices reported has not been established. This is a GMP and SIA International) and in in the Global Fund Price and Quality clear example of different guidelines 2008 ceased production of Reporting (PQR) Tool between 2007 providing different recommendations. cycloserine. Two of these and today ranging between $0.48 There is an urgent need for further manufacturers (Aspen & Purdue and $0.68 per capsule34. research (pharmacokinetics, GMP) now produce quality-assured pharmacodynamics, safety data), into cycloserine. For a number of years, Eli Lilly the use of this drug in the younger subsidised the price of the cycloserine populations, in particular children In additional, another manufacturer for programmes approved by the aged under five, so that dosages can (Macleods) has cycloserine approved Green Light Committee. Since be clarified and child adapted by WHO Prequalification and three transferring the technology to other formulations developed to be able to other manufacturers (including Lupin manufacturers, however, the price of deliver these dosages to children. and Cipla) have submitted dossiers to cycloserine has increased by more WHO Prequalification and have been than 300% to $0.59 per capsule. As there are no paediatric accepted for evaluation. formulations commercially available This remains considerably more today, dosages for children are The supply of quality-assured affordable than prices paid in rich obtained by manipulation of adult cycloserine is therefore relatively countries - the British National formulations. All of the quality-assured secure. Formulary lists a price of $5.43 per sources available today are capsules, capsule29,30. which means that it is not possible to Active Pharmaceutical accurately fraction the capsule. Ingredient Until 2006, the only quality-assured HIV co-infection source for the active pharmaceutical The metabolism of cycloserine is not ingredient was Eli Lilly. completely understood, and hence interactions are unpredictable28. There Eli Lilly started the technology transfer is a need for more research into the for the API to Shasun, India, in 2003 a interactions between antiretrovirals process that was concluded in 2006. and cycloserine. This was a success with the Shasun API being approved by the US FDA in June 2008.

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TERIZIDONE (Trd)

General Information

• Therapeutic Class: • Not included in the 16th edition • First approved by German analog of D-alanine23 of the WHO Model List of Essential Federal Institute for Drugs Medicines24 nor in 2nd edition of and Medical Devices (BfArM): • ATC Code: J04AK0322 the WHO Model List of Essential First marketed in Germany in the • Included in the WHO Medicines for Children25 1970s and is still in the process of Guidelines as a Group 4 oral the posterior registration process in • Presentations available: 250mg bacteriostatic second-line agent 23 Germany. The filing date for this capsule process was 1 January 197850 • Approved indication in Germany: Treatment of tuberculosis in adults and juveniles aged 14 or older54

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Fatol GDF pooled procurement price

Quality status Approved by SRA GDF Quality Assurance Policy

250mg capsule 1.68* 1.65* (Fatol)

* Price received in Euro and converted to US$ on 7 March 2011

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Spotlight on access issues GROUP 4

Terizidone is a combination of two Evolution in price HIV co-infection molecules of cycloserine, and as such No price for terizidone was reported As terizidone is a combination of a has a similar mode of action as in the Global Fund Price and Quality couple of molecules of cycloserine cycloserine. There is complete cross Reporting (PQR) Tool. and the metabolism of cycloserine is resistance to cycloserine54. It is being not completely understood, used in some countries instead of Paediatrics interactions are unpredictable28. There cycloserine, and assumed to be as The safety and effectiveness in is a need for more research into the efficacious; however, there are no children has not been established. interactions between antiretrovirals direct studies comparing the two While there are dosages published in and terizidone. drugs, and terizidone is therefore not several guidelines, there is an urgent yet recommended by WHO23. need for further research (pharmacokinetics, Number of quality sources pharmacodynamics, safety data), into Today there is only one quality- the use of this drug in the younger assured source of terizidone available. populations, in particular children There are no manufacturers with aged under five, so that dosages can dossiers submitted to WHO PQ, and be clarified and child adapted no manufacturers likely to submit formulations developed to be able to dossiers in 2011. The supply of deliver these dosages to children. quality-assured terizidone therefore remains extremely vulnerable to As there are no paediatric disruption. formulations commercially available today, dosages for children are Additional manufacturers may exist in obtained by manipulation of adult China, India and the former Soviet formulations. The only quality-assured Union and other countries, but source available today is a capsule, whether they comply with WHO which cannot be accurately quality standards is unknown. fractioned.

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PARA-AMINOSALICYLIC ACID (PAS) and PARA-AMINOSALICYLATE SODIUM (PAS-Sodium)

General Information • Therapeutic Class: • Presentations available: • Approved indication in the US: salicylic acid -anti folate23 PAS: 4g sachet. PAS-Sodium: 60% PAS is indicated for the treatment • ATC Code: for PAS: J04AA01 weight for weight granules 9.2g of tuberculosis in combination with For PAS-Sodium: J04AA0222 sachet and 100g jar; powder for other active agents. It is most solution 5.52g sachet (equivalent commonly used in patients with • Included in the WHO to PAS 4g sachet) multidrug-resistant TB or in Guidelines PAS: as a Group 4 oral situations when therapy with • First approved by U.S. Food bacteriostatic second-line agent. isoniazid and rifampicin is not 23 and Drug Administration PAS-sodium: not included possible due to a combination of (FDA): PAS-Sodium was first resistance and/or intolerance55 • PAS included in the 16th edition registered in a tablet formulation in of the WHO Model List of Essential the US on 8 March 1950. There are 24 Medicines and in the 2nd edition no manufacturers of PAS-Sodium of the WHO Model List of Essential on the market in the US today. The 25 Medicines for Children . PAS- only product on the market today Sodium is not included in either in the US is PAS and this was document. registered on 30 June 199455

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Manufacturer Jacobus Macleods Olainfarm GDF pooled procurement price

Quality status Approved by SRA Approved by WHO Approved by SRA GDF Quality PQ Assurance Policy

1.57 xx xx 1.57 PAS 4g sachet (Jacobus)

PAS-Sodium - 60% xx No price xx No price w/w granules - information given information given 9.2g sachet

PAS-Sodium - 60% xx No price xx 24.00 w/w granules - information given (2.21)* 100g jar (Macleods)

PAS-Sodium - xx xx No price 1.50 powder for information given (Olainfarm) solution- 5.52g sachet

*Price of 9.2g (equivalent to 4g of PAS) of this formulation

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Spotlight on access issues GROUP 4

Para-aminosalicylate sodium (PAS - Heat-stable PAS-Sodium is available Paediatrics Sodium) is the sodium salt of para- today range in price between $1.5 The safety and effectiveness in aminosalicylic acid (PAS). 1.38g of and $2.21 for an equivalent dose of children has not been established. PAS-Sodium is approximately PAS. While there are dosages published in 56 equivalent to 1g of PAS . None of the several guidelines, there is an urgent quality-assured sources of either PAS While the price of PAS and PAS- need for further research or PAS-Sodium come in the same Sodium has remained relatively stable (pharmacokinetics, formulation as each other, which in recent years, the medicine accounts pharmacodynamics, safety data), into means depending on the product, for between 25 and 50% of the total the use of this drug in the younger different doses of granules and cost of a patient's treatment overall populations, in particular children powders are required to deliver the cost, depending on which medicines aged under five, so that dosages can same quantity of PAS. This can be can and which products are used. A be clarified and child adapted be particularly confusing if multiple reduction in the price of PAS and PAS- formulations developed to be able to formulations exist in one treatment Sodium would therefore have a large deliver these dosages to children. programme. impact on the overall cost of treatment. As there are no paediatric Number of quality sources formulations commercially available Today there is only one quality- Adaptability today, dosages for children are assured source of PAS (Jacobus), and The PAS marketed by Jacobus, must obtained by manipulation of adult two quality-assured sources of PAS- be stored at temperatures below formulations. As all the available sodium (Macleods and Olainfarm), 15°C. This is problematic for many formulations are either granules or with no products in the pipeline. This settings where DR-TB is prevalent, as powders, measuring the exact dose means the supply of quality-assured maintaining a functional cold chain for a child is difficult and requires product is vulnerable. requires a certain level of investment calibrated scales to be available at the both in infrastructure and human point of dispensing. The PAS-Sodium The PAS-Sodium formulation from resources. product from Macleods that is Macleods was approved by WHO PQ supplied in the 100g jar is however in 2009, but the unexpectedly large The product information states “the supplied with a graduated measuring demand for this product led to packets may be stored at room cup to allow for some estimations of capacity problems, resulting in long temperature for short periods of dose, but this is still not accurate lead times for orders. This should be time”. This should be clarified to give enough. rectified in 2011. treatment providers guidance on the exact length of time the product may An additional complexity is that Additional manufacturers may exist in be stored above 15°C before dosages are not given for PAS- China, India, the former Soviet Union dispensing to patients, without risk of Sodium, and that doses have to be and other countries, but whether they degradation. The availability of a PAS calculated based on the content of comply with WHO quality standards is product that can be kept at room PAS in PAS-Sodium. This has the unknown. temperature for a determined period potential to increase the risk of of time will have positive implications, prescribing and dispensing errors. Evolution in price especially where programmes are In 2001, Green Light Committee- moving to a decentralised approach There is therefore a need for a approved programmes were able to and may not have access to cold commercially available paediatric access PAS for US$1.51 per 4g chain. formulation. sachet27. Since this time the price has slowly increased, with prices for this The PAS-Sodium products do not HIV co-infection product reported in the Global Fund require any special storage conditions. There have been no studies Price and Quality Reporting (PQR) performed, but based on the Tool between 2007 and today pharmacokinetic profile of the PAS, ranging from $1.88 and $2.00 per 4g drug interactions are unlikely. Studies sachet. should be performed to confirm this28.

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CLOFAZIMINE (Cfz)

General Information

• Therapeutic Class: • Included in the 16th edition of • First approved by U.S. Food Phenazine Derivative23 the WHO Model List of Essential and Drug Administration Medicines (as an anti-leprosy (FDA): 15 December 198657 • ATC Code: J04BA0122 medicine)24 and in the 2nd edition • Approved indication in US: • Included in the WHO of the WHO Model List of Essential Clofazimine is indicated in the Guidelines as a Group 5 Medicines for Children (as an anti- treatment of lepromatous leprosy, medicine; agents with unclear leprosy medicine)25 including dapsone-resistant efficacy23 • Presentations available: 50mg lepromatous leprosy and and 100mg soft-gel capsules lepromatous leprosy complicated by erythema nodosum leprosum57

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Clofazimine is a Group 5 medicine which today represents a very small market, as they are essentially used in patients with XDR-TB. While there is a quality- assured source available, Novartis was not contacted regarding a price for this product. This medicine does not exist in the GDF product catalogue.

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Spotlight on access issues GROUP 5

Clofazimine was first synthesised in Even if demand is low, there is a need HIV co-infection 1954 as an anti-TB compound. The to have an alternative source to the There have been no studies drug was thought to be ineffective Novartis product which is not easily performed, but clofazimine is a weak against TB but in 1959 effectiveness available and/or too expensive. inhibitor of CYP3A4, and so protease against leprosy was demonstrated. inhibitor and etravirine concentrations After clinical trials the product was Evolution in price may be increased. launched in 1969 and marketed by In late 1999, Novartis signed a Novartis for use in leprosy. Memorandum of Understanding Further studies are required to confirm (MoU) with the WHO leprosy this28. Even though clofazimine has no programme for a donation of official indications for the treatment of clofazimine and rifampicin47. In DR-TB, clinical data on use in TB has November 2005, this donation was been published and the drug is extended until the end of 2010. recommended by WHO. For patients who require this drug, it Number of quality sources can be purchased through certain Today there is only one source private pharmacies, but the cost is approved by a stringent regulatory quite high, at US$ 0.86 for the 50mg authority. This product is produced by capsule and $1.43 for the 100mg Sandoz for Novartis. Additional capsule in Switzerland, for example58. manufacturers may exist in China, India, the former Soviet Union and Paediatrics other countries, but whether they The safety and effectiveness in comply with WHO quality standards is children has not been established, but unknown. several case reports of children treated with clofazimine have been published Clofazimine was not included in the in the literature. While there are 10th Invitation to Manufacturers to dosages published in several submit an Expression of Interest (EoI) guidelines, there is an urgent need for for product evaluation by WHO further research (pharmacokinetics, Prequalification (August 2010 - pharmacodynamics, safety data), into revised February 2011). Because of the use of this drug in the younger this, there are no manufacturers with populations, in particular children dossiers currently under evaluation. aged under five, so that dosages can The drug was however included in be clarified and child adapted the joint GDF/Global Fund Invitation formulations developed to be able to to manufacturers to submit an deliver these dosages to children. Expression of Interest for product evaluation issued by the Expert Today there is a 50mg soft-gel capsule Review Panel in January 2011. available, but this formulation makes it impossible to fraction the dose, and With no market for this product in clinicians are put in a difficult position wealthy countries, there is no reason to either over-dose the child and for a manufacturer to seek increase the risk of side effects or authorisation through a stringent under-dose and increase the risk of regulatory authority. It is therefore amplification of the child's resistance imperative that WHO Prequalification profile. This is far from ideal. includes clofazimine in the next EoI, to send a clear message to manufacturers that the product is needed.

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LINEZOLID (Lzd)

General Information • Therapeutic Class: • Not included in the 16th edition • First approved by U.S. Food Oxazolidinone antibiotic of the WHO Model List of Essential and Drug Administration Medicines24 nor in the 2nd edition (FDA): 18 April 200059 • ATC Code: J01XX0822 of the WHO Model List of Essential • Approved indication in US: • Included in the WHO Medicines for Children25 Linezolid is indicated for treatment Guidelines as a Group 5 • Presentations available: 600mg of susceptible strains of designated medicine; agents with unclear tablet, 100mg/5ml powder for microorganisms for the following efficacy23 suspension conditions, nosocomial pneumonia, complicated and uncomplicated skin and skin structure infections. It is not indicated for the treatment of Gram-negative infections and community acquired pneumonia60

Price (in US$) and quality information Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Linezolid is a Group 5 medicine which today represents a very small market, as they are essentially used in patients with XDR-TB. While there is a quality- assured source available, Pfizer was not contacted regarding a price for this product. This medicine does not exist in the GDF product catalogue.

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Spotlight on access issues GROUP 5

Even though linezolid has been the joint GDF/Global Fund Invitation Paediatrics classified by WHO as an agent with to manufacturers to submit an Pharmacokinetic studies have been unclear efficacy, it has been shown to Expression of Interest for product completed in children from birth, have in-vitro activity against evaluation issued by the Expert and dosages are approved by the US Mycobacterium Tuberculosis. Data has Review Panel in January 2011. FDA. Safety data is based on trials, been presented at international where patients took linezolid for 28 conferences and small case series As linezolid has a market in wealthy days. As children with DR-TB may be reports have been published on its countries, manufacturers with SRA treated with this drug for up to two use in treatment of DR-TB67. Linezolid approval should be approached to years, there is a need for more safety is associated with a relatively high make their products available for the data on the use of linezolid for number of adverse effects, including DR-TB market. It is imperative that extended periods of time. myelosuppression, anaemia and WHO Prequalification includes peripheral and optical neuropathies. linezolid in the next EoI to send a Today there is a paediatric Linezolid does however play an clear message to manufacturers that formulation available. It is supplied as important role in patients with XDR- this product is also needed for the TB a powder for suspension and so TB. Pfizer and Astra Zeneca are market. requires reconstitution at the point of currently investigating other dispensing. This requires trained staff medicines in the oxazolidinone group Evolution in price to accurately measure the required in the hope of developing a more There was no price supplied for water needed to suspend the powder efficacious and safer molecule than linezolid from GDF and no entries and access to clean, safe water. The linezolid. reported in the Global Fund Price and reconstituted product can be stored Quality Reporting (PQR) tool. at room temperature. Number of quality sources Today only one manufacturer, Pfizer, An indicative price is given in the HIV co-infection is approved by a stringent regulatory British National Formulary - US$ There have been no studies authority. A further four 72.37 for the 600mg tablet and performed, but interactions are manufacturers (Teva, Mylan, $361.82 for a 150ml bottle of the unlikely. There may be increase risk of Glenmark and Gate Pharma) have paediatric suspension. myelosuppression and mitochondrial tentative approval from the US FDA, toxicities with long-term use in waiting to enter the US market when The arrival of alternative source will be combination with certain the patent expires. critical to ensure price reductions. antiretrovirals (zidovudine, stavudine, didanosine).28 Further studies are Additional manufacturers may exist in required to confirm this. China, India, the former Soviet Union Patents and other countries, but whether they The basic patent claiming linezolid comply with WHO quality standards is was first filed in 1993 by Upjohn unknown. Company in the US and is due to expire in May 201561. Similar patents Linezolid was not included in the 10th were also granted in China, the Invitation to Manufacturers to submit Philippines and South Africa. an Expression of Interest (EoI) for product evaluation by WHO Upjohn Company also filed patents Prequalification (August 2010 - claiming crystal forms62 and to a tablet revised February 2011). Because of formulation63 of linezolid in 2001 in this, there are no manufacturers with many developing countries including dossiers currently under evaluation. Argentina, Brazil, China, Colombia, The drug was however included in India, EAPO countries, Mexico, Ukraine and South Africa.

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Methodology

This report looks at the sources and Price information: Prices are listed Quality information: Products that prices of anti-tuberculosis medicines where manufacturers agreed to share are either listed on the WHO List of classified in World Health information. A number of Prequalified Medicinal Products or Organization Groups 2 (injectable manufacturers, including Cipla, approved by a stringent regulatory agents), 3 (fluoroquinolones), 4 (oral Macleods, Bayer, Meiji, and Olainfarm authority are listed in the price tables bacteriostatic second-line agents) and did not have prices available or did as 'approved'. Products that are 5 (agents with unclear efficacy)1. not agree to publish prices, and no undergoing review by either the Questionnaires were sent only to responses were received from Eli Lilly, WHO Prequalification or by a companies that had at least one anti- Mylan, Chao Centre and APP Pharma. stringent regulatory authority are tuberculosis product listed on the Prices paid for by the Global Drug listed in the price tables as 'under WHO List of Prequalified Medicinal Facility pooled procurement evaluation'. Submissions to WHO Products or quality-approved by a mechanism are also listed, although Prequalification are confidential and stringent regulatory authority these prices are reserved for projects all companies mentioned that have according to MSF or The Union’s that have received approval from the the dossier accepted for review have knowledge. The data were collected Green Light Committee. given permission to do so. Products up to March 2011. that have not yet been submitted to Prices are given in US$, rounded up WHO Prequalification or to a to the nearest second decimal point, stringent regulatory authority have and correspond to the lowest unit not been included in the table. price (i.e. the price of one tablet, capsule or vial). When prices that Products procured by the Global varied according to packaging (e.g. Drug Facility comply with the GDF's blisters or bottle) were received from Quality Assurance policy. This deems a manufacturer for the same eligible for GDF procurement all formulation, the lowest price was products that are included on the selected. Prices received in currencies WHO List of Prequalified Medicinal other than US$ were converted on Products, that are approved by a 7 March 2011 using the currency stringent regulatory authority, or that converter site www.oanda.com. Prices are approved by the Expert Review listed are 'ex-works'. Panel (ERP) also used by the Global Fund. The GDF quality assurance The prices listed in this publication policy can be found at: are the ones provided by the http://www.stoptb.org/gdf/drugsuppl manufacturers. The prices paid by the y/quality_sourcing_process.asp purchaser might be higher because of add-ons (such as import taxes and As the information on the WHO List distribution mark-ups), or may be of Prequalified Medicinal Products is lower after negotiations. The updated regularly, the list should be document should not be viewed as a consulted for up-to-date information manufacturer's price list, and regarding quality: procurement agents are advised to http://apps.who.int/prequal/ contact manufacturers directly to confirm prices.

1 WHO guidelines for the Programmatic Management of Drug-resistant Tuberculosis - Emergency update 2008

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Glossary and abbreviations

Abbreviated New Drug Drug-susceptible/drug-sensitive TB ethambutol (E), pyrazinamide (Z) and Application (ANDA) Bacteria are said to be sensitive to a streptomycin (S). These drugs are An Abbreviated New Drug drug when the drugs are effective in highly effective in drug-susceptible TB Application (ANDA) contains data killing or stopping the multiplication and patients usually tolerate them that, when submitted to FDA's Center of bacteria in the body and can well. for Drug Evaluation and Research, therefore clear the infection. The Global Drug Facility (GDF) Office of Generic Drugs, provides for strains of TB which are sensitive to all A mechanism hosted by WHO to the review and ultimate approval of a first-line drugs are called drug- expand access to, and availability of, generic drug product. Generic drug susceptible. applications are called "abbreviated" quality-assured anti-TB drugs and Ex works because they are generally not diagnostics through pooled A commercial term (incoterm) required to include preclinical procurement. Products procured meaning that the seller delivers when (animal) and clinical (human) data to comply with the GDF's Quality the goods are placed at the disposal establish safety and effectiveness. Assurance policy. This deems eligible of the buyer at the seller's premises or Instead, a generic applicant must for GDF procurement all products another named place (i.e. works, scientifically demonstrate that its that are included on the WHO List of factory, warehouse etc.), not cleared product is bioequivalent (i.e. Prequalified Medicinal Products, that for export and not loaded on any performs in the same manner as the are approved by a stringent collecting vehicle. innovator drug). Once approved, an regulatory authority, or that are applicant may manufacture and Expert Review Panel (ERP) approved by the Expert Review Panel market the generic drug product to An independent technical body also used by the Global Fund provide a safe, effective, low cost composed of external technical Global Fund alternative to the American public1. experts, hosted by the WHO The Global Fund to Fight AIDS, Department of Essential Medicines Active pharmaceutical Tuberculosis and Malaria is an and Pharmaceutical Policies. Their ingredient (API) international financing institution that purpose is to review the potential Any substance or mixture of invests the world's money to save quality risk of using antiretroviral, substances intended to be used in the lives. To date, it has committed US$ anti-TB and antimalarial products manufacture of a pharmaceutical 21.7 billion in 150 countries to which are not yet WHO prequalified dosage form and that, when so used, support large-scale prevention, or authorised by a stringent becomes an active ingredient of that treatment and care programs against regulatory authority, and to give 3 pharmaceutical dosage form2. the three diseases . advice to the Global Fund and the Green Light Committee (GLC) Culture Global Drug Facility whether The GLC Initiative helps countries Bacterial culture is a laboratory procurement of such products can be gain access to quality-assured second- method to multiply bacteria in order authorised. to assess their presence or not in a line anti-TB drugs so they can provide Extensively drug-resistant TB patient's sample. This is done by treatment for people with multidrug- see XDR-TB letting the bacteria grow in resistant tuberculosis in line with the predetermined culture media under Extra-pulmonary TB WHO guidelines, the latest scientific controlled laboratory conditions, Form of TB where M. tuberculosis evidence and country experiences. outside the natural environment infect parts of the body other than The Initiative consists of a secretariat, where they usually grow (e.g. for TB, the lungs. This is most commonly the the Green Light Committee (an the human body). lymph nodes, bones, central nervous expert review and WHO advisory system, cardiovascular and body) and the Global Drug Facility Drug resistance gastrointestinal systems. (the drug procurement arm of the When a drug used to treat Initiative). tuberculosis is in fact ineffective First-line drugs against a strain of M. tuberculosis, the The drugs used as the first resort to Microscopy bacteria is said to be resistant to the treat a disease. In the case of TB, the Microscopy is currently the most drug (as opposed to drug-susceptible following five drugs are usually commonly used technique to or drug-sensitive). chosen: isoniazid (H), rifampicin (R), diagnose TB. Two to three sputum

1 http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm#N) 2 QAS terminology database: http://www.who.int/medicines/services/expertcommittees/pharmprep/TermListcategory.pdf 3 WHO

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samples are taken from the patient Point-of-Care testing (POC) binding mutual recognition and the sample will be stained and Testing at the point-of-care means agreement including Australia, later read under the microscope. If TB that diagnosis is carried out as close Norway, Iceland and Liechtenstein. bacilli are present, they occur in the as possible to the site of patient care. (as may be updated from time to form of small red rods, while the rest The driving notion behind point-of- time)5. of the sample is blue. care testing is having a test as TB Alliance convenient to the patient as possible Multidrug-resistant TB (MDR-TB) The TB Alliance is a not-for-profit, and giving immediate results that can Patients infected with strains of TB product development partnership lead to prompt initiation of that are resistant to (at least) the two accelerating the discovery and treatment. most powerful first-line antibiotics development of new TB drugs that used to treat TB, namely rifampicin Pulmonary TB will shorten treatment, be effective and isoniazid, are said to have Form of TB where M. tuberculosis against susceptible and resistant multidrug-resistant TB, or MDR-TB bacteria are infecting the lungs. strains, be compatible with antiretroviral therapies for those HIV- Mycobacteria QT Interval TB patients currently on such Types of bacteria, of the genus In cardiology, the QT interval is a therapies, and improve treatment of Mycobacterium, that cause diseases measure of the time between the latent infection. The TB Alliance is such as TB and leprosy. start of the Q wave and the end of committed to ensuring that approved the T wave in the heart's electrical M. Tuberculosis new drug regimens are affordable, cycle. This represents the total A pathogenic bacterial species of the widely adopted and available to those duration of electrical activity of the genus Mycobacterium and the who need them. ventricles. A prolonged QT interval is causative agent of most cases of TB. a biomarker of life-threatening Tentative FDA approval First discovered in 1882 by Robert ventricular tachyarrhythmias - Is awarded by the US Food and Drug Koch. including torsdes de pointes. Administration (FDA) to a drug New Drug Application (NDA) product that has met all required Second-line drugs When the sponsor of a new drug quality, safety and efficacy standards, Second-line drugs are used when the believes that enough evidence on the but is not eligible for marketing in the first-line drugs are no longer effective drug's safety and effectiveness has US because of existing patent to cure a patient. In the case of been obtained to meet FDA's protection. Tentative approval does tuberculosis, they are less effective requirements for marketing approval, make the product eligible for and have many more side-effects the sponsor submits to FDA a new purchase outside the US under the than first-line drugs. This report looks drug application (NDA). The PEPFAR programme6 at the sources and prices of second- . application must contain data from line anti-tuberculosis medicines WHO Prequalification (PQ) specific technical viewpoints for classified in World Health The Prequalification Programme, set review, including chemistry, Organization Groups 2 (injectable up in 2001, is a service provided by pharmacology, medical, agents), 3 (fluoroquinolones), 4 (oral the World Health Organization biopharmaceutics, and statistics. If bacteriostatic second-line agents) and (WHO) to facilitate access to the NDA is approved, the product 5 (agents with unclear efficacy) medicines that meet unified may be marketed in the United standards of quality, safety and States. For internal tracking purposes, Stringent regulatory authority efficacy for HIV/AIDS, malaria and all NDA's are assigned an NDA (SRA) tuberculosis7. number4. Is a regulatory authority which ‘is (a) a member of the International XDR-TB Pharmacokinetic (PK) Conference of Harmonization (ICH); Patients, who have MDR-TB and also The way the body affects the drug or (b) an ICH Observer, being the show resistance to second-line drugs, with time. European Free Trade Association including at least one from the class (EFTA) as represented by Swiss Medic, known as fluoroquinolones and one Pharmacodynamic (PD) Health Canada and World Health of the injectable drugs, are described The effects of the drug on the body. Organization (WHO); or (c) a as suffering from extensively drug- regulatory authority associated with resistant TB or XDR-TB. an ICH member through a legally

4 http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm#N 5 http://www.theglobalfund.org/documents/psm/List_of_Countries_SRA.pdf 6 QAS terminology database: http://www.who.int/medicines/services/expertcommittees/pharmprep/TermListcategory.pdf 7 WHO

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53. The Chao Center. Seromycin; 60. US FDA. Zyvox drug details. [Online] &FT=D&CC=US&NR=4382892A&KC=A Cycloserine capsules USP. [Online] 2005, United States Food and Drug 66. Espacenet. Optically active April 28 (revised) [cited 2011, March 18] Administration. 2010, June (revised) [cited pyridobenzoxazine derivatives and Available at: http://www.thechaocenter. 2011, March 18] Available at: anti-microbial use. [Online] European com/seromycin/product_insert.pdf http://www.accessdata.fda.gov/scripts/cder Patent Office. [cited 2011, March 22] /drugsatfda/index.cfm Available at:http://v3.espacenet.com/ 54. Axel A, Dr. Terizidon: Summary of publicationDetails/biblio?DB=EPODOC&at= Product Characteristics, Revision Dec 2009 61. Espacenet. Substituted oxazine and 26&locale=en_EP&FT=D&CC=US&NR=505 (English Translation supplied by Fatol). thiazine oxazolidinone antimicrobials. 3407A&KC=A Personal communication with Karen Day. [Online] European Patent Office. [cited [E-mail] 2011, March 11. 2011, March 22] Available at: 67. Erturan Z, Uzun M..In vitro activity of http://v3.espacenet.com/publicationDetails linezolid against multidrug-resistant 55. US FDA. Paser drug details. [Online] /biblio?DB=EPODOC&adjacent=true&locale Mycobacterium tuberculosis isolates. Expe United States Food and Drug =en_EP&FT=D&date=19950316&CC=WO Int J Antimicrob Agents. 2005 July, Vol 26 Administration. [cited 2011, March 18] &NR=9507271A1&KC=A1 (1):78-80 Available at: http://www.accessdata.fda. gov/scripts/cder/drugsatfda/index.cfm?fuse 62. Espacenet. Linezolid-crystal form II. 68. Working group on new TB drugs. action=Search.DrugDetails [Online] European Patent Office. [cited Pipeline : View by phase. [Online] 2011, March 22] Available at: [cited 2011 March 14] Available from: 56. Sweetman, S.C. Martindale Complete http://v3.espacenet.com/publicationDetails http://www.newtbdrugs.org/pipeline.php Drug Reference Guide, 33rd Edition. /biblio?DB=EPODOC&adjacent=true&locale Pharmaceutical Press, 2002. pp148-3 =en_EP&FT=D&date=20010809&CC=WO 69. TB Alliance. More than ever: 2010 &NR=0157035A1&KC=A1 Annual report. [Online] 2010. 57. US FDA. Lamprene drug details. Available from: http://www.tballiance.org/ [Online] United States Food and Drug 63. Espacenet. Oxazolidinone tablet downloads/publications/TBA021_AR2010.p Administration. 2002, July (revised) [cited formulation. [Online] European Patent df 2011, March 18] Available at: Office. [cited 2011, March 22] Available at: http://www.accessdata.fda.gov/scripts/cder http://v3.espacenet.com/publicationDetails 70. Mukadi YD, Maher D, Harries A. /drugsatfda/index.cfm /biblio?DB=EPODOC&adjacent=true&locale Tuberculosis case fatality rates in high HIV =en_EP&FT=D&date=20010927&CC=WO prevalence populations in sub-Saharan 58. Novartis. Lamprene pricing info. &NR=0170225A2&KC=A2 Africa. AIDS 2001;15:143-52. [Online] Pharmaworld.com. 2007 [Cited 2011, March 18]. Available at: 64. The Global Fund. Price and quality 71. US FDA. Drug product details. [Online] http://www.lamprene.com/index.php?id=4 reporting. [Online] 2011 [cited United States Food and Drug 2011, March 16] Available at: Administration. [cited 2011, March 7] 59. US FDA. Linezolid drug details. [Online] http://www.theglobalfund.org/en/procure Available at: http://www.accessdata.fda. United States Food and Drug ment/pqr/ gov scripts/cder/drugsatfda/index.cfm Administration. [cited 2011, March 18] Available at: http://www.accessdata.fda. 65. Espacenet. Benzoxazine derivatives. 72. WHO. Towards Universal Access to gov/scripts/cder/drugsatfda/index.cfm?fuse [Online] European Patent Office. Diagnosis and Treatment of Multi-Drug- action=Search.Overview&DrugName=LINE [cited 2011, March 22] Available at: Resistant and Extensively Drug-Resistant ZOLID http://v3.espacenet.com/publicationDetails Tuberculosis by 2015. WHO Progress /biblio?DB=EPODOC&at=24&locale=en_EP Report. Publication pending 2011.

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Company contacts

Akorn Inc Lupin Lake Forest, Illinois, USA India www.akorn.com www.lupinworld.com Sean Brynjelsen Shrikant Kulkarni Vice President, New Business Development Vice President - Exports Phone: +1 847 279 6149 Phone: +91-22-66402042 E-mail: [email protected] E-mail: [email protected]

Aspen Pharmacare Mr. Mukul Jerath South Africa Sr. Manager - Global TB www.aspenpharma.com Phone: +91-22-66402077 Stavros Nicolaou E-mail: [email protected] Senior Executive Phone: +27 (0) 11 239 6734 Medochemie E-mail: [email protected] Limassol, Cyprus www.medochemie.com FATOL Arzneimittel Phaedon Ellinas Production Facility of RIEMSER Arzneimittel AG Phone: +357 25 867 618 Schiffweiler, Germany E-mail: [email protected] www.fatol.de Elke Rinkes PanPharma International Business Coordinator Fougères, France Phone: +49 (0) 68 21/ 96 05 17 www.panpharma.fr E-mail: [email protected] Michel LE BELLEGO Head of Sales & Contract-Manufacturing HELP S.A. Phone: +33.2.99.97.92.12 Athens, Greece E-mail: [email protected] www.help.com.gr Jaro Matusiewicz Pfizer Business Development New York, USA Phone: +30 210 2847984 www.pfizer.com E-mail: [email protected] Eleanor Levine Gebauer Director, Global Access Phone: +1 (212) 733-5026 Jacobus Pharmaceutical Company, Inc Email: [email protected] Princeton, New Jersey, USA Laura R Jacobus Phone: +1 (609) 799-8221 ex 207 E-mail: [email protected]

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ACKNOWLEDGMENTS: MSF and The Union wish to thank manufacturers and the Global Drug Facility (particularly Caroline Brogen and Kaspars Lunte) for sharing price information for this publication.

Front cover photos: Bruno de Cock Brendan Bannon

Design/artwork: Sue Grant/ Twenty 3 Crows +44 (0)1848 200331

Cover design: TaunusGrafik +1 917 584 8033

DISCLAIMER DR-TB drugs under the microscope - The sources and prices of medicines for drug- resistant tuberculosis 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 or The Union have made every effort to ensure the accuracy of prices and other information presented in this report, but MSF or The Union make 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 or The Union purchases or uses the product. Information in this guide is indicative only and not exhaustive, and should be verified with relevant offices when used for other than reasons of general information. Clinical decisions should not be made based on this document. MSF TB print 3/22/11 5:27 PM Page 48