2nd

DR-TB DRUGS UNDER THE MICROSCOPE SOURCES AND PRICES FOR DRUG-RESISTANT TUBERCULOSIS MEDICINES 3rd Edition – October 2013

www.msfaccess.org www.theunion.org THE MSF ACCESS CAMPAIGN In 1999, in the wake of Médecins Sans Frontières (MSF) being awarded the Nobel Peace Prize, MSF launched the Access Campaign. 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. MSF has been involved in tuberculosis care for more than 25 years, often working alongside national health authorities to treat patients in a wide variety of settings, ranging from urban slums to rural areas, prisons and refugee camps. MSF started treating multidrug-resistant tuberculosis (MDR-TB) in 1999, and the organisation is now one of the biggest NGO providers of MDR-TB care.

LATEST RESOURCES FROM MSF ON TB Beyond the Microscope This briefing document looks at the current issues with existing TB diagnostic tests and the challenges ahead if new tests are to close the medical gaps and meet needs. Available from: msfaccess.org/content/beyond-the-microscope

Out of the Dark: Meeting the Needs of Children with TB This report outlines the current state of paediatric TB care, looking at current practices, new developments and research needs – in paediatric TB diagnosis, treatment and prevention. Available from: www.msfaccess.org/our-work/tuberculosis/article/1667

Support the ‘Test me, treat me’ DR-TB Manifesto! People with drug-resistant TB and their medical providers worldwide call for urgent change to improve drug-resistant TB care. Sign on at: msfaccess.org/TBmanifesto/

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 15,000 members and subscribers from 150 countries, The Union has its headquarters in Paris and offices serving the Africa, Asia Pacific, Europe, Latin America, 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 leading to health solutions for the poor.

LATEST RESOURCES FROM THE UNION ON TB Guidelines for the Clinical and Operational Management of Multidrug-Resistant Tuberculosis Based on The Union’s 93-years of working in the field, this guide tackles the challenges of fulfilling each patient’s potential for cure from both the clinician’s and the programme manager’s perspective. Available from: http://bit.ly/19zpNCu

Management of Tuberculosis: A Guide to the Essentials of Good Clinical Practice (6th ed.) The 6th edition of “the Orange Guide” provides practical guidance to health workers on the front line of TB control. It includes sections on HIV, MDR-TB and a review of the recommended treatment regimens. Available from: http://bit.ly/16HhLbO

Desk-guide for diagnosis and management of TB in children The Union, in partnership with experts from sub-Saharan African countries, has produced for NTPs a desk-guide of child TB management for health workers aimed at the district or more peripheral level of care. Available from: http://bit.ly/1ekSfLl

Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 T Table of contents able of C ontents

Background 2 DR-TB drugs under the microscope 4 Sources and prices of DR-TB medicines: sluggish progress 11 R&D: breakthrough drugs offer new hopes, but significant research gaps remain 15 What needs to happen

21 Methodology

Drug Profiles Group two: Injectables 22 Amikacin 24 Kanamycin 26 Capreomycin

Group Three: Fluoroquinolones 28 Moxifloxacin 30 Levofloxacin 32 Ofloxacin

Group Four: Oral bacteriostatic second-line agents 33 Ethionamide 34 Prothionamide 35 Cycloserine 37 Terizidone 38 PAS and PAS-sodium

Group five: Agents with unclear efficacy 40 Clofazimine 42 Linezolid

NEW DRUGS: 44 Bedaquiline

Annexes 46 Annex 1: Summary table of all prices 48 Annex 2: Conditions of offer, as quoted by companies 49 Annex 3: Company contacts 50 References 54 Glossary 56 Abbreviations

DR-TB Drugs Under the Microscope 1 DR-TB DRUGS UNDER THE MICROSCOPE

This report – now in its third edition – analyses the sources and prices of medicines used to treat drug-resistant tuberculosis (DR-TB), examines the key factors that shape the access environment for DR-TB medicines, reviews the research and development landscape for DR-TB treatment regimens, and makes recommendations for the way forward to reach more people and improve treatment outcomes.

MSF clinics and The Union TB experts of unnecessary death and sickness, and there are many barriers to wider are recording alarming rates of people and saddling treatment programmes use, including cost, regulatory issues with drug-resistant forms of TB, not with much higher costs.3 and a lack of incentives for industry only among patients for whom first-line to promote access. Although far from ideal, today’s current treatment has failed, but also in patients recommended regimens represent one Looking further ahead, it is important newly diagnosed with TB – a clear sign

DR-TB DRUGS UNDER THE MICROSCOPE of the few lifelines currently available that the drug pipeline for TB has that DR-TB is being transmitted from to people living with DR-TB. Until a range of new candidates in each person to person in the communities improved treatment options are phase of clinical development, to in which we work. widely available, continued use and ensure clinicians can stay ahead Treatment regimens for drug-resistant scale up of the existing treatment of new resistance patterns. forms of the disease, which are more regimens must remain a critical Some of these gaps and barriers difficult to diagnose and treat than component of any strategy to may take years to resolve, but in drug-sensitive (DS) TB, are notoriously control the DR-TB epidemic. the meantime, governments can lengthy, toxic, expensive and and should increase rapid screening burdensome to patients. DR-TB Today, we’re closer than ever to and diagnosis of DR-TB, increase patients must endure about two years having more tolerable, all-oral, access to today’s treatments, and of treatment with excruciating side short-course regimens that, if made take concrete steps to ensure that new effects, including psychosis, deafness widely accessible, could fundamentally DR-TB drugs are approved, affordable, and constant nausea, with painful daily transform DR-TB treatment. At the end of and available. injections for up to eight months. Those 2012, the first new TB drug in 50 years who make it through the treatment for received accelerated approval for use Global health actors, including the multidrug-resistant TB (MDR-TB) only in treating MDR-TB, and a second new Global Fund to fight AIDS, Tuberculosis have about a 50% chance of being drug is currently under review. and Malaria and the Global Drug cured; for extensively drug-resistant Many questions remain unanswered Facility, should act now to mobilise (XDR) strains, it’s just 13%.1,2 Meanwhile about how these new drugs should funding, consolidate demand, and the current recommended treatment be incorporated into optimal treatment ensure a sustainable supply of new course for MDR-TB costs at least $3,000 regimens. A historic opportunity and existing effective DR-TB drugs. per patient today, compared to just could be squandered amid a lack of The world has waited half a century $22 for drug-sensitive TB treatment. collaboration and transparency that is for newer and more effective TB and critical to evaluating new multi-drug DR-TB treatments. Now that hope The utter inadequacy and high costs of treatment regimens. Furthermore, is on the horizon, concerted efforts today’s current recommended DR-TB meaningful treatment scale up will are needed on all fronts to avoid any treatment regimens contribute directly only occur if these new regimens further delay in relieving unnecessary to abysmally low treatment coverage, are made available at prices that pain and suffering for patients and which in turn allows drug-resistant are substantially lower than today’s their families, and in permanently forms of the disease to spread rapidly. prohibitively expensive options. turning the tide against DR-TB. Inadequately treated patients, poor treatment adherence due to intolerable In addition, there is growing evidence side effects, poor efficacy and the use that repurposed drugs – drugs with of low quality TB medicines are also indications for diseases other than major contributing factors to the TB – can significantly improve patient unchecked spread of DR-TB strains. outcomes, particularly for XDR-TB. DR-TB represents a serious threat to Unfortunately, these drugs are not public health, burdening families yet readily accessible either for and communities with high rates further research or to treat patients,

2 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 A growing health crisis: DR-TB DRUGS UNDER THE MICROSCOPE ten facts about drug-resistant tuberculosis

• Although tuberculosis is a preventable • Globally in 2011, there were in an on-going infection.5 As a and curable disease, it ranks as the an estimated 630,000 prevalent consequence, in some countries, second biggest infectious disease killer cases of MDR-TB. for example in Kyrgyzstan and behind HIV, killing nearly 1.4 million Uzbekistan, upwards of 20% of 4 • India, China, Russia and South Africa people each year. 4 carry the burden of almost 60% of the newly-infected patients have DR-TB. 4 • Drug-resistant tuberculosis is increasingly world’s cases of MDR-TB. • Globally, amongst those previously recognised as a public health emergency • The highest proportions of TB patients treated for TB, about 20% develop across the globe, even as the true scope with MDR-TB are in Eastern Europe MDR-TB, and about 3.7% of of the problem remains largely hidden and Central Asia, where in some newly-infected TB patients receive and many people living with DR-TB go countries 50% of previously treated an initial diagnosis of MDR-TB. undiagnosed and uncounted due to cases have MDR-TB.4 inadequate access to diagnostic services. • According to the Stop TB • Extensively drug-resistant (XDR) TB • The number of people receiving Partnership’s Global Plan to Stop TB has been identified in 84 countries.4 treatment globally remains shockingly for the years 2006 to 2015, 1.3 low, in particular for MDR forms of TB: • A growing concern is the number of million MDR-TB cases will need in 2011, just one in five people estimated patients acquiring MDR-TB through to be treated in the 27 high to have contracted MDR-TB, among primary transmission of drug-resistant MDR-TB burden countries between notified TB cases, were diagnosed strains of the disease, rather than 2010 and 2015, at an estimated and put on treatment.4 through the evolution of resistance total cost of US$16.2 billion.6

Alphabet soup

Drug-sensitive tuberculosis, also Multidrug-resistant tuberculosis The phrase ‘totally drug-resistant TB’ called drug-susceptible tuberculosis, (MDR-TB) is defined by TB that is (TDR-TB) has been used since late 2010 to is responsive to standard first-line resistant to at least isoniazid and rifampicin, describe a group of patients in India that TB drugs and is not the subject of the two most powerful anti-TB drugs. have developed resistance to all drugs for which they were tested. However, this is this report. Extensively drug-resistant tuberculosis not accepted WHO terminology, and these (XDR-TB) is caused by strains of MDR-TB Drug-resistant tuberculosis (DR-TB) cases are officially defined as XDR-TB. that are also resistant to second-line is used to describe strains of TB that show drugs, including at least one from the Polydrug-resistant TB (PDR-TB) is defined resistance to one or more first-line drugs, class of fluoroquinolones, and at least by TB that is resistant to more than one of and is an umbrella term encompassing one of three injectable second-line drugs the first-line drugs, but is neither MDR-TB MDR-, XDR- and PDR-TB. (capreomycin, kanamycin and amikacin). nor XDR-TB. MSF TB TREATMENT PROGRAMMES in 2012

MSF TB AND DR-TB PROGRAMMES + ARMENIA MALI BANGLADESH + MOZAMBIQUE + CAMBODIA + MYANMAR CENTRAL AFRICAN REPUBLIC PAKISTAN CHAD PAPUA NEW GUINEA + COLOMBIA + RUSSIA DEM. REP. OF CONGO SOMALIA + ETHIOPIA + SOUTH AFRICA + GEORGIA + SOUTH SUDAN GUINEA + SWAZILAND + INDIA + TAJIKISTAN + KENYA UGANDA + KYRGYZSTAN + UKRAINE LESOTHO + UZBEKISTAN MALAWI + ZIMBABWE

+ Projects providing drug-resistant tuberculosis (DR-TB) care

TB project DR-TB project

RAMMES GRAMM OG IN RO ES R 3 P IN P 0 B B -T 1 C R 8 T O D F C U S F O

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I E 29,000 S 1,780 people TREATED FOR TB people TREATED FOR DR-TB

MSF has been involved in TB care for 25 years. MSF started treating MDR-TB in 1999 and has grown to become one of the largest NGO providers of MDR-TB care. In 2012, MSF treated 29,000 patients for DS-TB in 30 countries, and 1,780 patients for DR-TB in 18 countries.

DR-TB Drugs Under the Microscope 3 Sources and prices of DR-TB medicines: sluggish progress

• Additional quality-assured sources have become • The biggest obstacles to affordable second-line available for some medicines, pushing prices TB medicines are the small size and fragmented down by about $1,000 per patient per course from nature of the DR-TB market, and high cost of 2012; however, the current recommended MDR-TB S ources and P rices patented drugs like linezolid regimens remain prohibitively expensive, at $3,000 to $5,000 per treatment course • The newest TB drug, bedaquiline, is priced at a level that sustains high prices for DR-TB regimens, and • For some key repurposed medicines, such as clofazimine and linezolid, affordable patents could further delay generic production of access to quality-assured products remains cheaper versions of this and other new TB drugs, extremely challenging particularly in combinations.

Uncovering the epidemic: persistent gaps in the DR-TB diagnostic landscape

The impact of potential game-changing advances in treatment can only be © Eddy McCall maximised with parallel advances in the diagnostic landscape for DR-TB. Speed and accuracy of DR-TB diagnosis has been boosted by the rollout of rapid molecular testing, but this new technology doesn’t fill every gap in the complex diagnostic algorithm required to diagnose DR-TB. Scale up of an optimal package of diagnostic technologies and services will be a critical factor in reversing today’s trends where people die while waiting for a proper diagnosis or are given sub-optimal treatment. Read MSF’s brief, Beyond the Microscope: addressing the critical need for TB diagnostics, available at http://www.msfaccess.org/content/beyond-the-microscope

Due to the limited capacity to diagnose competitors, prices are still high and there This year, there are only two medicines (see box) and treat people with is a limited number of quality-assured – clofazimine and terizidone – with a DR-TB and the structure of the DR-TB sources for DR-TB medicines. single quality-assured source, while last drugs market, the demand expressed 30 per cent of the drugs profiled in this The trend is largely positive, however. to manufacturers for medicines has report were reliant on a single supplier In recent years, the number of sources been historically small, even though for quality-assured products. the number of people who would be supplying quality-assured DR-TB drugs Nevertheless, the overall number of eligible for treatment each year, if they has increased. Several new sources quality-assured sources remains limited, were properly diagnosed, is at least five for DR-TB medicines were approved leaving the supply of quality-assured times the number actually treated.4 by the WHO Prequalification (PQ) programme: three in 2011 (ofloxacin, DR-TB medicines vulnerable to disruption. Scale-up of the new rapid testing levofloxacin, ethionamide), five In some cases, multiple manufacturers platform Xpert MTB/RIF is expected in 2012 (ofloxacin, levofloxacin, are relying on the same source for Active to peel back the lid on the scale of moxifloxacin, ethionamide) and Pharmaceutical Ingredient (API), as for 7 the epidemic, for example in four in the first nine months of 2013 cycloserine and capreomycin. Myanmar, where new rates of detection (prothionamide, amikacin, cycloserine, Furthermore, there is still minimal are beginning to outstrip current levofloxacin). In 2013 the joint commitment by donors and governments, treatment capacity,8 and this trend Global Drug Facility/Global Fund including middle-income countries, to may help increase the number of Expert Review Panel, an additional purchase medicines which meet WHO people treated with second-line mechanism for the assessment of drug standards. As a largely domestically TB drugs in the coming years. quality, gave temporary permission to funded market, the stringent rules around The global MDR-TB market was purchase one source of ofloxacin, two procuring quality-assured drugs are in estimated to be worth $300 million sources for moxifloxacin, two sources many countries not in place, allowing in 2011, with only approximately of cycloserine, two sources of cheaper, non-quality-assured versions $170 million procured through the public prothionamide and one source of drugs to outcompete quality-assured sector.9 As a consequence, there are few of linezolid. versions – further fragmenting the market.

4 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 MDR-TB regimens: prices decreasing, but still very high S ources and prices

Whereas first-line TB treatment is Since 2012, the overall cost for the current overall cost of today’s recommended affordable, costing only $22 per patient recommended regimen using cycloserine DR-TB regimens; the others are for a six-month treatment course,4 has decreased, from a range of $3,953 to capreomycin and PAS. No additional DR-TB treatment remains considerably $5,254 in 2012, to a range of $2,909 to quality assured source of capreomycin more expensive. The exact price varies $4,014 in 2013 (see Table 1). The overall or PAS/PAS-sodium were approved over considerably, as treatment must be cost for the current recommended the last year. The price of the PAS-sodium product dropped slightly, by 10%, individualised according to a patient’s regimen using PAS has also decreased, compared to last year. Capreomycin’s drug resistance profile. Based on the from a range of $4,788 to $5,786 in price increased by 4.5%, despite having 2011 WHO treatment guidelines, the two 2012, to a range of $3,900 to $5,148 five sources under evaluation by WHO current recommended MDR-TB regimens in 2013 (see Table 2). PQ, three dossiers of which were already – one with cycloserine, one with PAS, The main reason behind the drop is that under assessment last year (the main and both lasting 24 months and with increased competition over the past year barrier to approve new quality-assured eight months of injectable capreomycin has lowered prices for moxifloxacin and sources relies in the complex process of – provide an approximate ‘benchmark’ cycloserine, which dropped by 60% and API production). A future price drop price with which to assess MDR-TB 30% respectively. These are two of the four can be expected once these new regimen prices. medicines that contribute heavily to the sources are qualified.

TABLE 1: The cost in US$ of an MDR-TB regimen lasting 24 months, including cycloserine and eight months of injectable capreomycin, using quality-assured medicines, based on prices provided for this report.

LOWEST quoted QUALITY-ASSURED Highest quoted quality-assured PRICES in 2013 (US$) prices in 2013 (US$) Unit price Regimen price Unit price Regimen price

capreomycin 1g vial 5.557 1333.68 6.250 1,500.00

cycloserine 250mg capsule 0.408 881.28 0.520 1,123.20

ethionamide 250mg tablet 0.068 146.88 0.128 276.48

moxifloxacin 40mg tablet 0.680 489.60 1.460 1051.20

pyrazinamide 400mg tablet* 0.020 57.60 0.022 63.36

Total regimen cost 2909.04 4014.24

TABLE 2: The cost in US$ of an MDR-TB regimen lasting 24 months, including PAS and eight months of injectable capreomycin, using quality-assured medicines, based on prices provided for this report.

LOWEST quoted QUALITY-ASSURED Highest quoted quality-assured PRICES in 2013 (US$) prices in 2013 (US$) Unit price Regimen price Unit price Regimen price

capreomycin 1g vial 5.557 1333.68 6.25 1,500.00

PAS 4gr sachet 1.300 1,872.00 1.567 2256.48 PAS-sodium 60% w/w granules 9.2g sachet

ethionamide 250mg tablet 0.068 146.88 0.128 276.48

moxifloxacin 400mg tablet 0.680 489.60 1.460 1051.20

pyrazinamide 400mg tablet* 0.020 57.60 0.022 63.360

Total regimen cost 3899.76 5147.52

*Drug beyond the scope of this report, so prices were sourced from the GDF online catalogue at http://www.stoptb.org/gdf/drugsupply/drugs_available.asp

It is possible to purchase a more affordable regimen, since some medicines are in some contexts interchangeable. For example, using kanamycin instead of capreomycin decreases the cost per patient by approximately $1,000, while replacing moxifloxacin with levofloxacin will decrease the price by approximately $500. However, cost considerations should not be the sole driving factor in selecting the regimen; safety profiles of medicines and resistance prevalence at country level are also key decision criteria.

DR-TB Drugs Under the Microscope 5 Repurposed drugs: extremely limited access

New approaches to treating DR-TB are being explored to optimise the use of existing medicines, including the testing regimens containing medicines used to treat other diseases, repurposed for use in DR-TB.

Repurposed medicines with proven S ources and P rices efficacy in TB or potential efficacy in highly resistant TB cases can fill important gaps in DR-TB treatment, and are of increasing importance in both trial and operational research for DR-TB. But they need to be made accessible. These drugs are included in WHO treatment guidelines as “agents with unclear efficacy”.13 However, because they have no approved indication for DR-TB and they are not included in the WHO and/or countries’ essential medicines lists, accessing these drugs for DR-TB treatment is particularly difficult. Access for further research around optimal use of these products with other medicines is also very problematic. © Sami Siva

These barriers do not apply to all 70% from $2,909, the best possible medicine, which can only be accessed repurposed drugs. Fluoroquinolones benchmark price for a quality-assured for off-label use on named-patient and the injectable agents are also current recommended MDR-TB basis, remains a key obstacle. There is used for DR-TB on an off-label regimen (see Table 1), to under $900 no quality-assured generic producer. basis, but there are no access issues (see Table 3). Such dramatic changes associated with such use. Where in regimen length and price would go Linezolid there is concern is around access a long way to removing key barriers For another repurposed drug, to clofazimine 10 and linezolid,11,12 to treatment scale up by governments linezolid, new studies are adding which are increasingly being used and global health actors. to the evidence base of this drug in treating DR-TB, although neither in treating MDR-TB and in particular have an indication for TB. Clofazimine Despite the fact that the STREAM trial’s 15 is used to treat leprosy, and linezolid nine-month regimen for MDR-TB is XDR-TB. MSF is using linezolid in is primarily used to treat hospital- showing promising results,14 Novartis several projects. A strengthened acquired bacterial infections that has failed to take a proactive approach XDR-TB regimen pilot programme mostly occur in developed countries. to clofazimine on the basis of unclear in Khayelitsha, South Africa, showed efficacy for DR-TB. This approach promising early clinical outcomes: as Clofazimine has made it very difficult for those of the end of August 2013, 78% of patients have culture-converted – an Securing affordable access to who require it for research purposes clofazimine is important because to clarify the efficacy, and role of, early clinical outcomes are promising: the drug is included in the STREAM clofazimine in new regimens. Access to as of the end of August 2013, 75% of clinical trial, which is assessing a the drug is similarly difficult for those patients have culture-converted nine-month DR-TB regimen that uses requiring it for complicated DR-TB – an early sign that treatment may be a combination of first- and second-line patients and operational research for successful – and one patient has been TB drugs. If proven effective, the STREAM. While price is currently not clinically cured.16 Furthermore, results nine-month regimen would cut the considered one of the main barriers suggest that linezolid’s efficacy is not length of treatment by more than to accessing clofazimine, Novartis’s compromised when patients are also half and decrease its cost by about approach to the supply of this taking HIV treatment.17

6 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 S ources and prices

But price is a major barrier. Until this ($8 per pill). Hetero had previously The capacity of generic competition year, Pfizer was the only quality-assured indicated that it would price its generic to bring prices down needs to be source for linezolid. The company’s linezolid at $2.50 per pill,18 which harnessed. In 2014, additional patent-protected monopoly in many would have pushed the cost down to quality-assured versions of linezolid countries allows them to keep prices approximately $450 for six months’ should enter the US and European prohibitively high. In South Africa, treatment. Since then, however, Hetero markets, creating the opportunity to for example, where no generics are has taken advantage of its position as the improve supply and further decrease available, MSF pays ZAR676 ($68) per only quality-assured generic source, more the price, at least in countries where 600mg tablet for the Pfizer product; than tripling the promised price on the Pfizer’s patents do not exist or can at these prices, a six-month course of grounds of higher manufacturing costs be overcome. WHO should also treatment for a DR-TB patient costs over owing to limited demand. encourage generic manufacturers ZAR 121,680 ($12,240), a high price to produce these needed medicines. Government health programmes in for a single drug that, as with all DR-TB But to date, neither clofazimine nor South Africa, where more than 10,000 drugs, must be added to an expensive linezolid has been added to the WHO people a year are diagnosed with MDR-TB, combination of other drugs. Private Essential Medicines List for DR-TB or could save over 70% on the cost of sector actors like MSF must pay more to the Expression of Interest for the linezolid by overcoming Pfizer’s patent than double that price, which limits WHO prequalification programme. barrier and accessing generic products. the ability to offer the drug to a greater Adding clofazimine and linezolid to One key strategy that the government number of patients. these lists with an indication for could consider includes fast-tracked DR-TB is a critical step towards In May 2013, however, Indian generic registration of generic linezolid products securing generic alternatives, adding manufacturer Hetero became the first in South Africa in anticipation of Pfizer’s the drugs to country treatment generic source temporarily eligible (until compound patent expiring in August protocols and national procurement June 2014) for Global Fund procurement, 2014. Pfizer’s secondary patents on plans, and supporting the creation based on the recommendation of the linezolid in South Africa have lapsed due of a sustainable supply chain for joint Global Drug Facility/Global Fund to non-payment of renewal fees, which DR-TB treatment. Expert Review Panel. The company is means any registered generic competitor charging more than $1,440 per patient could launch upon expiration of the for a six-month treatment course compound patent next year.

TABLE 3: The cost in US$ of a shortened MDR-TB regimen lasting nine months, designed according to the STREAM trial regimen and using quality-assured medicines, based on prices provided for this report (regimen still under trial).

LOWEST quoted Highest quoted QUALITY-ASSURED PRICES quality-assured prices in 2013 (US$) in 2013 (US$)

Unit price Regimen price Unit price Regimen price

kanamycin 1g vial 0.800 96.00 2.580 309.60

clofazimine 100mg capsule 1.208 326.16 1.208 326.16

ethambutol 400mg tablet* 0.033 26.73 0.033 26.73

moxifloxacin 400mg tablet 0.680 367.20 1.460 788.40

pyrazinamide 400mg tablet* 0.020 27.00 0.022 29.70

prothionamide 250mg tablet 0.109 39.24 0.167 60.12

isoniazid 300 mg tablet* 0.020 4.80 0.022 5.28

Total regimen cost 887.13 1,545.99

*Drug beyond the scope of this report, so prices were sourced from the GDF online catalogue at http://www.stoptb.org/gdf/drugsupply/drugs_available.asp

DR-TB Drugs Under the Microscope 7 Phumeza Tisile: cured of XDR-TB, and advocating for change

After enduring more than two After an arduous journey, Phumeza As a committed TB activist, years of a gruelling treatment regimen, has beaten the odds: only 13% of Phumeza is calling for access which involved taking an estimated XDR-TB patients are cured by the to drugs like linezolid, which offer 20,000 tablets plus months of painful treatment. But she lost a great deal one of the best hopes of successful injections, 23-year-old South African along the way: she had to give up treatment for XDR-TB patients, and

S ources and P rices student Phumeza Tisile has been cured her studies during treatment, and for new regimens to be developed of XDR-TB. amongst the many side effects that that are safer, shorter and more she suffered while on treatment, effective than those she and her Diagnostics for drug-resistant forms of there is one she will have to live with fellow patients have had TB were not readily available in South forever: she is now permanently deaf, to endure. Africa when Phumeza was initially from a drug that her form of XDR-TB diagnosed with TB. She therefore “I had to take at least three was resistant to from the start. started the standard six-month medications, more than 20 tablets regimen for drug-sensitive TB in “Phumeza fought hard for this,” her daily, supplements and injections. the public sector, but her condition MSF doctor Jenny Hughes recalls. It is just too much. Many other did not improve. “She stuck to her treatment, even patients will agree,” says Phumeza. through the nausea and vomiting, “It seems impossible until it’s done.” Following further lab tests, she even after she lost her hearing.” was diagnosed with drug-resistant Phumeza has also shared her TB, and put on a recommended Phumeza has been using her experiences through MSF TB&Me MDR-TB treatment regimen. When experience to advocate for change on blog (http://blogs.msf.org/tb/), this regimen also failed to improve behalf of her fellow patients. Phumeza a collaborative blogging project Phumeza’s condition, further analysis is the patient co-author of the ‘Test that allows DR-TB patients to share of her sputum samples diagnosed me, treat me’ DR-TB manifesto, a their stories and engage with an pre-XDR-TB, and finally XDR-TB. campaign launched to pressure the TB online community. Despite excellent adherence to community, governments and donors her treatment regimen, the time into ensuring universal access to required to obtain an accurate XDR- DR-TB diagnosis and treatment, TB diagnosis meant Phumeza took developing better treatment regimens, drugs that were not effective for and providing adequate funding her for over eight months. to do both.

JOIN Phumeza AND THE FIGHT FOR BETTER DR-TB CARE

I never thought this day would come – I’ve beaten XDR-TB! Getting cured at last is very exciting. It was scary at first. But you live in hope – hope that one day you will be cured. I didn’t want to be a TB statistic and that kept me going. Phumeza Tisile © Sydelle Willow Smith

Support the ‘Test me, treat me’ DR-TB Manifesto! Sign on at: msfaccess.org/TBmanifesto/

8 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 New chemical entities: registration and affordability S ources and prices

The most momentous development for DR-TB treatment is the advent of the first new drugs in 50 years developed specifically to treat MDR-TB. These two novel drugs have the potential to greatly improve DR-TB treatment options. One of the drugs, bedaquiline, was given conditional, accelerated US FDA approval in December 2012, based on phase IIb data. The second drug, delamanid, is still undergoing stringent regulatory approval at the time of going to print.

How accessible these new drugs will be made, and whether their potential will be maximised for new regimens for DR-TB, remains unclear. Speedy registration is one issue: outside the US, © Bruno De Cock bedaquiline is so far only available through compassionate use or clinical access Patents in countries with generic Otsuka’s patents on delamanid cover programmes (see box overleaf), although manufacturing capacity will prevent not only the compound but also its registration is underway in six countries. companies from producing more intermediate, isomer, salt, ester and affordable versions, and will even combinations.23 A patent covering the Prices are another. This is a moment prevent them from exporting to pipeline drug sutezolid in combination where bold action to slash high prices countries where no such patent barriers with other pipeline investigational for DR-TB regimens would be welcome, exist. For these newer drugs, it will be drugs may become a problem but the pricing framework disclosed by therefore more difficult to replicate in developing optimal treatment Janssen for bedaquiline does not meet the effects that price-busting generic regimens, for example.104 such expectations. The company has competition had on HIV treatment.20 suggested its framework will attempt to If countries are unable to secure balance a country’s ability to pay with The patent landscape also indicates that affordable access to newer medicines, the burden of disease. Thus, a six-month secondary patents – additional patents governments like Brazil, India and treatment course will cost $3,000 in other than the patent on the basic Thailand should consider exercising countries in middle and upper middle- compound and that cover new uses, their rights under international trade income bracket, compared to $900 in formulations or combinations and serve rules to overcome patent barriers, least-developed and resource-limited to block generic competition even after for example by issuing compulsory countries. The $3,000 price is completely the original patent expires – are a threat licences to enable production, unaffordable for any developing country, to future generic production. domestic supply and export of and the $900 price keeps overall regimen more affordable versions. In any The compound patents of both costs – still likely to be thousands of case, secondary patents, where bedaquiline and delamanid, if granted dollars per treatment course – too high possible, should be challenged to in developing countries, expire in to facilitate urgently-needed treatment ensure that generic competition is approximately 2023. The patent terms scale up. The company has not disclosed not unnecessarily delayed through could be extended, however, under which price would be paid by countries abuse of the patent system. supplementary protection or through that are classified as ‘middle-income’ secondary patents.22, 23 For example, Looking beyond price, country and which have a high burden of TB, secondary patents that have been filed preparedness could be another limiting including high-burden countries like for bedaquiline would extend the term factor for a rapid access to new drugs. China, India, Ukraine and Uzbekistan. of patent protection by at least four years In 2012, WHO set up the Task Force High prices are likely to persist unless until the end of 2027. Patents are also for New Drug Policies,19 which will patent barriers are challenged and being filed on combination pills that issue a toolkit in October 2012 to help overcome. Unlike most existing DR-TB include the new drugs in a fixed-dose guide national TB programmes in the drugs (with the exception of linezolid), combination together with existing roll-out of new drugs and regimens all of the new drugs are covered under medicines, which would be a serious for TB treatment at the country level. patent protection. Multiple patent barrier to the development of regimens Key contents will include a checklist applications are underway or have been combining new and repurposed TB for country preparedness, requirements granted in several countries, including drugs. Patent barriers even apply to drugs for monitoring & evaluation, and those with high burdens of disease. that are still in clinical development. pharmacovigilance.

DR-TB Drugs Under the Microscope 9 Compassionate use: getting experimental treatments to patients with no options

Compassionate use programmes In South Africa, bedaquiline is Despite the published evidence on are intended to provide potentially now available for patients that have the potential efficacy of delamanid in lifesaving experimental treatments exhausted treatment options in four MDR-TB,26 manufacturer Otsuka has to patients suffering from a disease select clinical access sites; however, not yet initiated a compassionate use for which no satisfactory authorised the cumbersome approval process programme. With other new drugs in phase III trials, with results expected S ources and P rices therapy exists, or who cannot for patients needing the drug soon, there are a number of drugs that enter a clinical trial. Also called can delay the initiation of XDR-TB will soon make a compelling case for ‘clinical access’ or ‘special access,’ treatment. MSF’s experience in compassionate use. compassionate use became a trying to secure compassionate use common approach over the years access to bedaquiline in Armenia, Further guidance on compassionate to fight diseases such as cancer Colombia, Swaziland and South use is expected from WHO soon in the Africa has demonstrated that and HIV/AIDS, and represents a programmatic guidelines to accompany political will is required to ensure the 2011 MDR-TB guidelines, which critical opportunity to help people that this happens.25 should help countries implement this who would otherwise die for lack important regulatory framework with of effective treatment options. In Armenia (see Spotlight on benefits beyond the immediate goal of The World Health Organization page 17), MSF has been able to allowing access to bedaquiline (in the approved the application of secure access to bedaquiline for short term while registration is awaited this concept to DR-TB in 2008, 23 patients because this year the in the country) and delamanid. There taking into consideration new government adapted its national needs to be greater awareness of and TB compounds under clinical regulations to allow compassionate political willingness to use this option to development.19 use of medicines in their country.25 treat DR-TB patients failing on current In Colombia and Swaziland, MSF treatments, as well as the necessary The drug developer has the final is currently supporting national regulatory framework to allow it. decision on whether a drug will be TB programmes in advocating supplied for compassionate use and for the inclusion of a regulatory * Note that according to current WHO under which conditions. Janssen framework for compassionate use. recommendations bedaquiline should has operated a compassionate use Still, the majority of the high- no longer be reserved for patients * programme for bedaquiline since burden countries do not allow with no other therapeutic options 2011 and to date more than 120 compassionate use, even when it (i.e. through compassionate use), patients have gained access to the is considered the last chance for but should be used earlier in a drug through this scheme. patients to be cured. patient’s treatment course. © Natasha Seregeeva

10 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 R&D: breakthrough drugs offer R esearch and D e v elopment new hope, but significant research gaps persist

• For the first time in half a century, there is for DR-TB. To avoid the development of resistance a relatively robust late-stage TB drug pipeline and to produce optimal regimens, targeted incentives with several drugs showing promising results. should be created to encourage collaborative research Nevertheless, the long-term sustainability of combining new TB drugs the TB R&D pipeline is far from secure • The specific needs of children with DR-TB and • The current system for R&D favours the development people co-infected with HIV and DR-TB remain of single drugs, but complete regimens are needed neglected and require further R&D efforts.

The pipeline: more robust, but not robust enough

For decades, research and development 50mg tablets in healthy adults.29, 30 S Q109 is an ethylenediamine which (R&D) for TB has been woefully No compassionate use programme is being developed by Sequella. neglected, with no new drugs for close is available. It is currently being evaluated in a to half a century and very little research phase IIa EBA study to determine safety, PA-824 is a nitroimidazole developed by to determine the best use of existing sputum clearance of mycobacteria, the TB Alliance which is currently being DR-TB drugs. This has meant that today’s and pharmacokinetics of multiple doses developed as part of a new regimen DR-TB treatment is largely based on of SQ109 alone or with rifampicin in with two trials in phase II (NC002 and experience and expert opinion rather patients with smear-positive pulmonary NC003).31, 32 The results of NC002 than randomised clinical trials, leaving TB.33 SQ109 has the potential for a (a combination of PA-824, moxifloxacin, a number of ‘grey areas’ where expert compassionate use programme once and pyrazinamide) are due end of opinions may be conflicting. In addition, further data are available. 2013, with the potential for a phase III the difficulty in accessing ‘repurposed’ trial of this regimen to commence if AZD-5847 is an oxazolidinone being drugs illustrates the lack of incentive to these results are positive. There are developed by Astra-Zeneca. A phase IIa assess whether drugs that have been no imminent plans to submit a dossier study is underway to assess the EBA at brought to market for other indications for registration of PA-824 as a single four different doses and schedules in can also be used in DR-TB treatment. clinical entity, and no compassionate subjects with newly-diagnosed sputum With one entirely new drug having reached use programme is available. smear-positive pulmonary TB. AZD-5847 the market in 2013, and with one expected has the potential for a compassionate Sutezolid (PNU-100480) is an to follow shortly, at a first glance the R&D use programme once further data oxazolidinone developed by Pfizer over pipeline for tuberculosis is finally delivering. are available. a decade ago for use in resistant gram- And indeed, the late-stage TB drug pipeline positive bacterial infections. Despite early Although these compounds in clinical is fuller than it has been in decades. evidence of activity against TB, the drug development might hold the potential Below is a list of new compounds that was left without significant development for a more promising future for DR-TB are currently in phase II or phase III trials: for over a decade. A phase II early treatment than has been the case bactericidal activity (EBA) trial has been for decades, it would be premature Delamanid is a nitroimidazole which completed, although the results have to conclude that the long-standing recently received a negative opinion yet to be published. Pfizer’s decision to neglect of R&D into TB had come for registration with the European abandon its entire anti-infectives R&D to an end. Medicines Agency (EMA).27, 28 section has delayed the publishing of A re-application is pending at EMA the data as well as the development of a The drug pipeline for TB needs to and their decision is expected by the formulation for sutezolid, adding further be kept full with a range of different end of 2013.24 Registration applications delay to this potentially useful drug compounds in each phase of clinical are pending at the US FDA and being able to be used in the treatment development. According to the annual Pharmaceutical and Medical Devices of DR-TB. The drug was recently survey by the Stop TB Partnership Agency of Japan.36 A phase III trial is transferred from Pfizer to Sequella for Working Group on New Drugs,34 there underway, as are paediatric open-label, continued development. The phase II are no new compounds in phase I clinical uncontrolled pharmacokinetics and safety EBA trial results need to be published. development, and eight new compounds studies of delamanid in children from The phase IIb studies and the clinical in late pre-clinical development. Given birth to less than 18 years of age (Trial development plan are being planned. that a robust early stage development 232), which will take place concurrently Sutezolid has the potential for a pipeline is the only way to ensure with a bioequivalence study to compare compassionate use programme continued advances in DR-TB regimen delamanid suspension to delamanid once further data are available. development, this is a source of concern.

DR-TB Drugs Under the Microscope 11 Historic opportunity squandered? The need for combinations

Above and beyond the lack of In the immediate instance, this is the to protect their realm, and to ensure compounds in early stages of the R&D case with bedaquiline and delamanid. that data is shared collaboratively for pipeline, other significant research As MDR-TB is rightly considered as a the purpose of exploring new regimens gaps remain, so much so that the serious public health threat by health that can improve patient outcomes and unprecedented opportunity presented authorities, bedaquiline was granted shorten treatment, with the ultimate aim by the availability of new TB drugs accelerated market approval for based of developing new ‘pan-TB’ regimens today is at a high risk of being squandered on early development data collected that are suitable for both drug-sensitive because of the current R&D environment. through phase II trials. Bedaquiline and drug-resistant strains of the disease. and delamanid, as well as the other Effective TB treatment requires a robust A key part of the solution will also involve drugs in clinical development, are thus combination of different classes of drugs delinking the cost of drug research coming through the pipeline, or even to be taken concurrently for prolonged and development from the price of to market, with little information on medicines, and promoting collaborative

R esearch and D e v elopment periods of time – this prevents, or at safety and efficacy relating to the use of least greatly hinders, the development open innovation and access to the fruits these drugs in combination with other of R&D. Public investment should be of resistance to individual drugs. Simply drugs. This means that clinicians in deployed through a mixture of classic adding the new TB drugs, bedaquiline the field are in the dark about how to push funding (e.g. grants) as well as and delamanid (if approved), to current use these new drugs safely with other innovative pull incentives (e.g. milestone WHO-approved regimens risks the medicines. This in turn leads to a situation and end stage prizes). One of the rapid loss of their efficacy because the where these drugs could be used in strategies that has worked in many other underlying regimens are still too arduous settings without information on how to fields of technology (namely aeronautics for patients: they will still contain toxic, appropriately monitor adverse reactions and consumer electronics) is to pool burdensome medicines that must be in patients until phase III programmes intellectual property to remove barriers for endured for long periods of time, and deliver their complete outcomes. In the subsequent innovations and development, patients who cannot tolerate them will meantime, significant efforts towards like fixed-dose combinations. These be at risk for treatment interruptions and pharmacovigilance will be required from ‘patent pools’ have the potential to development of resistance. countries which will be early dispensers function as a ‘one-stop-shop’ and To fundamentally change and improve of these new TB medicines. therefore simplify and encourage further development of technologies that are DR-TB treatment, robust new regimens More fundamentally, the problem lies covered by more than one patent from containing multiple novel and better largely with the current incentive system more than one actor. As MDR-TB regimens tolerated drugs are desperately needed for R&D, which inhibits the collaboration must be developed from drugs with to completely replace the old, toxic and transparency that is critical to multiple patents from multiple different drugs that will necessarily remain a part evaluating new drug-resistant treatment developers, pools may be well suited for of the current recommended DR-TB regimens. Companies are often unwilling MDR-TB regimen development. regimens for the foreseeable future. to conduct pre-clinical studies and clinical trials to establish the efficacy of a particular However, there is a deep lack of interest drug or new drug combination against by industry to perform the collaborative TB, or even to submit registration for research needed to develop new a new indication of their drug based regimens, as opposed to individual on trials financed and run by others. drugs. If new molecules were combined For them this holds potential risks and earlier in the clinical research process, offers little benefit. effective new regimens that are shorter and more tolerable could be made In order to sustainably overcome available to patients as soon as the drugs these R&D failings and ensure a full TB are registered. This would avoid the drug pipeline that results in effective, current situation whereby regimen-based tolerable all-oral therapy, far more public research cannot start in earnest until investment is needed. Throughout the each individual drug is well into the late R&D process it is important to overcome clinical development stage, if not actually the strategy of exclusivity and silos. registered. Presently, clinical trials for new There is an urgent need to incentivise regimens are not completed until years collaboration between different R&D © Ron Haviv/VII after the individual drugs are registered. actors that are currently putting up barriers

12 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 R esearch and D e v elopment

Wanted: combination regimens that fulfil the following conditions MSF gathered a group of experts in July 2012 that outlined eight key principles for designing future DR-TB regimens to ensure new drugs are used to their maximum advantage.35 Regimens should:

• contain at least one new class of drugs; • have a maximum duration of six months; and,

• be broadly effective against MDR and XDR strains; • have minimal interaction with antiretroviral drugs • contain a minimum of three and a maximum of five to treat HIV. effective drugs, each from a different drug class; These principles should be used to help ensure that • be an oral regimen (i.e. not include an injectable agent); future regimen development maximises the potential • have a simple dosing schedule; of new compounds while addressing the individual, • have a good side-effect profile that allows programmatic and scale-up issues that plague the limited monitoring; current regimen.

Clinical trial landscape for DR-TB regimens

A number of clinical trials are underway Below is an overview of ongoing initiatives. Each trial listed here includes patients to assess optimal combinations of co-infected with HIV, but with different inclusion criteria: re-purposed and new TB drugs. STREAM Trial: This is a NC003 Trial: An EBA study, funded by Although there are a number of USAID-funded, Union-sponsored TB Alliance, looking at combinations of promising regimen trials, the scope and MRC UK-implemented randomised PA-824 with bedaquiline, clofazimine and slow progress of these trials are clinical trial looking at a nine-month and pyrazinamide.38 The trial includes concerning. Some trials, including combination of existing TB drugs patients co-infected with HIV. Results the Nix trial, plan to only include for the treatment of MDR-TB.37 are expected towards the end of 2013. those people with XDR-TB, however The study regimen is ethambutol, Combinations showing promise will people with pre-XDR- and pyrazinamide, moxifloxacin and be taken forward for phase IIb trials. MDR-TB are also in desperate need clofazimine throughout, supplemented Nix TB Trial: This proposed of improved regimens. These trials by kanamycin, prothionamide and isoniazid in the first four months. open-label study proposed by should include a plan to rapidly Participating patients are randomised to TB Alliance involves bedaquiline incorporate broader populations the STREAM regimen or the optimised given only with other new drugs of DR-TB patients, especially if initial background MDR-TB regimen. The trial (PA-824 and an oxazolidinone) to safety of the regimen is assessed. includes patients co-infected with HIV. patients with XDR-TB, including A greater sense of urgency is needed Recruitment has started in Ethiopia, patients co-infected with HIV. in bringing these trials forward to Vietnam and South Africa and the Marvel TB Trial: A proposed develop much-needed new regimens. results may be ready by 2018. phase II trial, currently undergoing Better cooperation is required NC002 Trial: This is a TB final protocol confirmation, looking from manufacturers, as the lack of Alliance-funded phase II trial at the efficacy and toxicity at cooperation is also hindering trial looking into the combination of two months of combinations of progress. Currently, none of these moxifloxacin, PA-824 and pyrazinamide bedaquiline, sutezolid, PA-824, trials have a paediatric component, in patients with DS- and DR-TB.31 The SQ-109, pyrazinamide, levofloxacin meaning that, yet again, the needs trial includes patients co-infected with and clofazimine for MDR-TB of children will be excluded from HIV. The trial has been completed and treatment.39 The trial includes new treatment developments. the results are expected in early 2014.  patients co-infected with HIV.

DR-TB Drugs Under the Microscope 13 Significant gaps in research persist for vulnerable populations

The needs of children and people living Even when recommendations are in People co-infected with HIV represent with HIV continued to be neglected place, the paucity of safety, efficacy another population neglected by TB by ongoing initiatives in research and and pharmacokinetic data available for R&D initiatives. The interactions of DR-TB development for tuberculosis. drugs used to treat DR-TB in children drugs with HIV medicines are also largely and the lack of paediatric formulations unknown.42 This research has not been a A dearth of research to address the makes implementation challenging. priority for HIV drug developers because needs of childhood TB, and DR-TB Only three medicines featured in this co-infection with TB is now uncommon in particular, is partly because little is report (amikacin, levofloxacin and in wealthy countries. This is particularly known about the disease burden in linezolid) have been developed as problematic given that TB is the biggest children. Diagnostics appropriate for paediatric formulations, but only for killer of people living with HIV today.43 paediatric use are sorely lacking, uses other than TB and for much shorter which contributes to the problem and For many DR-TB medicines, crucial R esearch and D e v elopment treatment courses than required for obscures the depth of treatment needs. TB. None of the paediatric versions are research is lacking. Kanamycin, amikacin The market for paediatric TB medicines widely available, nor are they included and capreomycin all have the potential in 2011 was estimated to be less than in the GDF product catalogue, which for renal toxicity, as does tenofovir (the 40 $10 million. means that treatment providers cannot backbone of the WHO-recommended first-line HIV treatment regimen). It is According to WHO, children account purchase them through the GDF. unclear what additional monitoring may for around half a million new TB cases Treatment providers who attempt to treat be needed for the potential additive renal and 74,000 deaths from TB each children must do so by manipulating toxicities of these drugs. Medicines from year.46 But the figure is known to be an adult formulations, such as breaking the fluoroquinolone class – moxifloxacin, underestimation – it doesn’t include or crushing tablets to approximate the levofloxacin and ofloxacin – are thought TB-related deaths in children infected required dose. This carries a major risk of to interact with crucial protease inhibitors with HIV, which are classified as HIV- over- or under-dosing a child. In addition, like lopinavir and atazanavir (both part related deaths. No data exists regarding safety and efficacy data in children have of second-line HIV regimens). Drug the prevalence of DR-TB in children. not been established for the majority of interactions are also predicted between the medicines used in DR-TB treatment. The WHO MDR-TB programmatic ethionamide and prothionamide and guidelines released in 2011 did not Delamanid is the only new drug in antiretrovirals such as nevirapine and provide guidance on dosing or the the pipeline that has started trials for efavirenz, and there is very little knowledge use of DR-TB drugs in children and use in children, and none of the new about possible interactions for other adolescents. The updated WHO regimen trials for TB have a paediatric medicines, such as cycloserine, terizidone childhood TB guidelines expected component. This means that children and PAS. People living with HIV desperately by the end of 2013 are expected to will have to wait longer to benefit from need updated, less toxic regimens, with give more guidance on the dosages any new development in new drugs or more acceptable drug-drug interactions required for second-line drugs. new regimens. with antiretroviral therapy. © Eddy McCall

14 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 What needs to happen What needs to happen

Ensuring affordable access to quality-assured DR-TB medicines

The inadequate ability to diagnose manage accurate consumption Economies of scale and further price DR-TB and insufficient numbers of forecasting and to put new DR-TB decreases could be possible if countries patients on treatment means that patients on treatment, are a detriment with high burden of disease, including demand for DR-TB drugs is low, not to treatment scale-up in a number of all middle-income countries, would least for medicines which meet WHO contexts. And worse, supply problems pool their demand for DR-TB drugs standards. Therefore, there is little have results in acute stockouts of drugs and commit to use only medicines that in some areas. incentive either for new producers to meet WHO standards. A drug which enter the market or for existing producers The market for DR-TB drugs is not only complies with WHO quality standards to invest in meeting WHO quality low in volume, but also remains very is more expensive to produce than a standards or increase production capacity. fragmented for a number of reasons, non-quality-assured drug, increasing including insufficient pooled demand the cost to countries which prioritise This creates a vicious circle, as limited for quality-assured drugs that meet quality-assured products. However, a drug supplies and expensive medicines WHO standards, the different quality stronger, more consolidated market in turn contribute to hindering the standards for medicines applied without patent barriers must be scale up of DR-TB treatment. Supply by national medicine regulatory developed, especially for the new TB insecurity due to delivery delays or authorities, as well as the high degree drugs, if prices for quality-assured interruptions, together with sometimes of variation between regimens used medicines are to come down to weak capacity at country level to by country programmes. affordable rates.

Pooled procurement By aggregating individual countries’ GDF, with UNITAID support, has The problem of too few quality-assured demand, pooled procurement has the taken some steps to address these sources for international supply potential to bring a global solution to issues, including implementation could be partially resolved by linking problems of supply disruption of API of a limited stockpile to be able to funding to procurement for and/or finished formulations, and to expedite shipments in emergencies. quality-assured medicines. While favour the economies of scale needed GDF is currently working with the Global Fund requires medicines to decrease prices and increase access partners like Global Fund and other procured by the DR-TB programmes to quality-assured medicines. donors to develop a rapid response it finances to meet WHO quality mechanism, increase the size of standards, thus contributing to pooled Orders for DR-TB drugs placed with current stockpile and implement some demand for quality-assured medicines, GDF are often small, do not reach more flexible procurement funding other donors such as the World Bank optimum production quantities, facilities to overcome current supply do not yet set specific quality criteria. and need to be pooled before chain barriers: this could significantly manufacturers will produce a new When weak regulatory authorities shorten lead times and offer the batch. This process, coupled with allow marketing of products that do needed flexibility to adequately the consolidation of several products not meet WHO quality standards but support in-country scale-up challenges within the same shipment and the are nevertheless procured by national at the time of Xpert MTB/RIF roll-out. need for up-front payment before tuberculosis programmes, quality orders are processed, leads to long In a fragmented and volatile market, of medicine is clearly not being standard lead times of four to six pooled procurement could facilitate prioritised enough (see box overleaf). months from order placement. global solutions to supply disruptions, To date, institutions, governments Late payments and inadequate as very few countries have the and WHO have not done enough procurement planning by countries capacity or resources to identify new to address this serious issue. can lead to even longer lead times sources of quality-assured medicines and even stock ruptures. Support to on their own. However, a pooled build up in-country drug procurement procurement mechanism on its own and management capacities, as well will not secure and maintain a market as improved cash flow between of affordable quality-assured drugs, donors and countries, could improve unless the size of the demand it covers the situation. is substantial.

DR-TB Drugs Under the Microscope 15 Quality: a critical question for DR-TB medicines - The use of poor quality medicines to Securing the quality of DR-TB the manufacturers on the WHO treat TB is one of the key contributing medicines also implies securing the Prequalification of Medicines factors fuelling drug resistance and quality of the active pharmaceutical website.i This list is intended to increasing the burden of MDR- and ingredients (API) they contain. make it easier for manufacturers XDR-TB. API quality is directly related to the to identify APIs of verified-quality. quality of the finished product, and Since the commencement of the One reason is that the capacity of APIs weigh heavily in the production API-PQ procedure nearly three years national medicine regulatory authorities costs of a finished product. The ago, 43 APIs have been prequalified, is highly variable between countries, main bottleneck preventing including 13 APIs used in the needs to happen What and many have difficulty assessing more quality-assured sources of treatment of TB. Another dozen quality when it comes to production kanamycin and capreomycin is the anti-TB APIs are under assessment. complex manufacturing process of and importation of medicines. the APIs for these drugs; worldwide Although major donors are Stringently regulated countries are production is today controlled by increasingly recognising the able to evaluate adherence to WHO the few manufacturers who have importance of quality standards, 9, 44 standards, for quality assurance, adequate technical capacity. the insistence on API quality and whereas weaker regulatory authorities manufacturing standards is often do not necessarily have the human There are currently only a few not vigorously verified. In both and financial resources to ensure API sources available for DR-TB countries producing API and drugs that meet WHO quality all required quality criteria are met. countries buying API to produce standards. For example, the a finished product, regulations In addition, quality standards for four manufacturers producing to control the API manufacturing production differ from country cycloserine in blisters are all process and its quality are either to country. For example, India using the same quality-assured new, underdeveloped or absent. API source, thus increasing the produces many medicines that meet This allows drug manufacturers to vulnerability of the supply. WHO standards and are eligible for use API sources that may be much procurement by major donors, such It is essential to start considering more affordable, but which are of as the Global Fund and UNITAID. ways to increase access to substandard or unverified quality. Not only does this have an impact However, quality procedures differ quality-assured affordable APIs on patient safety and treatment, depending on whether the purchases for DR-TB drugs. In November it perpetuates the struggle that are covered by domestic funding 2010, WHO developed the Active Pharmaceutical Ingredient- manufacturers producing or Global Fund grants, with WHO Prequalification (API-PQ) procedure quality-assured medicines face prequalification required for some in response to calls to ensure that in competing with products that products but not for others.45 APIs used in essential medicines might be cheaper, but that use In addition, there is considerable were of acceptable quality. The API of unverified quality. confusion between the terms that API-PQ procedure first verifies define the quality of a source used sources of API that meet in tenders for the procurement of international standards, and i http://apps.who.int/prequal/info_ TB drugs. then publishes details about applicants/API_PQ-List.htm

The role of middle-income countries

The market for DR-TB drugs is largely be consolidated, likely leading to more Finally, these countries should develop concentrated in the BRICS countries. Russia, quality-assured suppliers of both API and common approaches to tackle, at India, South Africa and China account for finished formulations entering the market. the national level, the intellectual 60% of all notified DR-TB cases among property and regulatory barriers that These countries also play a major role the 22 high-burden countries.4 These interfere with access to low-cost in manufacturing of both API and countries also have the largest population generic versions of new medicines. finished formulations. 80 – 85% of active of undiagnosed and untreated DR-TB.4 Competition is the only sustainable pharmaceutical ingredients, including for route to overcome unaffordable prices Procurement decisions made in these second-line DR-TB drugs, are produced charged to middle-income countries countries will have a considerable impact in China, largely due to its advanced by multinational pharmaceutical on the future shape of the market but have fermentation technology and cost position companies. Such efforts would not the potential to reduce average global for manufacturing.9 India is a major only improve access to treatment in costs for both diagnostics and treatment. producer of finished TB formulations. the BRICS, but would also benefit If these countries committed to using Yet not all medicines produced and other developing countries. DR-TB medicines that meet WHO quality marketed in these countries meet standards, global demand for these would WHO quality standards.4

16 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 Ensuring R&D initiatives deliver for patients in need What needs to happen Today’s treatment is expensive, complex, There is a need for a wider funding base Enforcement of intellectual property toxic, and insufficiently effective, and too, as the almost half (45%) of TB R&D rights does not provide an incentive to the need for better, shorter regimens is funding comes from two organisations, encourage development of appropriate pressing. All donors and governments and the vast majority (78%) comes regimens that can treat neglected should therefore substantially increase from the first 10 funding sources. More diseases like TB. Pharmaceutical public investment for R&D in TB. governments need to invest, particularly companies should therefore collaborate emerging economies which face a large with, rather than fight, efforts to Yet the 2013 figures from the Treatment domestic burden of disease. create R&D incentives outside of the Action Group’s annual survey of TB research46 show that for the first time, Ensuring this investment is used to create patent system for the development of funding dedicated to TB R&D is actually the biggest impact for patients with TB, by affordable and appropriate new drug declining – down by $30 million to an embracing new models of R&D funding combinations. What is needed now are annual investment of $627 million. This based on open collaborative approaches, treatment regimens to effectively treat represents only 31% of the needs, and the pooling of intellectual property and the all forms of TB. The current business leaves a shortfall of $1.39 billion compared structuring of incentives so as to prioritise model that is built on exclusivity, rather to funding targets set by the Stop TB the development of drug regimens rather than on collaboration and openness, Partnership. The survey results point to than single drugs or agents will be critical. is not capable of delivering the desired wavering commitments from the private This public investment should be protected outcome. New, open approaches are sector placing greater pressure on public through specific provisions that ensure that needed in order not only to produce sector donors, just as they begin to face the full benefits of innovation developed drugs but effective, safe, easy-to-tolerate, unprecedented budget cutbacks. with public funds are enjoyed by the public. short and all-oral treatment regimens.

Securing the funding base In addition to securing greater middle-income countries, unless national for the 118 countries that are eligible.47 investment in R&D, more funding and international funding is increased. Should the GFATM be fully-funded for DR-TB diagnostics and treatment at its December 2013 replenishment scale-up is needed. According to the The largest TB donor, the Global Fund conference, an estimated 17 million WHO Global TB Report 2012, an annual to fight AIDS, TB, and Malaria, estimates people with TB and DR-TB could receive $3 billion funding gap will persist out of the costs of combating TB and DR-TB treatment, compared to a flat-funded the $8 billion needed per year between over the next three-year replenishment scenario where three million would 2013 and 2015 to fight TB in low- and period (2014 – 2016) to be $15 billion have to go without.

SPOTLIGHT ON Armenia

In 2013, the National Tuberculosis Programme (NTP) of Armenia, supported by Médecins Sans Frontières, was confronted by growing numbers of XDR-TB patients for whom the WHO-recommended treatment for drug-resistant tuberculosis was failing. In response, the NTP established a mechanism to access experimental drugs for compassionate use in treating XDR-TB. © Eddy McCall

The NTP formed an Ethics Committee to review bedaquiline In addition to bedaquiline, all patients needed linezolid and 13 use for TB patients in November 2012. Importation of out of 23 also needed imipenem. Both drugs posed particular bedaquiline on humanitarian grounds was approved in challenges: there are significant side effects for linezolid and January 2013, whilst waiting for the formal introduction imipenem requires twice-daily intravenous administration. of legislation on compassionate use of experimental drugs. Enhanced monitoring requirements for bedaquiline and An external expert medical committee reviewed the first linezolid proved challenging under programmatic conditions. case in January 2013, and the Armenian NTP presented the case to the manufacturer in February 2013. The NTP proved flexible and adopted an innovative approach on the administration of these drugs in ambulatory settings, Between February 2013 and July 2013, 23 out of 28 patients adapting informed consent and counselling for the new were approved to receive bedaquiline under compassionate drugs, and unresolved questions on the duration of use by both the expert committee and the manufacturer. individual drug therapy.

Armenia showed that it is feasible for NTPs to implement mechanisms allowing access to experimental drugs for patients in need. Putting in place the required regulatory framework and technical support can be a lengthy process. Despite the challenges, accessing experimental TB drugs has given new hope to patients who have no further therapeutic options. Dr. Saiful Qayyum, Medical Coordinator, Armenia, Médecins Sans Frontières

DR-TB Drugs Under the Microscope 17 SPOTLIGHT ON INDIA

India currently faces enormous challenges in controlling However, whatever gains are made in rationalising treatment an unchecked drug-resistant tuberculosis epidemic, with protocols will be lost if problems with drug procurement a large burden of cases and an increasing number of are not also solved. This year, India experienced stock outs drug-resistant strains. According to WHO, India had about of DR-TB drugs across the country. Under India’s public TB 66,000 MDR-TB patients in 2011, but only 3,384 patients treatment programme, the central government is responsible were put on treatment.4 for buying drugs and distributing them to the states, which then provide treatment. The stock outs are related to One of the main contributing factors to the epidemic long-standing problems with the drug procurement agency is the fact that India’s private health care sector is allowed that supports all public health programmes – leading needs to happen What to diagnose and treat TB without adherence to any standard to chronic and deadly delays in the supply of drugs. protocols. Antibiotics and anti-TB medicines are widely available for sale over the counter, without adequate system Stock outs of DR-TB drugs have been consistently to ensure adherence to treatment. Chronic misuse of the reported in a number of Indian states since May 2013. The medicines is fuelling drug-resistant TB in the country. mismanagement in the procurement of DR-TB drugs and As a result, the Indian context is very unique in terms of stock out at facility levels have increased concerns regarding baseline drug resistance profiles. Especially notable is the the growing levels of drug resistance in the country.50 high level of baseline resistance to fluoroquinolones, and this MSF has called for the Indian government to urgently occurs independent of previous exposure to TB treatment. address the issue of chronic stock outs for TB drugs.51 An effective response to the DR-TB epidemic must include a A continuous, sustainable supply new rational approach to treatment, and some encouraging steps are being undertaken. The government of India has of quality-assured medicines is vital for already made the notification of all TB cases mandatory TB patients to have even half a chance for all private practitioners.48 Next, India’s National TB of being cured. I feel powerless because programme is developing a plan to make quality-assured anti-TB drugs available to all citizens free of charge. we don’t have the medicines to treat. In addition, the national TB programme is expected It’s just not good enough that India talks to take control of all TB medicines in the country, and of scaling up DR-TB treatment, but finds to restrict over the counter sale of TB drugs. the medicine cabinet empty at a time According to the proposed plan, the drugs would be available when people diagnosed with DR-TB are only to patients enrolled in the national TB programme and to those who obtain vouchers from qualified private most desperate to get the medicines that practitioners, who in turn can obtain the vouchers after can treat them. The Government must notifying the patient to a national registry.49 If these measures act now to address this dire situation. are implemented, the result should be better treatment outcomes and better epidemiological control of the disease, Dr. Homa Mansoor, TB Medical Referent, which will help stem the emergence of drug-resistant TB. India, Médecins Sans Frontières © Siddharta Singh

18 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 What needs to happen

SPOTLIGHT ON INDIASOUTH AFRICA

South Africa has a high-burden of DR-TB, with over 10,000 new cases of MDR-TB diagnosed each year and just over half receiving treatment. The increased availability of Xpert MTB/RIF machines in South Africa means patients are being diagnosed more rapidly and starting on DR-TB treatment much more quickly than before, but this poses a threat to the capacity of the health system to handle higher case loads.

MSF has started piloting decentralised care for DR-TB patients in Khayelitsha in 2007, in order to offer an alternative to compulsory hospitalisation, and provide evidence that patients could start treatment faster and relieve overburdened health systems through a community-based approach to treatment. This model has proved successful and is now being piloted more widely by the Department of Health in Cape Town. However, despite decentralisation of services to increase diagnosis and treatment initiation, one of the ongoing challenges in DR-TB care is helping patients complete a full treatment course. Due to the high number of debilitating side effects and the high HIV co-infection rate, patients with DR-TB may take in excess of 15 tablets per day to manage all of these © Jose Cendon conditions. MDR-TB patients also need to endure months of excruciating injections. Patients urgently need better Drug stock outs pose additional risks to DR-TB drug regimens that are more efficacious, require fewer treatment adherence and success in South Africa. pills, and have fewer side effects; this in turn would enable 40% of the 70 facilities surveyed by MSF and TAC decentralisation programmes to be rolled out more easily. during May 2013 in the Mthatha catchment area of Eastern Cape Province had experienced HIV or TB A further complicating factor for patients in South Africa drug stock-outs, or both. At 24% of the affected is that TB treatment is not always accessed at the same facilities, medical staff were forced to send patients facility as HIV treatment. Given the high burden of home without treatment because the facilities HIV/TB co-infection in South Africa, efforts should experienced stock-outs of essential HIV and TB drugs. be made to consolidate HIV and TB points of care. These stock-outs were reported to last, on average, New, more effective and tolerable DR-TB regimens are 45 days at a time and remain almost as common and on the horizon, but patients in South Africa may have severe as they were when the problem was investigated a long wait before they are made available locally. five months previously.52 The Medicines Control Council (MCC) of South Africa Another issue for the South African government typically takes a minimum of two years to register a new to address in order to effectively respond to the drug, which could delay use of these newer treatments. DR-TB epidemic is the question of patent barriers. While the MCC approved a “clinical access” programme These are preventing affordable access to linezolid, for the new TB drug bedaquiline in January 2013, and must be urgently and appropriately addressed. registration is undergoing. Through the clinical access The country’s Department of Trade and Industry has programme, bedaquiline is now available for patients shown its intention to improve processes for issuing that have exhausted treatment options in four select compulsory licences in its Draft National Policy on sites in South Africa, though the cumbersome approval Intellectual Property – a reform that, if implemented, process for patients needing the drug can delay the may prove critical in accessing newer DR-TB drugs initiation of XDR-TB treatment. at affordable prices.

In South Africa the sheer magnitude of the MDR-TB epidemic alone warrants renewed commitment from the Department of Health and the MCC to allow patients to receive the best possible treatment as soon as possible. Newer drugs offer the opportunity to save lives, and while regulatory review is essential, increased patient access is urgently needed.

Dr. Vivian Cox, Deputy Medical Field Coordinator, South Africa, Médecins Sans Frontières

DR-TB Drugs Under the Microscope 19 Recommendations Affected country governments: Should continue to work with Should support research to define a Should increase DR-TB diagnostic non-donor supported countries, better and shorter DR-TB treatment capacity and scale-up of DR-TB including middle-income countries, regimen with the inclusion of treatment, and make improvements to increase procurement of quality- newer drugs, including through in procurement and supply systems assured medicines. alternative models to incentivise drug to prevent stock outs of TB and development that de-link the cost of DR-TB medicines The World Health Organization: R&D from the final product price. Should promote the use of quality- Should strengthen the national Pharmaceutical companies: regulatory framework, commit to use assured medicines at country level All companies must invest in R&D to medicines which meet WHO standards Should include all DR-TB drugs in the advance clinical development of new (both for active pharmaceutical needs to happen What WHO Essential Medicines List and in drugs to address TB and work with ingredients and for finished products) the Expression of Interest list of the donors and developing countries to and pool demand for quality-assured WHO prequalification programme develop R&D programmes which medicines to secure the market, enable prioritise regimen development economies of scale and decrease prices Should ensure a comprehensive access and supply strategy for Janssen should ensure more Should establish a framework for DR-TB medicines, which includes affordable access to bedaquiline compassionate use programmes the removal of off-label use barriers in all low- and middle-income Should implement the WHO interim by registration of TB indications for countries by issuing a voluntary licence guidance on the use of bedaquiline all medicines, including clofazimine to encourage low-cost generic and linezolid production, or by offering a low price Should regulate access to DR-TB that includes middle-income countries medicines in order to preserve their Should, through its new TB drugs efficacy and avoid fuelling resistance, taskforce, issue a statement on Otsuka should develop a compassionate including among the private sector the need for registration for a TB use programme for delamanid, and a indication for repurposed drugs strategy that ensures rapid registration Should ensure national legislation including clofazimine and linezolid, and affordable prices for delamanid appropriately incorporates intellectual and provide guidance on the evidence in low- and middle-income countries property flexibilities allowed under accrued and needed to obtain Novartis should remove barriers to TRIPS, and should make full use of TRIPS a TB treatment recommendation flexibilities to ensure affordable access off-label use of clofazimine, whether for to new TB drugs Should advocate and facilitate research purposes or for patients with interventions to address intellectual limited treatment options, by filing for Should invest in R&D for new TB drug property barriers associated with a TB registration, and by increasing regimens, especially through alternative new TB drugs production to meet projected demand models to incentivise drug development or by expediting technology transfer that de-link the cost of R&D from the Should support the rapid evaluation to another company final product price of shorter treatment regimens, give timely advice on the use of new Pfizer should remove barriers to Specifically BRICS countries should use off-label use of linezolid by filing for effective compounds, and support the upcoming BRICS health ministerial a TB registration, and should reduce the development of new optimised meeting in January 2014 to further its price by not enforcing patents, regimens to treat DR-TB, in particular already stated commitments 84 on particularly secondary patents, that may those looking at alternative models scale-up and innovation, but also to take block entry of low-cost generic versions to incentivise drug development that steps to help lower-income countries. in low- and middle-income countries de-link the cost of R&D from the final product price Hetero should offer linezolid at the The Global Drug Facility: price of $2.50 per tablet quoted in Should give guidance to countries Should continue to publish prices of 2012, and should neither file nor about initiating a compassionate use medicines on its website in order to enforce secondary patents on a programme and facilitating registration improve transparency generic version of linezolid and appropriate scale up of the new Should finalise the expansion of the compounds Sequella should ensure that the existing rotating stockpile to decrease development of sutezolid resumes its progress, including by manufacturing the time it takes for countries to receive Donors: medicines for all orders, and not only sufficient quantities of the product, Should increase financial support emergency ones by commencing a phase IIb trial for DR-TB diagnostics and treatment in a timely manner, by making the Should further develop a strategic scale-up, including through the compound available for research revolving fund with international donors largest funder for TB programmes, for other combination trials, and by to provide manufacturers a financial the Global Fund to fight AIDS, publishing toxicity information and guarantee to secure the production Tuberculosis and Malaria 2009 phase IIa data and supply of second-line TB drugs Should promote and monitor the AstraZeneca should ensure that the Should work towards worldwide access use of quality-assured medicines at development of AZD-5847 continues to additional quality-assured sources country level by harmonising quality and that it is made available for of clofazimine and linezolid criteria for procurement other combination trials.

20 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 M ethodolog y Methodology

This report looks at the sources and prices of anti-tuberculosis medicines classified in World Health Organization (WHO) Groups 2 (injectable agents), 3 (fluoroquinolones), 4 (oral bacteriostatic second-line agents) and 5 (agents with unclear efficacy) and new medicines for which an interim policy guidance was recently granted by WHO such as bedaquiline.

Data collection Prices received in currencies other Products that have not yet been than US$ were converted on 12 Questionnaires were sent to submitted to WHO Prequalification companies listed on the Global Fund August 2013 using the currency or to a stringent regulatory authority List of Tuberculosis pharmaceutical converter site www.oanda.com. have not been included. products,i producing at least one Prices listed are ‘ex-works’ except Submissions to WHO Prequalification are anti-tuberculosis product either listed for prices provided by Apotex confidential and all companies mentioned on the WHO List of Prequalified (CIF, Toronto, Canada) – see Annex 2 that have a dossier accepted for review Medicinal Products or approved for details, and the glossary for have given MSF and The Union the by a stringent regulatory authority an explanation of incoterms. permission to disclose this information. (SRA) or temporarily approved by As the information on the WHO List the Expert Review Panel (ERP) of The prices listed in this publication are of Prequalified Medicinal Products is the Global Fund. In addition, for the ones provided by the manufacturers. updated regularly, the list should be medicines with fewer than two The prices paid by the purchaser might be consulted for up-to-date information.iii generic quality-assured sources higher because of add-ons (such as import available, such as for linezolid and taxes and distribution mark-ups), or may Products procured by GDF comply moxifloxacin, manufacturers with US be lower after negotiations or as a result with the GDF’s Quality Assurance FDA tentatively approved products of effective procurement procedures. policy.iv This deems eligible for were included. The data were Prices offered by the Global Drug collected up to August 2013. GDF procurement all products that Facility (GDF) pooled procurement are included on the WHO List of Price information mechanism are also ‘ex-works’. Note that Prequalified Medicinal Products, ii prices in the GDF price catalogue can that are approved by a stringent Prices are listed where manufacturers fluctuate during the year if, for example, regulatory authority, or that are agreed to share information. a long-term agreement with different approved by the joint GDF/Global A number of manufacturers, including suppliers comes to an end. In addition, Fund ERP. Bayer, Glenmark, Lupin, Meiji, for certain manufacturers, GDF has Novartis, Pfizer, Sandoz and Teva provided so-called ‘staircase prices’, The ERP is an independent technical did not have prices available or where price per unit varies depending body whose purpose is to review did not agree to publish prices, on the quantities that are purchased. and no responses were received the potential quality risk of using medicines which are not yet from Biocom, Cadila, Chao Center Quality information Purdue, and Pharmathen Hellas. WHO-prequalified or authorised Products that are either listed on the by a stringent regulatory authority, Prices are given in US dollars (US$), WHO List of Prequalified Medicinal and give advice to the Global Fund rounded up to the nearest third Products or approved by a stringent and the Global Drug Facility whether decimal point, and correspond to regulatory authority are listed in the time-limited procurement of such the lowest unit price (i.e. the price price tables as ‘approved’. Products products can be authorised. of one tablet, capsule or vial). that are undergoing review by either The list of ERP reviewed products When prices that varied according WHO Prequalification, by a stringent for tuberculosis can be consulted to packaging (e.g. blisters or bottle) regulatory authority, or that have on the Global Fund website.v were received from a manufacturer been reviewed and listed by the ERP for the same formulation, the lowest of the Global Fund, are listed in the price was selected. price tables as ‘under evaluation’.

i. http://www.theglobalfund.org/en/procurement/quality/pharmaceutical/ ii. http://www.stoptb.org/gdf/drugsupply/drugs_available.asp iii. http://apps.who.int/prequal/a iv. http://www.stoptb.org/gdf/drugsupply/quality_sourcing_process.asp v. http://www.theglobalfund.org/en/procurement/quality/pharmaceutical/#A_B

DR-TB Drugs Under the Microscope 21 AMIKACIN ( Am ) GROUP 2 ) GROUP 2

GENERAL INFORMATION

• Therapeutic Class: • Presentations available: solution for • Approved indication in the US: Amikacin Aminoglycoside antibiotic. injection: 500mg/2ml; 100mg/2ml. is indicated for the short-term treatment

AMI K ACIN ( A m As powder for injection: 100mg, of serious infections due to susceptible • ATC Code: J01GB06.85 500mg & 1g. strains of Gram-negative bacteria, • Included in the WHO Guidelines including bacterial septicaemia (including • First approved by US Food and as a Group 2 injectable agent.13 neonatal sepsis), serious infections of the Drug Administration (FDA): The date respiratory tract, bones and joints, central • Included in the 18th edition of of the original New Drug Application nervous system (including meningitis) the WHO Model List of Essential (NDA) is not publicly available on the and skin and soft tissue; intra-abdominal Medicines 86 and in the 4th edition US FDA website. The first Abbreviated infections (including peritonitis); of the WHO Model List of Essential New Drug Application (ANDA) was burns and post-operative infections Medicines for Children.87 approved on 22 January 1981.88 (including post-vascular surgery).89

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

Cipla Medochemie Pharmathen Hellas Pharmatex GDF pooled procurement

WHO PQ

Quality status WHO PQ approved SRA approved SRA approved GDF Quality Assurance Policy approved

500mg/2ml No response 0.805 (Pharmatex) solution for 2.060 0.750 received from 0.741 1.016 – 1.059 (Medochemie)* injection manufacturer 1.950 (Cipla)

* These are the highest and lowest of a range of prices offered, depending on the quantities ordered.

22 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 CN ( A m AMI K ACIN

Spotlight on access issues

There is little clinical difference between kanamycin and amikacin. As they have similar side effect profiles and show high levels of cross-resistance, factors including price, availability and adaptability of formulations will influence national TB programmes or treatment providers when selecting these drugs.

Capreomycin may be effective in cases showing resistance to amikacin. ) GROUP 2

Number of quality sources burdens both on treatment manufacturer contacted for this There are several stringent programmes, as qualified staff publication. There is at least one regulatory authority-approved need to administer the product. stringent regulatory authority- sources of amikacin. In 2011, a approved source available (e.g. Amikacin is available in both generic source of amikacin (Cipla) Bristol-Myers Squibb). The product powder and liquid formulations; was prequalified by WHO for the is not available through the GDF. the latter is more adaptable first time, with a second source to resource-limited settings as HIV co-infection (Pharmathen Hellas) being reconstitution is not required. No antiretroviral interaction studies WHO-prequalified in April 2013. An have been performed, but based additional two products are currently Paediatrics on pharmacokinetic profiles, the undergoing WHO prequalification; Amikacin is licensed for use in potential for drug interactions are 1g/vial and 500mg/vial. neonates, infants and children. low. However, there is potential Suitability for use in There is a smaller dosage for additive toxicities, in particular developing country settings (100mg/2ml) available which with antiretrovirals which may Amikacin, like other aminoglycosides allows for more accurate dosing cause renal toxicity, such as and capreomycin, cannot be in children. This formulation is tenofovir. Further studies are administered orally. This imposes not part of the portfolio of any required to confirm this.

DR-TB Drugs Under the Microscope 23 KANAMYCIN ( Km ) GROUP 2 ) GROUP 2

GENERAL INFORMATION

• Therapeutic Class: • Presentations available: solution for • Approved indication in the US: Aminoglycoside antibiotic. injection: 1g/4ml, 500mg/2ml, 1g/3ml. Kanamycin is indicated in the As powder for injection: 1g/vial. short-term treatment of serious 85 • ATC Code: J01GB04. infections caused by susceptible K ANAM Y CIN ( K m • First approved by US Food and Drug strains of micro-organisms.90 • Included in the WHO Guidelines Administration (FDA): The date of the as Group 2 injectable agent.13 original New Drug Application (NDA) is not publicly available on the US FDA • Included in the 18th edition of website. The first Abbreviated New the WHO Model List of Essential Drug Application (ANDA) was approved 86 Medicines and in the 4th edition on 13 February 1973. The only of the WHO Model List of Essential currently registered product in the US Medicines for Children.87 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)

Macleods Meiji Panpharma GDF pooled procurement

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

1g powder for 1.500 xx 0.800 0.826 (Panpharma) injection

1g/4ml solution Manufacturer did not xx xx 2.580 (Meiji) for injection agree to publish prices

24 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 I ( K m K ANAM Y CIN

Spotlight on access issues

There is little clinical difference between kanamycin and amikacin. As they have similar side effect profiles ) GROUP 2 and show high levels of cross-resistance, factors including price, availability and adaptability of formulations will influence national TB programmes or treatment providers when selecting these drugs.

Capreomycin may be effective in cases showing resistance to kanamycin.

Number of quality sources source in 2010; however their limited Suitability for use in In the past, kanamycin formulations production capacity means the developing country settings from several different manufacturers price of their product is considerably Kanamycin, like other were registered in the US. However, higher than Panpharma’s. aminoglycosides and capreomycin, as Fresenius Kabi has discontinued cannot be administered orally. Additional manufacturers exist in production, only two kanamycin This imposes burdens both on China, India, in countries from sources are currently approved by treatment programmes, as qualified the former Soviet Union, and in a stringent regulatory authority: staff need to administer the product. other countries, but it is unknown Meiji (in Japan) and Panpharma (in whether they comply with WHO Kanamycin is available in both France). Meiji did not respond to quality standards. powder and liquid formulations; questionnaires for the purpose of the latter is more adaptable this publication and noted that all Active Pharmaceutical to resource-limited settings as supply goes through GDF. Ingredient reconstitution is not required. Issues with the production of the No sources of kanamycin are Paediatrics active pharmaceutical ingredient WHO-prequalified, although one The safety and efficacy of kanamycin (API) have been and still are a manufacturer (Macleods) has submitted in children has not been established. a dossier for WHO prequalification barrier in increasing the number for the 500mg/vial formulation and of quality-assured sources for While dosages are published in has been accepted for evaluation. the finished product. several guidelines, there is need for further research (in pharmacokinetics, An additional source for 1g/vial is Kanamycin API is manufactured pharmacodynamics, and safety data) undergoing WHO prequalification. by a specialised process of into the use of this drug in younger fermentation. There are few The supply of kanamycin remains populations, in particular in children manufacturers globally who vulnerable, with only two sources aged under five. (Panpharma and Meiji) available for have the capacity to produce HIV co-infection TB procurement, both of which have quality-assured API through this No antiretroviral interaction studies experienced production limitations. fermentation process, and the have been performed, but based on Panpharma has resolved issues with complexity is further increased pharmacokinetic profiles, the potential active pharmaceutical ingredient as the API should be sterile. The for drug interactions are low. (API) production which had resulted quality assurance of the API is a in an interruption of supply to key factor and is often what However, there is potential for several national TB programmes in prevents companies from securing additive toxicities, in particular with 2010, although the production only approval of the finished product antiretrovirals which may cause renal resumed in late 2011. Meiji was through WHO Prequalification or toxicity, such as tenofovir. Further identified by GDF as an alternative a stringent regulatory authority. studies are required to confirm this.

DR-TB Drugs Under the Microscope 25 CAPREOMYCIN (Cm) GROUP 2 ) GROUP 2

GENERAL INFORMATION

• Therapeutic Class: • Presentations available: 1g capreomycin-susceptible strains of Polypeptide antibiotic. powder for injection. M. tuberculosis when the primary agents (isoniazid, rifampicin, • ATC Code: J01GB06.85 • First approved by US Food and Drug ethambutol, aminosalicylic acid, and Administration (FDA): 2 June 1971.91 • Included in the WHO Guidelines streptomycin) have been ineffective, CAPREOM Y CIN (C m 13 or cannot be used because of as a Group 2 injectable agent. • Approved indication in the toxicity or the presence of resistant US: Capreomycin is to be used • Included in the 18th edition of tubercle bacilli.91 the WHO Model List of Essential concomitantly with other Medicines 86 and in the 4th edition appropriate anti-tuberculosis of the WHO Model List of Essential agents; it is indicated for use in Medicines for Children.87 pulmonary infections caused by

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

Akorn Aspen Macleods Vianex GDF pooled procurement

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

1g powder for 6.250 (Akorn) 6.250 9.065 5.000 5.850* injection 5.557 (Vianex)

* MSF negotiated price; please contact the manufacturer for additional pricing information.

26 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 CAPREOM Y CIN (C m

Spotlight on access issues

Capreomycin shows moderate cross-resistance to amikacin and kanamycin. ) GROUP 2 With moxifloxacin, PAS and cycloserine, capreomycin is one of the four medicines which weigh heavily in the overall cost of a DR-TB regimen.

Number of quality sources WHO Prequalification or a stringent GDF procurement at $5.58 per vial. GDF have identified two regulatory authority. However, with a new quality-assured quality-assured sources available source identified and five suppliers Eli Lilly transferred the technology for supply: Akorn – which had set to receive WHO prequalification, for capreomycin API to only one bought Eli Lilly’s US licence; and, it is anticipated the price will manufacturer, Chinese generic in 2011, Vianex – a manufacturer eventually decrease. producer Hisun, which received based in Greece, which has US FDA approval in 2006. As the Suitability for use in received stringent regulatory majority of manufacturers are developing country settings authority approval in Spain. Capreomycin, similarly to still using Hisun’s API, access to amikacin and kanamycin from the With only two quality-assured sources capreomycin remains vulnerable, aminoglycosides class, cannot be currently available for TB procurement, even as increasing numbers of administered orally. This imposes the supply of capreomycin is still sources of the finished product burdens both on treatment considered vulnerable; however, five become available. It is therefore programmes, as qualified staff companies, including Macleods and important to secure a second need to administer the product. Aspen, have submitted a dossier for quality-assured API source. WHO prequalification. Paediatrics Other API manufacturers exist, The safety and efficacy of Active Pharmaceutical but have not been approved by a capreomycin in children has not Ingredient stringent regulatory authority or by been established. Issues with the production of the the WHO Prequalification Programme. active pharmaceutical ingredient While dosages are published in (API) have been and are still the Evolution in price several guidelines, there is need for main barrier in increasing the For a number of years, Eli Lilly further research (pharmacokinetics, number of quality-assured sources subsidised the price of capreomycin pharmacodynamics, safety data) for the finished product. for GLC-approved programmes, into the use of this drug in younger charging US$1.02 per vial until a populations, in particular in children Capreomycin API is manufactured by certain volume had been ordered, aged under five. a specialised process of fermentation. and $4.00 thereafter. The price There are few manufacturers globally HIV co-infection at which countries can procure who have the capacity to produce No antiretroviral interaction studies capreomycin has increased quality-assured API through this have been performed, but based on considerably since Ely Lilly stopped fermentation process, and the pharmacokinetic profiles, the potential production, and instead transferred complexity is further increased as for drug interactions are low. technology to other companies the API should be sterile. The quality However, there is potential for (Aspen, Hisun, and SIA International). assurance of the API is a key factor additive toxicities, in particular with and and is often what prevents GDF currently procures the Akorn antiretrovirals which may cause renal companies from securing approval product at $6.25 per vial. Vianex- toxicity such as tenofovir. Further of the finished product through sourced capreomycin is available for studies are required to confirm this.

DR-TB Drugs Under the Microscope 27 MOXIFLOXACIN (Mfx) GROUP 3

GENERAL INFORMATION

• Therapeutic Class: Fluoroquinolone. Medicines 86 nor in the 4th edition • Approved indication in the US: of the WHO Model List of Essential Moxifloxacin was initially approved for • ATC Code: J01MA14.85 Medicines for Children.87 the indications of bacterial sinusitis and • Included in the WHO Guidelines community-acquired pneumonia. This as a Group 3 Fluoroquinolone.13 • Presentations available: 400mg tablet. was further expanded to include acute bacterial exacerbation of chronic bronchitis, MO X IFLO ACIN (M fx ) G roup 3 • Not included in the 18th edition • First approved by US Food and Drug uncomplicated and complicated skin and 92 of the WHO Model List of Essential Administration (FDA): 12 October 1999. skin structure infection, and complicated intra-abdominal infections.93

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

GDF pooled Bayer Cipla Hetero Macleods Micro Labs Sandoz procurement

Under evaluation Under evaluation Under WHO PQ by WHO PQ WHO PQ by WHO PQ GDF Quality Quality status SRA approved evaluation approved (ERP approved till approved (ERP approved Assurance Policy by WHO PQ 30.11.2013) till 31.5.2014)

Manufacturer Manufacturer 0.680 (Macleods) 400mg tablet did not agree to 1.460 1.100 0.680 0.600 did not agree to 1.200 (Hetero) publish prices publish prices 1.430 (Cipla)

Spotlight on access issues

Moxifloxacin use is increasing due to the emergence of MDR-TB and the key role that fluoroquinolones play in the treatment of drug-resistant forms of the disease. A major study is currently looking at a shortened first-line treatment regimen, including moxifloxacin. If this regimen is proven to be effective and is recommended for widespread adoption, the demand for moxifloxacin could significantly increase. Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, such as moxifloxacin and levofloxacin, are preferred to ofloxacin. There is however potential for cross-resistance between the later generation fluoroquinolones.

Number of quality sources Bayer was the only quality-assured evaluation by WHO PQ, including Sandoz did not provide a price for source of moxifloxacin available Hetero and Micro Labs. this publication but indicated that prices would depend on volumes. for many years. In November In the meantime, the Hetero and 2010, Cipla’s product became Sandoz products have received With additional quality-assured the first generic moxifloxacin to the GDF/Global Fund Expert Review sources entering the market, access to be prequalified by WHO, and in Panel temporary approval for one year moxifloxacin appears to be relatively 2013 a second source (Macleods) (until November 2013 and May 2014 secure in the near future and prices, was prequalified. Currently respectively), making them eligible for which in the past represented a barrier four manufacturers are under procurement for Global Fund grants. to access, are continuously decreasing.

28 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 MO X IFLO ACIN (M fx ) G roup 3

Further sources of quality-assured Patents HIV co-infection moxifloxacin are also expected Although the basic patent which No antiretroviral interaction studies as other approved indications covered the moxifloxacin molecule have been performed, but based on of use exist for the drug. Four has now expired in most countries,53 the metabolism rate of moxifloxacin, generic manufacturers (Aurobindo, a subsequent patent claiming a crystal levels of the drug may be reduced Dr Reddy’s, Teva, and Torrent) monohydrate form of moxifloxacin 54 by use of ritonavir and increased by currently have tentative US FDA blocks access to generic sources until atazanavir. Further research is needed approval, waiting to enter the 2016 in the countries where it has to assess this. US market when the patent been granted. In addition, a patent Protease inhibitors and efavirenz expires in 2019. 55 on the tablet oral formulation may prolong QT interval, so caution Additional manufacturers exist in may prevent generic entry into the is advised in concomitant use with China, India, in countries from US market until 2019. moxifloxacin, with electrocardiogram the former Soviet Union, and in monitoring recommended. other countries, but it is unknown The following patents are listed by the 56 Oral absorption of fluoroquinolones whether they comply with WHO US FDA for moxifloxacin 400mg tablet: is reduced by buffered drugs, so quality standards. US patent number. Expiry date doses should be separated from 5607942 4 March 2014 didanosine-buffered tablets. Evolution in price 5849752 5 December 2016 Prior to the arrival of a 6610327 29 October 2019 Special caution quality-assured generic onto the Moxifloxacin can affect cardiac market, the only option available In India, although the patent conduction (QT prolongation). was Bayer’s product; prices for this application on the crystal monohydrate QT prolongation can infrequently source, as reported in the Global form was rejected after a pre-grant result in a serious (rarely fatal) Fund Price and Quality Reporting opposition, additional patents on fast/irregular heartbeat, known (PQR) Tool, have ranged between other pharmaceutical forms have been as torsades de point. This is an US$3.97 and $5.03 per tablet in granted. However, these patents do important consideration as several the last four years. not block generic production of the other new (such as bedaquiline Since the arrival of a first and now tablet formulation. and delamanid) and repurposed a second quality-assured source on Similarly, generic versions have now TB drugs (clofazimine) have a the market, prices have decreased been registered in South Africa and are similar risk and it is unclear if considerably. In 2012, prices for supplied for DR-TB treatment through this will be an additive effect. procurement through GDF were the National TB programme as part This is a class effect but is most between $1.50 (Macleods) and of the government tender awarded pronounced with moxifloxacin. $1.68 (Cipla) per tablet; this in 2011. Generic versions are also year prices range between $0.68 marketed in the Russian Federation. (Macleods) and $1.43 (Cipla). The lowest unit prices for a quality- Paediatrics assured source of moxifloxacin has The safety and efficacy of moxifloxacin thus dropped by 60% in one year, in children has not been established. allowing a considerable reduction in the cost of treatment regimens While dosages are published in several containing the drug. guidelines, there is an urgent need for further research (pharmacokinetics, As more generic manufacturers enter pharmacodynamics, safety data) the market, it is expected the price into the use of this drug in younger will fall yet further. populations, in particular in children aged under five. Approved indication While moxifloxacin has been shown As there is no paediatric formulation to be effective against M. tuberculosis available, paediatric doses are obtained and has been included in many by manipulating adult formulations to treatment guidelines for DR-TB, it achieve target doses. This requires a has not yet received an approved certain level of training, supervision and TB indication by any stringent resources, which may not be available in regulatory authority. many settings where DR-TB is prevalent.

DR-TB Drugs Under the Microscope 29 LEVOFLOXACIN (Lfx) GROUP 3

GENERAL INFORMATION

• Therapeutic Class: Fluoroquinolone. • Presentations available: 250mg, community-acquired pneumonia, 500mg and 750mg tablets; uncomplicated skin and skin • ATC Code: J01MA12.85 25mg/ml oral solution. structure infections, complicated urinary tract infections (UTI), and • Included in the WHO Guidelines • First approved by US Food and Drug 13 acute pyelonephritis. This was further as a Group 3 Fluoroquinolone. Administration (FDA): 20 December LE V OFLO X ACIN (L fx ) G roup 3 expanded to include uncomplicated 1996. The paediatric formulation • Included in the 18th edition of UTI, chronic bacterial prostatitis, and (25mg/ml oral solution) was the WHO Model List of Essential treatment of inhalational anthrax approved on 21 October 2004.94 Medicines86 and in the 4th edition (post-exposure).94 of the WHO Model List of Essential • Approved indication in the US: Medicines for Children.87 Levofloxacin Levofloxacin was initially approved is considered a better alternative for the indications of acute to ofloxacin, based on availability maxillary sinusitis, acute bacterial and programme considerations. exacerbations of chronic bronchitis,

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

GDF pooled Apotex Cipla Hetero Macleods Medochemie Micro Labs procurement Under evaluation Under WHO PQ WHO PQ by WHO PQ SRA WHO PQ GDF Quality Quality status evaluation approved approved (ERP expired approved approved Assurance Policy by WHO PQ on 31.6.2013) 0.051 (Hetero) 250mg tablet 0.090* 0.049 0.075 0.050 0.044 0.087 0.048 (Cipla) 0.087 (Micro Labs) 0.074 (Hetero) 500mg tablet 0.130* 0.077 0.140 0.070 0.076 0.163 0.075 (Cipla) 0.163 (Micro Labs)

750mg tablet 0.150* xx xx 0.150 xx xx xx

* Incoterm CIF

30 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 LE V OFLO X ACIN (L fx) Group 3

Spotlight on access issues

There is potential for cross-resistance between the later generation fluoroquinolones. Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, such as moxifloxacin and levofloxacin, are preferred to ofloxacin.

Number of quality sources Approved indication While there are two manufacturers of Levofloxacin 250mg and 500mg The 2011 WHO programmatic the paediatric formulations (25mg/ml oral formulations produced by guidelines for DR-TB recommend use oral solution) available in the US, these Cipla were prequalified by WHO in of later generation fluoroquinolones, are not widely available elsewhere. including levofloxacin. However, December 2011, with Micro Labs Currently, the majority of DR-TB levofloxacin does not have a TB following in October 2012 and programmes prepare paediatric doses Apotex in June 2013. Currently indication approved by any stringent by manipulating adult formulations an additional six manufacturers regulatory authority. to achieve target doses. This requires for the 250mg product and Patents a certain level of training, supervision four manufacturers for 500mg Patents on levofloxacin held by Daiichi and resources, which may not be (including Hetero and Macleods), Sankyo in the US and in several available in many settings where are under evaluation by WHO European countries expired in 2010. DR-TB is prevalent. Prequalification. A sizeable number Other patents in the US and in HIV co-infection of generic versions have been several European countries claiming No antiretroviral interaction studies approved by stringent regulatory levofloxacin expired in June 2011. have been performed, but based on authorities, since patents expired the metabolism rate of levofloxacin, in the US and in Europe in 2011. Paediatrics no interactions are expected. However, The US FDA has approved The first 750mg formulation further research is needed to assess this. levofloxacin for use in children (produced by Apotex) was aged over six months of age, but Protease inhibitors and efavirenz prequalified by WHO in June 2013, only for acute infections. The safety may prolong QT interval, so caution and one more source (Macleods) of levofloxacin in children treated is advised in concomitant use with is under evaluation by WHO PQ. levofloxacin, with electrocardiogram for more than 14 days has not been monitoring recommended. Evolution in price studied; as this drug may be taken The price of levofloxacin does for up to two years, there is an Oral absorption of fluoroquinolones not appear to be an issue, and it urgent need for more safety data on is reduced by buffered drugs, so has continued to decrease over the use of levofloxacin for extended doses should be separated from the last year. periods of time in children. didanosine-buffered tablets.

DR-TB Drugs Under the Microscope 31 OFLOXACIN (Ofx) GROUP 3

GENERAL INFORMATION

• Therapeutic Class: Fluoroquinolone. in the 4th edition of the WHO Model • Approved indication in the US: Ofloxacin 87 is approved for the indications of acute 85 List of Essential Medicines for Children. • ATC Code: JJ01MA01. bacterial exacerbations of chronic • Included in the WHO Guidelines • Presentations available: 200mg, bronchitis, acute uncomplicated uretheral OFLO X ACIN ( o fx ) G roup 3 as a Group 3 Fluoroquinolone.13 300mg, 400mg tablet. and cervical gonorrhoea, non-gonococcal urethritis and cervicitis, acute pelvic • Included in the 18th edition of the WHO • First approved by US Food and Drug inflammatory disease, and uncomplicated Model List of Essential Medicines 86 and Administration (FDA): 28 December 1990.95 skin and skin structure infections.95

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

GDF pooled Cadila Cipla Macleods Micro Labs procurement Under evaluation by WHO PQ GDF Quality Quality status WHO PQ approved WHO PQ approved WHO PQ approved (ERP approved Assurance Policy till 31.1.2014)

No response 0.048 (Cipla) 200mg tablet received from 0.049 0.060 0.063 manufacturer 0.060 (Macleods)

No response 0.089 (Cipla) 400mg tablet received from 0.090 xx 0.117 manufacturer 0.119 (Micro Labs)

Spotlight on access issues There is potential for cross-resistance between the later generation fluoroquinolones. Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, such as moxifloxacin and levofloxacin, are preferred to ofloxacin.

Number of quality sources Group 3 drugs, ofloxacin does not training, supervision and resources, Today, three 200mg formulations have a TB indication approved by which may not be available in many (Cipla, Macleods, Micro Labs) and any stringent regulatory authority. settings where DR-TB is prevalent. two 400mg formulations (Cipla and Paediatrics HIV co-infection Micro Labs) have been prequalified The safety and efficacy of ofloxacin No antiretroviral interaction studies by WHO. Macleods’ 400mg in children has not been established. have been performed, however formulation is still under evaluation one source suggests there may be a by WHO PQ. While dosages are published in several potential interaction with atazanavir guidelines, there is an urgent need for In addition, Cadila’s 200mg and and lopinavir. 400mg formulations have received further research (pharmacokinetics, joint GDF/Global Fund Expert Review pharmacodynamics, safety data) Protease inhibitors and efavirenz Panel temporary approval (until into the use of this drug in younger may prolong QT interval, so caution January 2014), making them eligible populations, in particular in children is advised in concomitant use with for Global Fund procurement. aged under five. ofloxacin, with electrocardiogram monitoring recommended. Approved indication As there is no paediatric formulation The 2011 WHO DR-TB available, paediatric doses are Oral absorption of fluoroquinolones programmatic guidelines obtained by manipulating adult is reduced by buffered drugs, so recommend use of later generation formulations to achieve target doses should be separated from fluoroquinolones. As with other doses. This requires a certain level of didanosine-buffered tablets.

32 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 ETHIONAMIDE (Eto) ETHIONAMIDE (E to ) GROUP 4 GROUP 4

GENERAL INFORMATION

• Therapeutic Class: Carbothionamides Medicine 86 and in 4th edition of the • Approved indication in the group, derivative of isonicotinic acid. WHO Model List of Essential Medicines US: ethionamide is primarily for Children.87 • ATC Code: J04AD03.85 indicated for the treatment of active tuberculosis in patients • Presentations available: 250mg tablet, • Included in the WHO Guidelines with M. tuberculosis resistant 125mg tablet. as a Group 4 oral bacteriostatic to isoniazid or rifampicin, or second-line agent.13 • First approved by US Food and Drug where the patient is intolerant • Included in the 18th edition of Administration (FDA): 30 April 1965.96 to other drugs.96 the WHO Model List of Essential

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

GDF pooled Cipla Lupin Macleods Micro Labs procurement

Under WHO PQ WHO PQ WHO PQ WHO PQ GDF Quality Quality status evaluation approved approved approved approved Assurance Policy by ERP

125mg tablet xx xx xx 0.112 xx xx

Manufacturer 0.068 (Lupin) 250mg tablet 0.077 did not agree to 0.128 xx 0.078 0.075 (Cipla) publish prices 0.128 (Macleods)

Spotlight on access issues

Prothionamide is the propyl analog of ethionamide. There is complete cross-resistance between the two drugs and they are used interchangeably.

Number of quality sources While dosages are published of training, supervision and resources, The supply and number of in several guidelines, there which may not be available in many sources of ethionamide 250mg is an urgent need for further settings where DR-TB is prevalent. research (pharmacokinetics, is gradually improving, with HIV co-infection pharmacodynamics, safety data) four WHO-prequalified products While no antiretroviral interaction into the use of this drug in younger available. In addition Macleods studies have been performed, populations, in particular in has developed a 125mg paediatric pharmacokinetic profiles suggest children aged under five. formulation that is currently under that drug interactions with evaluation by the GDF/Global Currently there are no paediatric ethionamide are possible. Fund Expert Review Panel. quality-assured formulations There is the possibility of additive available (at the time of going The price of ethionamide toxicities with antiretrovirals to print the Macleods 125mg does not appear to be an issue. which may cause hepatotoxicity, formulation has not received ERP including efavirenz and nevirapine. Paediatrics approval). Paediatric doses are The safety and efficacy obtained by manipulating adult With the potential for interactions with of ethionamide in children formulations to achieve target some classes of antiretrovirals, there has not been established. doses. This requires a certain level is an urgent need for further studies.

DR-TB Drugs Under the Microscope 33 PROTHIONAMIDE (Pto) GROUP 4

GENERAL INFORMATION

• Therapeutic Class: Carbothionamides of the WHO Model List of Essential • Approved indication in Germany: group, derivative of isonicotinic acid. Medicines for Children.87 Treatment of all forms and stages of pulmonary and extra-pulmonary 85 • ATC Code: J04AD01. • Presentations available: 250mg tablet. tuberculosis as second-line drug in the case of proven multidrug-resistance • Included in the WHO Guidelines • First approved by German Federal of the pathogens against first-line as a Group 4 oral bacteriostatic Institute for Drugs and Medical Devices 13 drugs; treatment of diseases caused PROTHIONAMIDE (P to ) G roup 4 second-line agent. (BfArM): First marketed in Germany by so-called ubiquitous (atypical) • Not included in the 18th edition in the 1970s but registered in the mycobacteria; treatment of leprosy of the WHO Model List of Essential framework of posterior registration in the context of modified therapy Medicines 86 nor in the 4th edition process in Germany on 14 June 2005.97 regimens.98

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

GDF pooled Cadila Fatol Micro Labs Olainfarm procurement

Under evaluation by WHO PQ GDF Quality Quality status SRA approved WHO PQ approved SRA approved (ERP approved till 31.12.2013) Assurance Policy

No response received 0.109 (Micro Labs) 250mg tablet 0.167 0.109 0.120 from manufacturer 0.155 (Fatol)

Spotlight on access issues

Prothionamide is the propyl analog of ethionamide. There is complete cross-resistance between the two drugs and they are used interchangeably.

Number of quality sources The increasing number of quality- obtained by manipulating adult In February 2013, Micro Labs was assured sources of prothionamide formulations to achieve target the first manufacturer to secure is gradually improving its supply, doses. This requires a certain level of WHO Prequalification approval and the price of prothionamide is training, supervision and resources, for prothionamide, making it the expected to fall further. which may not be available in many settings where DR-TB is prevalent. third quality-assured source for Paediatrics HIV co-infection the drug, given the two sources The safety and effectiveness of While no antiretroviral interaction approved by stringent regulatory prothionamide in children has studies have been performed, authorities (Germany’s Fatol and not been established. Latvia’s Olainfarm). pharmacokinetic profiles suggest that While dosages are published in several drug interactions with prothionamide An additional two manufacturers guidelines, there is an urgent need for are possible. have submitted their dossiers for further research (pharmacokinetics, There is the possibility of additive WHO prequalification. pharmacodynamics, safety data) toxicities with antiretrovirals which Cadila has received joint GDF/Global into the use of this drug in younger may cause hepatotoxicity, including populations, in particular in children Fund Expert Review Panel temporary efavirenz and nevirapine. aged under five. approval (running until the end of With the potential for interactions with 2013), making it eligible for Global As there is no paediatric formulation some classes of antiretrovirals, there is Fund procurement. available, paediatric doses are an urgent need for further studies.

34 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 CYCLOSERINE (Cs) C Y CLOSERINE (C s GROUP 4

GENERAL INFORMATION ) GROUP 4 • Therapeutic Class: Analog Medicines 86 and in 4th edition of • Approved indication in the US: of D-alanine. the WHO Model List of Essential Cycloserine is indicated in the treatment Medicines for Children.87 of active pulmonary and extra-pulmonary • ATC Code: J04AB01.85 tuberculosis (including renal disease), • Presentations available: • Included in the WHO Guidelines when the causative organisms are 250mg capsule. as a Group 4 oral bacteriostatic susceptible to this drug and when second-line agent.13 • First approved by US Food treatment with the primary medications • Included in the 18th edition of and Drug Administration (streptomycin, isoniazid, rifampicin and the WHO Model List of Essential (FDA): 29 June 1964.99 ethambutol) has proved inadequate.99

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

Chao Center / GDF pooled Aspen Biocom Cipla Dong A Lupin Macleods Micro Labs Purdue procurement

Under Under evaluation evaluation Under GDF Quality WHO PQ WHO PQ SRA by WHO PQ WHO PQ by WHO PQ WHO PQ evaluation Quality status Assurance approved approved approved approved (ERP approved approved by WHO (ERP approved Policy until until PQ 31.12.2013) 30.6.2014)

0.408 (Lupin – blister)* No response No response Manufacturer Manufacturer 0.430 (Macleods 250mg 0.781 received from received from did not agree 0.520 did not agree 0.430 0.389 – blister) capsule (bottle) manufacturer manufacturer to publish (blister) to publish (blister) (blister) – (bottle) (bottle) prices (bottle) prices (blister) 0.480 0.520 (Dong A – blister)**

*This price was provided by GDF and does not appear in the online catalogue. ** These are the highest and lowest of a range of prices offered, depending on the quantities ordered. Note: GDF pooled procurement no longer lists bottle pricing.

Continued overleaf

DR-TB Drugs Under the Microscope 35 Cycloserine (Cs) continued ) GROUP 4 Spotlight on access issues

With capreomycin, moxifloxacin, and PAS, cycloserine is one of the four medicines which weigh heavily in the overall cost of a DR-TB regimen.

Due to the hygroscopic characteristic of cycloserine, it is recommended to use the blister form in countries with high humidity and temperature. C Y CLOSERINE (C s Number of quality sources ingredient of cycloserine was Paediatrics Eli Lilly, the original licence holder of Eli Lilly. The company completed The British National Formulary cycloserine, has actively engaged in a technology transfer for the API provides doses for children aged two technology transfer to three generic to Indian manufacturer Shasun, in to 18, while the US FDA states that the manufacturers (Aspen, Chao Center/ 2006. Shasun API was subsequently safety and effectiveness of cycloserine Purdue GMP and SIA International) US FDA approved in June 2008 and in children has not been established. and ceased production in 2008. was WHO-prequalified in May 2013. There is an urgent need for further Another API manufacturer, Dong A, There are currently four research (pharmacokinetics, also exists. WHO-prequalified sources of pharmacodynamics, safety data) cycloserine, Aspen, Dong A, Currently the majority of the into the use of this drug in younger Macleods, and Biocom, the latter manufacturers producing the populations, in particular in children having secured approval in August blister form are using one API aged under five. 2013. In addition, Chao Center/ source. As a result, access to As there is no paediatric formulation Purdue have received approval from cycloserine remains vulnerable, available, paediatric doses are a stringent regulatory authority. even as increasing numbers of obtained by manipulating adult sources of the finished product Cipla and Lupin and have received formulations to achieve target become available. joint GDF/Global Fund Expert Review doses. This requires a certain level of Panel temporary approval (until Evolution in price training, supervision and resources, December 2013 and June 2014, In the last year, with the arrival which may not be available in many respectively), making them eligible of two more quality-assured settings where DR-TB is prevalent. sources, prices have decreased for Global Fund procurement. HIV co-infection from between US$0.58 and 0.80 Four other manufacturers, including The metabolism of cycloserine per unit, to between $0.41 and 0.52 Micro Labs and Lupin, have submitted is not completely understood, per unit. The lowest unit price for a dossiers for WHO prequalification. and therefore interactions with quality-assured source of cycloserine antiretrovirals are unpredictable. Active Pharmaceutical has dropped by 26% in one year, Ingredient which means a considerable fall There is a need for more research Until 2006, the only quality-assured in the cost of treatment regimens into potential interactions between source for the active pharmaceutical containing this drug. antiretrovirals and cycloserine.

36 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 TERIZIDONE (Trd) TERI Z IDONE (T GROUP 4

GENERAL INFORMATION rd ) G roup 4

• Therapeutic Class: Analog of D-alanine. WHO Model Lists of Essential in the 1970s and is still in the process Medicines for Adult and Children.86, 87 of the posterior registration process • ATC Code: J04AK03.85 in Germany. The filing date for this • Included in the WHO Guidelines • Presentations available: 250mg capsule. process was 1 January 1978.98 as a Group 4 oral bacteriostatic • First approved by German Federal • Approved indication in Germany: second-line agent.13 Institute for Drugs and Medical Devices Treatment of tuberculosis in adults • No longer included in the current (BfArM): First marketed in Germany and adolescents aged 14 or older.98

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

Fatol GDF pooled procurement

Quality status SRA approved GDF Quality Assurance Policy

250mg capsule 1.513 1.666 (Fatol)

Spotlight on access issues

Terizidone is a combination of two molecules of cycloserine, and as such has a similar mode of action as cycloserine. There is complete cross-resistance to cycloserine, and, in some countries, the drug is used instead of cycloserine.

Number of quality sources While dosages are published in several supervision and resources, which Germany’s Fatol is currently guidelines, there is an urgent need for may not be available in many the sole quality-assured source further research (pharmacokinetics, settings where DR-TB is prevalent. of terizidone. Currently no pharmacodynamics, safety data) HIV co-infection manufacturers have submitted into the use of this drug in younger As terizidone is a combination of dossiers for WHO prequalification. populations, in particular in children two molecules of cycloserine and Additional manufacturers exist, but aged under five. the metabolism of cycloserine it is unknown whether they comply As there is no paediatric is not completely understood, with WHO quality standards. formulation available, paediatric interactions with antiretrovirals are unpredictable. Paediatrics doses are obtained by The safety and effectiveness of manipulating adult formulations There is a need for more research terizidone in children has not to achieve target doses. This into potential interactions between been established. requires a certain level of training, antiretrovirals and terizidone.

DR-TB Drugs Under the Microscope 37 PARA-AMINOSALICYLIC ACID (PAS) and PARA-AMINOSALICYLATE SODIUM (PAS-sodium) GROUP 4

GENERAL INFORMATION

• Therapeutic Class: Salicylic acid anti-folate. • Presentations available: PAS: 4g • Approved indication in the US: sachet. PAS-sodium: 60% weight PAS is indicated for the treatment • ATC Code: for PAS: J04AA01; for for weight granules 9.2g sachet and of tuberculosis in combination PAS-sodium: J04AA02.85 100g jar; powder for solution 5.52g with other active agents. It is • Included in the WHO Guidelines PAS: as sachet (equivalent to PAS 4g sachet). most commonly used in patients a Group 4 oral bacteriostatic second-line with multidrug-resistant TB or in • First approved by US Food and agent. PAS-sodium: not included.13 situations when therapy with isoniazid Drug Administration (FDA): and rifampicin is not possible due • PAS is included in the 18th edition of the WHO PAS-sodium was first registered in a to a combination of resistance Model List of Essential Medicines and in the tablet formulation on 8 March 1950. and / or intolerance.100 4th edition of the WHO Model List of Essential Currently, only PAS is available in Medicines for Children. PAS-sodium is the US, with the product registered not included in either document. 86, 87 on 30 June 1994.100

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

PAS Jacobus GDF pooled procurement

Quality status SRA approved GDF Quality Assurance Policy

4g sachet 1.567 1.333 – 1.533* (Jacobus)

* These prices were provided by GDF and do not appear in the catalogue. These are the highest and lowest of a range of prices offered, depending on the quantities ordered.

PAS-SODIUM Macleods Olainfarm GDF pooled procurement sodium ) G roup 4 SODIUM (PAS- Y LATE and PARA-AMINOSALIC Y LIC ACID (PAS) PARA-AMINOSALIC WHO PQ WHO PQ and GDF Quality Quality status approved SRA approved Assurance Policy

60% w/w granules 1.300 xx 1.300 (Macleods) – 9.2g sachet

60% w/w granules 14.250 xx 14.250 (Macleods) – 100g jar (1.311 per 9.2g)

Powder for solution xx 1.520 1.370 (Olainfarm) – 5.25g sachet

38 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 PARA-AMINOSALIC Y LIC ACID (PAS) and PARA-AMINOSALIC Y LATE SODIUM (PAS- sodium ) G roup 4

Spotlight on access issues

With moxifloxacin, capreomycin and cycloserine, PAS is one of the four medicines which weigh heavily in the overall cost of a DR-TB regimen.

Para-aminosalicylate sodium (PAS-sodium) is the sodium salt of para-aminosalicylic acid (PAS), 1.38g of PAS-sodium equivalent to approximately 1g of PAS.

Number of quality sources – the concentration of PAS varies Paediatrics There is currently only one between product and manufacturer The safety and effectiveness of PAS quality-assured source of PAS – dosing can be can be particularly and PAS-sodium in children has not (Jacobus), and two quality-assured confusing if multiple formulations been established. sources of PAS-sodium (Macleods exist in one treatment programme. While dosages are published in several and Olainfarm), with no other The conversion is as follows: one guidelines, there is an urgent need for sources in the pipeline. 4g sachet of Jacobus’s PAS = one further research (pharmacokinetics, With three quality-assured sources 9.2g sachet of Macleods 60 % w/w pharmacodynamics, safety data) of PAS and PAS-sodium now PAS-sodium granules = one 5.52g into the use of this drug in younger available for procurement, supply sachet of Olainfarm PAS-sodium populations, in particular in children has improved, but is still considered powder for solution. aged under five. vulnerable, particularly as the In addition, the various formulations As there is no paediatric formulation different formulations available have different storage conditions, available, paediatric doses are are not easily interchangeable. which can present issues for obtained by measuring the adult Evolution in price treatment programmes. While granular formulations. Jacobus The price of PAS has stagnated for PAS-sodium products do not require supply a graduated dosage scoop more than a year, although the any special storage conditions, for PAS, and Macleods offer lowest price for a quality-assured PAS is required to be stored in measuring spoons for PAS-sodium, source of PAS-sodium has dropped a cold chain below 15°C. This is both of which allow for a more by 13.91%. Nevertheless the problematic for many settings where accurate paediatric dosage. These prices of both PAS and PAS-sodium DR-TB is prevalent, as maintaining spoons are product-specific and remain a concern, and no additional a functional cold chain requires a cannot be interchanged. quality-assured sources have been certain level of investment both in HIV co-infection identified since 2011. infrastructure and human resources. No antiretroviral interaction studies Suitability for use in However, the latest PAS stability data have been performed, but based developing country settings states that PAS can be kept frozen on the pharmacokinetic profile of With none of the quality-assured and stored in conditions at 40°C PAS, drug interactions are unlikely. sources of either PAS or PAS-sodium and 75% humidity for one month Studies should be performed to presented in the same formulation without risk of degradation. confirm this.

DR-TB Drugs Under the Microscope 39 CLOFAZIMINE (cfz) GROUP 5

GENERAL INFORMATION

• Therapeutic Class: Phenazine Derivative. in the 4th edition of the WHO Model • Approved indication in US: List of Essential Medicines for Children Clofazimine is indicated in the • ATC Code: J04BA01.85 (as an anti-leprosy medicine).87 treatment of lepromatous leprosy, • Included in the WHO Guidelines including dapsone-resistant • Presentations available: 50mg Z IMINE (C fz ) GROUP 5 CLOFA as a Group 5 medicine; agents lepromatous leprosy and lepromatous 13 and 100mg soft-gel capsules. with unclear efficacy. leprosy complicated by erythema 101 • Included in the 18th edition of the • First approved by US Food nodosum leprosum. WHO Model List of Essential Medicines and Drug Administration (as an anti-leprosy medicine)86 and (FDA): 15 December 1986.101

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

Novartis GDF pooled procurement

Quality status SRA approved GDF Quality Assurance Policy

50mg soft-gel Manufacturer did not agree capsule to publish prices

100mg soft-gel Manufacturer did not agree 1.208 (Novartis capsule to publish prices via Pharmaworld)

40 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 CLOFA Z IMINE (C fz ) GROUP 5

Spotlight on access issues

Clofazimine is a Group 5 medicine which is mainly used in patients with pre-XDR-TB and XDR-TB, currently a very small market. With no official indication for DR-TB, and owing to its effectiveness having not clearly been established, it is not routinely used for DR-TB treatment. The 2011 WHO programmatic guidelines recommend the use of clofazimine for patients with MDR or XDR-TB, when there are no other options available.

However, clofazimine is a key component of a shortened nine-month regimen (see introduction), and systematic reviews published in the last year and a half suggests that clofazimine could be considered as an additional therapeutic option in the treatment of DR-TB.10

Novartis does not make this drug available for DR-TB treatment on the basis of a lack of efficacy and safety data, and owing to concerns over liability for off-label use. Because the company donates clofazimine to WHO as part of a multi-drug co-blistered therapy for leprosy,57 Novartis did not submit a price for this publication.

As TB programmes’ demand for this drug increased, WHO has since 2008 been in discussion with Novartis to address the liability for off-label use and patient safety of clofazimine for TB use, in order to make the drug available for MDR and XDR-TB treatment.

Five years on, the difficulties in accessing clofazimine for DR-TB treatment remain acute,58 with no concrete plan having yet been disclosed by the company to increase production to meet TB needs, nor to transfer technology for the finished product formulation to another manufacturer. Novartis needs to ensure a secure affordable supply of clofazimine for the use in MDR-TB treatment or provide the necessary details for a tech transfer to allow another manufacturer to take over the supply of quality-assured clofazimine.

Number of quality sources As demand for clofazimine is expected Paediatrics Clofazimine produced by Sandoz to grow in light of the increased use of The safety and effectiveness of India for Novartis is currently the sole shortened regimens, there is a need for clofazimine in children has not quality-assured source of the drug. alternative quality-assured sources of the been established. drug other than the existing Novartis Although there are additional While dosages are published in several manufacturers in India and Europe, product, which is not easily available. guidelines, there is an urgent need for efforts to engage a second Evolution in price further research (pharmacokinetics, quality-assured source in order to The price is not currently a barrier pharmacodynamics, safety data) ensure access to clofazimine for DR-TB for patients to access clofazimine, into the use of this drug in younger have not been successful so far. but rather Novartis’s restrictive populations, in particular in children aged under five. In order to send a clear message approach to the supply of this to manufacturers that clofazimine medicine, which it reserves A 50mg soft-gel capsule is currently is needed, there was a call to exclusively for leprosy treatment. available, but this formulation makes include the drug in the WHO The GDF catalogue lists clofazimine it impossible to fraction the dose. Prequalification Expression of 100mg, but not the 50mg strength. HIV co-infection Interest (EoI). This has yet to The product can be procured for Clofazimine may have a significant happen. Clofazimine is included non-leprosy use on a named-patient drug-drug interaction with some however in the joint GDF/Global basis only. With this caveat, it can be antiretrovirals. No studies have been Fund Invitation to Manufacturers procured at a price of US$1.21 per performed, but clofazimine is a weak to submit an Expression of Interest 100mg and $0.68 per 50mg capsule inhibitor of the CYP3A4 metabolism for the evaluation of products by through Pharmaworld, a supplier pathway and may increase levels of the Expert Review Panel.59 in Switzerland.60, 61 protease inhibitors and etravirine.

DR-TB Drugs Under the Microscope 41 LINEZOLID (Lzd) GROUP 5

GENERAL INFORMATION

• Therapeutic Class: • Not included in the current edition • Approved indication in US: Linezolid is Oxazolidinone antibiotic. of the WHO Model Lists of Essential indicated for treatment of susceptible Medicines for Adult and Children.86, 87 strains of designated microorganisms for • ATC Code: J01XX08.85 LINE Z OLID (L zd ) GROUP 5 nosocomial pneumonia; and complicated • Presentations available: 600mg tablet, • Included in the WHO Guidelines and uncomplicated skin and skin structure 100mg/5ml powder for suspension. as a Group 5 medicine; agents infections. It is not indicated for the with unclear efficacy.13 • First approved by US Food and Drug treatment of Gram-negative infections Administration (FDA): 18 April 2000.102 and community-acquired pneumonia.103

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

Hetero Pfizer GDF pooled procurement

Under evaluation by SRA Quality status SRA approved xx (ERP approved till 31.5.2014) Manufacturer did not agree 600mg tablet 8.000 6.900 (Hetero)* to publish prices 100mg/ml powder Manufacturer did not agree xx xx for suspension to publish prices

* This price was provided by GDF and does not appear in the online catalogue.

Spotlight on access issues

Although linezolid has no official indication for DR-TB treatment, the 2011 WHO programmatic guidelines recommend the use of linezolid as a Group 5 drug for DR-TB.13 In April 2012, a systematic review outlined the efficacy of linezolid in DR-TB treatment. Data has also been presented at international conferences, and small case series reports have been published.62

Linezolid has a relatively high number of adverse side effects, including myelosuppression, anaemia, and sometimes irreversible peripheral and optical neuropathies. Nonetheless, linezolid is a critical drug to have as an available option for treatment of patients with XDR-TB, and could be a promising candidate for inclusion in an improved MDR-TB regimen.

Number of quality sources have tentative approval from is needed for DR-TB treatment, Currently, only one manufacturer the US FDA. The basic patent and incentivise wider production, – Pfizer – is approved by a stringent on linezolid expires in the US in there was a call to include the regulatory authority. November 2014 – after this date, drug in the WHO Prequalification In May 2013, however, Hetero companies could produce Expression of Interest (EoI). This has received temporary approval from quality-assured linezolid for the yet to happen. Linezolid is included the GDF/Global Fund Expert Review treatment of nosocomial infections however in the joint GDF/Global Panel (valid until the end of May in Europe and the US. If so, the Fund Invitation to Manufacturers to 2014), meaning the Hetero product increased availability of additional submit an Expression of Interest for is now eligible for Global Fund quality-assured sources will the evaluation of products by the procurement. In parallel, Hetero has represent an opportunity to address Expert Review Panel.59 more affordably the needs of DR-TB also submitted a dossier for linezolid Products from additional to the US FDA. programmes for this product. manufacturers exist in India, but it A further four manufacturers (Teva, In order to send a clear message is unknown whether they comply Mylan, Glenmark and Gate Pharma) to manufacturers that linezolid with WHO quality standards.

42 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 LINE Z OLID (L zd ) GROUP 5

Evolution in price Four generic companies have already But the patents do not necessarily Due to patents covering linezolid in the received Abbreviated New Drug block generic production altogether. US and a number of other countries, Application (ANDA) approvals in the Generic companies such as Hetero may the cost of the drug is extremely high. US, allowing them to manufacture be able to circumvent patent barriers Patients for whom conventional DR-TB linezolid once the patent barriers are and develop alternative formulations, treatment is failing but who could removed. After Teva announced that provided they either develop a have a chance to survive through the it intended to launch its product, non-infringing form of linezolid or use of linezolid are denied this option file for revocation of certain patents. the company was sued by Pfizer in due to the prohibitively expensive Linezolid should, however, serve as January 2010, with Pfizer alleging cost of the drug. an example to countries to enact and that Teva’s plan was an infringement enforce stricter patentability criteria in In South Africa, for example, MSF of its patents. In 2012, Pfizer national legislation, in order to prevent pays ZAR676 ($68)i per tablet for successfully blocked the launch of companies like Pfizer from extending the price of Pfizer-produced linezolid Teva’s generic version through a 63 their patent monopolies, and blocking through the private sector. With 67 settlement between the parties. access to life-saving medicines. treatment duration lasting four to six months, this makes the cost of In India, the basic compound patent Paediatrics linezolid alone $8,000 – $13,000 could not be filed in 1993 since Pharmacokinetic studies have been per patient, to which the cost of India’s patent law did not allow for completed in children from birth, other medicines in the complete pharmaceutical product patenting at and dosages are approved by the two-year regimen needs to be added. the time. The patent application on US FDA exclusively for infections the crystalline form II was rejected. with gram-positive bacteria resistant The arrival of the first quality-assured to other antibiotics. generic linezolid, now eligible With no patent barriers preventing for Global Fund procurement generic production, Hetero was able A paediatric formulation exists as a through GDF, has changed matters to manufacture a new source to solution for suspension, produced somewhat. But the price of the drug compete with the Pfizer product. by Pfizer. The reconstituted product remains very high, currently at $8 But the patent status in other can be stored at room temperature. per tablet. Last year, for the purpose countries with high burdens of There is a need for further safety of this publication, Hetero quoted disease is not clear. The patent on and efficacy data on the use of a price of $2.50 per tablet – and the crystalline form II has been linezolid for extended periods in attributed the 300% price increase applied for or granted in many children with DR-TB. to higher manufacturing costs, developing countries including owing to limited demand. HIV co-infection Argentina, Brazil, China, Colombia, No antiretroviral interaction studies Securing a number of quality-assured Mexico, and Ukraine. In South have been performed but interactions generic sources will be critical to Africa, Pfizer managed to obtain are unlikely. The MSF projects in bringing down the price of linezolid. two key patents on linezolid related Khayelitsha, South Africa, and Mumbai, National TB programmes and to composition of matter 68 and India for example, are using linezolid in international agencies must also crystalline form II.69 The first patent DR-TB regimens for co-infected patients forecast their demand for linezolid, on composition of matter will who are also on antiretrovirals. As of and make estimates known to expire in 2014 while the patent on August 2013 in Khayelitsha, 78% of manufacturers in order to guarantee HIV-positive patients taking linezolid supply and secure lower prices. crystalline form II, though lapsed due to non-payment of renewal fees, is for one month or more (treatment Patents set to run until June 2022.70 Patent duration range: 2 –17 months) had The basic patent claiming linezolid barriers in South Africa are further culture-converted and remained culture was filed by Upjohn Company ii in negative – an early sign that treatment complicated by Pfizer’s product being the US in 1993 and will expire on 18 may be successful. There may, however, unregistered for a TB indication, and November 2014.64 Upjohn Company be an increased risk of myelosuppression the company subsequently failing to also filed patents in the US on a and mitochondrial toxicities with bid on government TB drug tenders crystalline form II 65 and on a tablet long-term use in combination with requesting linezolid suppliers.71 formulation in 2002; 66 these patents certain antiretrovirals (zidovudine, could impede generic competition Secondary patents, and in stavudine, didanosine). Further in the US until 2021. particular the patent on the studies are required to confirm this. The following patents are listed crystalline form II may block 56 generic competition even after the by the US FDA for linezolid: i. Prices converted on www.oanda.com expiration of the basic compound on 21 September, 2013 US patent number. Expiry date in 2014. As with Teva in the ii. In 1995, Upjohn merged with Pharmacia 5688792 18 November 2014 US, Pfizer could use a threat of AB, to form Pharmacia & Upjohn. After 6514529 15 March 2021 litigation to deter any efforts by subsequent restructuring today the 6559305 29 January 2021 Hetero to market its product. remainder of Upjohn is owned by Pfizer.

DR-TB Drugs Under the Microscope 43 BEDAQUILINE (Bdq)

GENERAL INFORMATION

• Therapeutic Class: diarylquinoline • Bedaquiline was not allocated a treatment • Approved indication in US: BEDA Q UILINE (B dq ) (first-in-class) with bactericidal group, but its use is similar to Group 5 drugs. Treatment of multidrug-resistant and sterilising activity against pulmonary tuberculosis in adults. • Not included in the current WHO Mycobacterium tuberculosis or Model Lists of Essential Medicines for Bedaquiline is indicated for 72 other mycobacterial species. Adult and Children. treatment of pulmonary multidrug-resistant tuberculosis • ATC Code: J04AK05.73 • Presentations available: 100mg as part of combination therapy uncoated tablet. • WHO issued interim guidelines only when an effective treatment on the use of bedaquiline to • First conditionally approved by regimen cannot otherwise treat MDR-TB in June 2013.74 US FDA: 28 December 2012.75 be provided.76

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

Janssen

Quality status SRA approved*

High-income countries: 159.574 100mg tablet Upper middle-income countries: 15.957 Least-developed/resource-limited countries: 4.787

* Bedaquiline received US FDA accelerated approval on the basis of phase IIb clinical trial data.

Spotlight on access issues

Bedaquiline received accelerated Culture conversion happened Number of quality sources approval by the US FDA in December 33% faster in patients taking Janssen is currently responsible for all 2012 based on phase II clinical trial data. bedaquiline as compared to the global manufacturing of bedaquiline. Janssen Pharmaceuticals are required to standard WHO-recommended When in the future greater numbers submit additional clinical data for the MDR-TB regimen.77, 74 of patients are reached worldwide, drug to receive full FDA approval. Janssen may look into engaging There are concerns around safety with other global partners. The first compound in the however. During drug trials, 10 out diarylquinoline class, bedaquiline’s of 79 patients in the bedaquiline Janssen has already submitted novel mechanism of action group died, compared to two out registration dossiers for bedaquiline inhibits mycobacterial adenosine of 81 patients in the standard in the EU and five additional 5’-triphosphate (ATP) synthase. treatment group. Although many countries (China, India, South Africa, The drug is intended as part of of these deaths are attributed to TB Thailand, Vietnam). Registration in combination therapy for DR-TB, and itself, the difference is significant a further 15 countries is planned it inhibits both actively replicating and a source of concern, and in the near future. In addition, Janssen entered into a licensing and non-replicating wild-type and needs careful future monitoring as agreement with Pharmstandard resistant M. tuberculosis. the use of bedaquiline increases. to register and commercialise Assessing these concerns should In placebo-controlled studies of MDR bedaquiline in the Commonwealth form part of phase III trials. and XDR-TB patients (including those of Independent States as well as in co-infected with HIV), 79% of patients WHO issued interim guidelines Georgia, Turkmenistan and Ukraine. given bedaquiline had negative TB on the use of bedaquiline to treat Pharmstandard has already submitted cultures after 24 weeks. MDR-TB in June 2013.74 a registration dossier in Russia.

44 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 BEDA Q UILINE (B dq )

Outside the US, the drug can be to the fact that its proposed pricing It is also important to note that accessed through compassionate use for the middle and lower pricing tiers bedaquiline is included in patents for programmes (see introduction) – MSF for is aligned with a WHO-sponsored cost tuberculosis combination therapies. These example is currently using bedaquiline effectiveness assessment of bedaquiline.78 patents, such as WO2010026526, can under compassionate use in Armenia Janssen have indicated that countries potentially block the development of and intends to do so in Colombia will be classified in the ‘framework’ both new treatment regimens. This patent and Swaziland. As of August 2013, according to World Bank gross national is pending in several countries and if 184 patients worldwide had received 81 income per capita definitions and granted it would not lapse before 2029. bedaquiline through a compassionate according to disease burden as per the use framework since 2011. Given the patent barriers on bedaquiline WHO’s MDR- and XDR-TB 2010 Global both as a standalone treatment and In South Africa, registration of Report on Surveillance and Response. as a part of combination therapies, a bedaquiline with the national regulatory However, the company was unwilling to proactive strategy will be needed to authority, the Medicines Control divulge placement of individual countries mitigate access challenges. Council (MCC), is still pending, but has in the three respective groups until been granted an accelerated review. A regulatory efforts had concluded Secondary and follow-on patents compassionate use programme treated (and, where applicable, ‘following are a typical problem in the area of four patients in South Africa in 2012, completion of reimbursement pharmaceuticals and such patents often however this programme was later processes’). It remains to be seen what extend monopolies even after the expiry changed to a clinical access programme. pricing will be offered to countries like of compound patents. This problem can In 2013, four sites, including the MSF Russia or China who are simultaneously partially be addressed by applying strict project in Khayelitsha, started providing high-burden TB countries and in the patentability criteria and by proactively bedaquiline to patients with pre-XDR upper middle-income bracket. challenging secondary patents. In India and XDR-TB through this programme, and in other countries where such In compassionate use programmes, with additional sites added gradually strategies can be employed, pre-grant Janssen provides bedaquiline across all provinces in South Africa. This examination of patent applications and free-of-charge. offers a chance for patients with limited patent oppositions by third parties on treatment options to access bedaquiline, Patents secondary patents for bedaquiline will though approval processes can be Bedaquiline is a newly approved drug therefore be an important strategy to onerous in order to prevent uncontrolled and comprehensive information on its avoid patent term extensions beyond widespread use while clinical trials are patent status is not yet publicly available. the expiry of the basic patent in 2023. still ongoing. Only approved sites are Patent searches show however that In addition, some governments, and eligible to prescribe bedaquiline, and several patents have been filed by particularly India, where the product doctors must apply to receive the drug Janssen covering the basic compound, patent blocks the manufacture of through Janssen’s compassionate use methods of use, formulation and generics even for export to countries programme on a named-patient basis preparation processes. where there is no applicable patent, – a process which can take weeks, and will have to decide whether to employ delay the start of treatment. The drug’s The patent which covers the basic unusual administration schedule – daily compound (WO2004011436)79 will compulsory licensing to enable the for the first two weeks of treatment, and not expire before July 2023. The basic production, use and export of more three times a week for the remaining six patent has already been granted in affordable generic versions. months – also requires additional training several countries including Armenia, Paediatrics of staff. As of the end of August 2013, Azerbaijan, China, Kazakhstan, Russia, The safety and effectiveness of seven patients had been started on South Africa, Tajikistan, Ukraine and a bedaquiline in children has not bedaquiline through the clinical access number of African Regional Intellectual been established. programme at the Khayelitsha site. Property Organization (ARIPO) and Organisation Africaine de la Propriété There is an urgent need for Prices Intellectuelle (OAPI) countries.80 further research (pharmacokinetics, Janssen communicated for the pharmacodynamics, safety data) into the purposes of this document that it In India, the patent application on the use of this drug in younger populations, will be implementing a three-tiered basic compound (220/DELNP/2005) in particular in children aged under pricing ‘framework’, in an attempt was filed by Janssen Pharmaceutica five. Paediatric studies are planned as ‘to balance a country’s ability to pay N.V. in January 2005, and granted part of the paediatric development plan with the burden of disease’. Countries (IN236811) in November 2009. The required for the company to complete will be classified into three groups, patent application on the salt form the regulatory approval process. which initial communication with the (1220/MUMNP/200) was also filed company suggests will be labelled by Janssen Pharmaceutica N.V. in June There is no paediatric formulation ‘high-income’, ‘upper middle-income’, 2009. A pre-grant opposition was filed currently available. and ‘least-developed/resource-limited’. against this application in March 2013 HIV co-infection For a six-month treatment course, a by the Network of Maharashtra People Early research shows that efavirenz country in the high-income bracket Living with HIV (NMP+). Other patent interacts with bedaquiline by reducing would pay US$30,000, a country in applications are still pending, including its blood concentration, while the upper middle-income bracket applications related to use of bedaquiline lopinavir/ritonavir slightly increases would pay $3,000, and a country in for treating drug-resistant Mycobacteria, the concentration of the drug.82, 83 the least-developed/resource-limited to the use of bedaquiline for treating bracket would pay $900. Janssen points latent TB, and for processes. More detailed studies are required.

DR-TB Drugs Under the Microscope 45 Annex 1: Summary table of prices provided by pharmaceutical companies

The price corresponds to the price of one unit (tablet, capsule, etc.)

Prices listed with a # were provided directly by GDF and do not appear in the GDF online catalogue.

Please refer to Annex 2 for the conditions of eligibility set by individual companies, and for the incoterms associated with these prices.

GDF pooled Drug Companies procurement

Pharmathen AMIKACIN GDF Cipla Medochemie Pharmatex Hellas

0.805 (Pharmatex) No response 500mg/2ml solution 1.016 – 1.059 2.060 0.750 received from 0.741 for injection (Medochemie)* manufacturer 1.950 (Cipla)

KANAMYCIN Macleods Meiji Panpharma

0.826 1g powder for injection 1.500 xx 0.800 (Panpharma)

Manufacturer 1g/4ml solution for injection 2.580 (Meiji) did not agree to publish prices

CAPREOMYCIN Akorn Aspen Macleods Vianex

6.250 (Akorn) 1g powder for injection 6.250 9.065 5.000 5.850** 5.557 (Vianex)

MOXIFLOXACIN Bayer Cipla Hetero Macleods

0.680 (Macleods) Manufacturer 400mg tablet 1.200 (Hetero) did not agree 1.460 1.100 0.680 1.430 (Cipla) to publish prices

LEVOFLOXACIN Apotex Cipla Hetero Macleods Medochemie Micro Labs of prices pro v ided b y pharmaceutical companies y table 0.051 (Hetero) 250mg tablet 0.048 (Cipla) 0.090*** 0.049 0.075 0.050 0.044 0.087 0.087 (Micro Labs)

0.074 (Hetero) 500mg tablet 0.075 (Cipla) 0.130*** 0.077 0.140 0.070 0.076 0.163 0.163 (Micro Labs)

750mg tablet 0.150*** 0.150

OFLOXACIN Cadila Cipla Macleods Micro Labs

0.048 (Cipla) A nne x 1: S ummar 200mg tablet 0.049 0.060 0.063 0.060 (Macleods) No response received from 0.089 (Cipla) manufacturer 400mg tablet 0.090 xx 0.117 0.119 (Micro Labs)

ETHIONAMIDE Cipla Lupin Macleods Micro Labs

125mg tablet 0.112

0.068 (Lupin) Manufacturer 250mg tablet 0.075 (Cipla) 0.077 did not agree 0.128 0.078 0.128 (Macleods) to publish prices

PROTHIONAMIDE Cadila Fatol Micro Labs Olainfarm

0.109 (Micro Labs) No response 250mg tablet received from 0.167 0.109 0.120 0.155 (Fatol) manufacturer

46 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 A nne x 1: S ummar y table of prices pro v ided b y pharmaceutical companies

GDF pooled Drug Companies procurement

CYCLOSERINE GDF Dong A Lupin Macleods Micro Labs

# 0.408 (Lupin) Manufacturer 250mg capsule (blister) 0.430 (Macleods) 0.520 did not agree 0.430 0.389 0.480-0.520* (Dong A) to publish prices

Chao Center/ Aspen Biocom Cipla Purdue

No response No response Manufacturer Not listed in 250mg capsule (bottle) 0.781 received from received from did not agree the catalogue manufacturer manufacturer to publish prices

TERIZIDONE Fatol

250mg capsule 1.666 (Fatol) 1.513

PAS Jacobus

1.333 – 1.533 #* 4g sachet 1.567 (Jacobus)

PAS-SODIUM Macleods Olainfarm

1.300 60% w/w granules – 9.2g sachet 1.300 (Macleods)

14.250 60% w/w granules – 100g jar 14.250 (Macleods) (1.311 per 9.2gr)

1.370 Powder for oral solution – 5.25g sachet 1.520 (Olainfarm)

CLOFAZIMINE Novartis

Manufacturer 50mg soft-gel capsule did not agree to publish prices

Manufacturer 1.208 (Novartis 100mg soft-gel capsule did not agree via Pharmaworld) to publish prices

LINEZOLID Hetero Pfizer

Manufacturer 600mg tablet 6.900 (Hetero) # 8.000 did not agree to publish prices

Bedaquiline Janssen

High-income countries: 159.574 Not listed in Upper middle-income countries: 15.957 100mg tablet the catalogue Least-developed/resource-limited countries: 4.787

* These are the highest and lowest of a range of prices offered, depending on the quantities ordered. ** MSF negotiated price; please contact manufacturer for additional pricing information *** Incoterm CIF

DR-TB Drugs Under the Microscope 47 Annex 2: Conditions of offer, as quoted by companies

Definitions of eligibility vary from company to company. The conditions detailed in the table below were those quoted by companies.

Company Eligibility Eligibility Additional comments Delivery (countries) (bodies) of goods

AKORN No restrictions No restrictions Akorn is the sole US manufacturer Ex works for Capreomycin 1g powder for injection and is FDA approved in the United States. Akorn has the capacity to produce approximately 2 million units annually

APOTEX No restrictions No restrictions CIF by air to airport of destination

ASPEN Excludes China, EU Excludes China, EU Ex works countries, India, Japan, countries, India, Japan, Russia and USA Russia and USA

BAYER Not applicable; Bayer’s Not applicable; Bayer’s Not applicable; Bayer’s moxifloxacin Not applicable; Bayer’s moxifloxacin is not yet moxifloxacin is not yet is not yet registered for treatment moxifloxacin is not yet registered for treatment registered for treatment of TB registered for treatment of TB of TB of TB

Biocom No restrictions No restrictions Ex works

Generic-accessible Public sector Ex works A nne x 2: C onditions of offer , as q uoted b y companies CIPLA countries

Dong A No restrictions No restrictions Ex works

Fatol No restrictions No restrictions Ex works

Hetero No restrictions No restrictions Ex works

Jacobus No restrictions if No restrictions if Shipping and handling purchased via MSF/GDF/ purchased via MSF/GDF/ are billed at actual cost GLC/Government GLC/Government to the customer

Lupin No restrictions No restrictions Ex works

Macleods Excludes Australia, No restrictions Pricing is based on the volumes given Ex works Brazil, Canada, EU, by GDF in their tender; for smaller Japan, New Zealand, volumes, prices may be higher Singapore, South Africa, South Korea, USA

Medochemie No restrictions No restrictions

Micro labs No restrictions No restrictions Ex works

Olainfarm No restrictions No restrictions Ex works

Panpharma No restrictions No restrictions Forecast required in order to plan Ex works the API order

Pharmatex No restrictions Prices valid for MSF, 30 days from the date of invoice Ex works Red Cross

Sandoz India No restrictions No restrictions

Vianex No restrictions Prices valid for MSF

For more information on incoterms, please refer to the glossary.

48 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 Annex 3: Company contacts A nne x 3: compan y contacts

This section reports the contact details of companies that have been contributing with price information to this publication.

Akorn Hetero PanPharma www.akorn.com www.heterodrugs.com www.panpharma.fr Sean Brynjelsen Mr. Prashant Sisodia Gildas Blonsard Vice President, New Business Development General Manager – International Marketing Esport Sales Manager 1925 W.Field Court, Suite 300, 607-608 Matharu Aracade, Subhash Road, ZI du Clairay 35300 Fougères, France Lake Forest, Illinois 60045 USA Vile Parle East, Mumbai, India Tel: +3 329 99 79 212 Tel: +1 847 279 6149 Tel: +91 22 66910809 E-mail: [email protected] E-mail: [email protected] E-mail: [email protected] Pharmatex Apotex Jacobus www.pharmatex.it www.apotex.com Laura R Jacobus Antonio Sergio Tripodi Owner CEO Patti Black 37 Cleveland Lane, PO Box 5290, Pharmatex Italia Srl, Via Appiani, Manager, International Tenders Princeton, New Jersey 08540 USA 22, Milan, Italy 150 Signet Drive, Toronto, Tel: +1 609 921 7447 Tel: +39 02 29000410 Ontario Canada M9l 1T9 E-mail: [email protected] Tel: +1 416 401 7345 E-mail: [email protected] E-mail: [email protected] Lupin Sandoz India www.lupinpharma.com Aspen www.sandoz.com Mr. Shrikant Kulkarni www.aspenpharma.com Tejasvi Sharma Lupin Limited, laxmi Towers, B Wing , 4th General Manager – Global TB & API Business Dumisani Mkwanazi Floor, Bandra Kurla Complex, Bandra (East), Sandoz Private Limited, i Think Techno Commercial Head – SSA Mumbai, India 400086 Campus, Phase 1, Alpha Building, Building 7, Healthcare Park, Woodlands Tel: +91 22 66402222 Ground Floor, Kanjur Marg (East), Drive, Woodmead, Sandton, South Africa E-mail: [email protected] Tel: +2 711 239 6797 Mumbai 400042, India Tel: +91 22 61529700 E-mail: [email protected] Macleods E-mail: [email protected] www.macleodspharma.com Bayer www.bayer.com Vijay Agarwal Vianex Business Development Director www.vianex.gr Dr. Ulrich Madeja 304 Atlanta Arcade, Marol Church Road, Mrs. Lemonia Xenitos Executive Director, Access to Medicines Andheri East, Mumbai, India Export Manager Bayer HealthCare Pharmaceuticals, CCR-SHCP, Tel: +91 22 66762800 Tatoiou Street, 18th km National Road Müllerstr 178, 13353 Berlin, Germany E-mail: [email protected] Athens-Lamia, 146 71 Nea Erythrea, Tel: +49 304 681 1803 Athens – Greece E-mail: [email protected] Medochemie Tel: +30 210 8009634 www.medochemie.com E-mail: [email protected] Cipla Phaedon Ellinas www.cipla.com Area Manager Mr. Sharadd Jain, Mr. Rahul Lande 1–10 Constantinoupoleos str., Global Institutional Business P.O.Box 51409, 3505 Limassol, Cyprus Cipla Ltd, 289, Belasis Road, Tel: +357 25 867618 Mumbai Central, Mumbai-08, India E-mail: [email protected] Tel: +91 22 2302 5387, 5686 E-mail: [email protected], Micro Labs [email protected] www.microlabsltd.com N.K.Kothari Dong A Executive Vice President www.en.donga.co.kr Micro Labs Ltd, No.11 Bank Street, Paul Ryu Kilpauk, Chennai 600010, India Regional Manager Tel: +91 44 26450789, 26471205, Dong-A ST Co., Ltd. 64, Cheonho-daero, Direct: +91 44 42857705 Dongdaemun-gu, Seoul Korea E-mail: [email protected], Tel: +82 2 920 8396 [email protected] E-mail: [email protected] Olainfarm Fatol http://olainfarm.lv/en/ www.riemser.com Mrs. Elena Vasilevskaya Elke Rinkes Business Development Division RIEMSER Pharma GmbH, Site Fatol JSC Olainfarm, 5, Rupnicu Street, Arzneimittel, Robert-Koch-Strasse, Olaine LV-2114, Latvia 66578 Schiffweiler, Germany Tel: +371 67013701/67013745 Tel: +49 6821 960517 E-mail: [email protected], E-mail: [email protected] [email protected]

DR-TB Drugs Under the Microscope 49 References

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Haas DW, Cramer Y, et al. Safety, tolerability, [cited 2013, September 14]. Available from: Overview&DrugName=LINEZOLID and pharmacokinetic interactions of the anti- http://www.accessdata. fda.gov/scripts/cder/ tuberculous agent TMC207 (bedaquiline) drugsatfda/index.cfm?fuseaction=Search. 103. US FDA. Zyvox drug details. [Online] with efavirenz in healthy volunteers: AIDS DrugDetails United States Food and Drug Administration. Clinical Trials Group study A5267. J Acquir 2010, June (revised) [cited 2012, September 92. US FDA. Cycloserine drug product details. 18] Available from: http://www.accessdata. Immune Defic Syndr [Online]. 2012 April [Online] United States Food and Drug. fda.gov/scripts/cder/drugsatfda/index.cfm 15 [cited 2013 Oct 07]; 59(5): 455–462. Available from: http://www.ncbi.nlm.nih. Administration. [cited 2013, September 7] 104. 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DR-TB Drugs Under the Microscope 53 y Glossary G lossar

Abbreviated New Drug Application (Use of experimental drugs outside of Extemporaneous preparation: (ANDA): An Abbreviated New Drug clinical trials “compassionate use”) of the Medicines prescribed by a physician Application (ANDA) contains data that, WHO Guidelines for the programmatic and compounded by a pharmacist to when submitted to the US FDA provides management of drug-resistant fit the unique need of a patient in the for the review and ultimate approval of tuberculosis: Emergency update 2008. absence of a commercially available, a generic drug product. Generic drug authorised, age-appropriate dosage or Culture: Bacterial culture is a laboratory applications are called “abbreviated” form of a medicine. They are a mixture method to multiply bacteria in order because they are generally not required of a commercially available active to assess their presence or not in a to include preclinical (animal) and clinical pharmaceutical ingredient or finished patient’s sample. This is done by letting (human) data to establish safety and product with an appropriate vehicle(s). the bacteria grow in predetermined efficacy. Instead, a generic applicant must culture media under controlled scientifically demonstrate that its product Extensively drug-resistant TB: see XDR-TB laboratory conditions, outside the natural is bioequivalent (i.e. performs in the same environment where they usually grow Extra-pulmonary TB: Form of TB where manner as the innovator drug). Once (e.g. for TB, the human body). M. tuberculosis infects parts of the approved, an applicant may manufacture body other than the lungs. This is most and market the generic drug product Culture-converted: a person whose commonly the lymph nodes, bones, to provide a safe, effective, low cost last two clinical samples are no longer central nervous system, cardiovascular alternative in the US. growing M. tuberculosis, implying that and gastrointestinal systems. bacteria are no longer present. Active pharmaceutical ingredient (API): FCA: “Free Carrier”. A commercial term Any substance or mixture of substances Drug resistance: When a drug used to (incoterm 2010) meaning that the seller intended to be used in the manufacture treat tuberculosis is in fact ineffective against hands over the goods, cleared for export, of a pharmaceutical dosage form and a strain of M. tuberculosis, the bacteria is into the disposal of the first carrier (named that, when so used, becomes an active said to be resistant to the drug (as opposed by the buyer) at the named place. The ingredient of that pharmaceutical to drug-susceptible or drug-sensitive). seller pays for carriage to the named dosage form. Drug-susceptible/drug-sensitive TB: point of delivery, and risk passes when the CIF: “Cost, Insurance and Freight” Bacteria are said to be sensitive to a drug goods are handed over to the first carrier. (named port of destination). when the drugs are effective in killing or First-line drugs: The drugs used as A commercial term (incoterm 2010), stopping the multiplication of bacteria the first resort to treat a disease. In the meaning that the seller must pay the in the body and can therefore clear the case of TB, the following four drugs are costs and freight to bring the goods to infection. The strains of TB which are usually chosen: isoniazid (H), rifampicin (R), the port of destination. Risk is transferred sensitive to all first-line drugs are called ethambutol (E), pyrazinamide (Z). to the buyer once the goods are loaded drug-susceptible. These drugs are highly effective in on the vessel. Insurance for the goods Ex works: A commercial term (incoterm drug-susceptible TB and patients usually is included and paid by the seller, only 2010) meaning that the seller delivers tolerate them well. Streptomycin (S) maritime transports are covered. when the goods are placed at the injectable is used in first line treatment Clinical trials: Sets of tests in medical disposal of the buyer at the seller’s of TB meningitis. research and drug development that premises or another named place FOB: ‘Free on board’. A commercial term generate safety and efficacy data (including (i.e. works, factory, warehouse etc.), (incoterm 2010) meaning that the seller information about adverse drug reactions not cleared for export and not loaded delivers when the goods pass the ship’s and adverse effects of other treatments) on any collecting vehicle. rail at the named port of shipment. This for health interventions (e.g., drugs, Expert Review Panel (ERP): An means that the buyer has to bear all costs diagnostics, devices, therapy protocols). independent technical body composed of and risks of loss or damage to the goods Compassionate Use: The terms external technical experts, hosted by the from that point. The FOB term requires “compassionate use,” “expanded WHO Department of Essential Medicines the seller to clear the goods for export. access” or “special access” programmes and Pharmaceutical Policies. Their purpose Global Drug Facility (GDF): A mechanism have essentially the same meaning. is to review the potential risk/benefit hosted by WHO to expand access to, They refer to programmes that are associated with the use of antiretroviral, and availability of, quality-assured anti-TB anti-TB and antimalarial products which intended to provide potentially lifesaving drugs and diagnostics through pooled experimental treatments to patients are not yet WHO-prequalified or authorised procurement. Products procured comply suffering from a disease for which no by a stringent regulatory authority. ERP with the GDF’s Quality Assurance policy. satisfactory authorised therapy exists will make recommendation to the Global This deems eligible for GDF procurement and/or who cannot enter a clinical Fund and the Global Drug Facility whether all products that are included on the WHO trial. It refers to programmes that make procurement of such products can be List of Prequalified Medicinal Products, that medicinal products available either on authorised. The recommendation shall are approved by a stringent regulatory a named-patient basis or to cohorts of be valid for a period of no more than 12 authority, or that are temporarily approved patients. Compassionate use needs to be months or until the product is either by the Expert Review Panel. framed within a national legislation which WHO-prequalified or SRA-authorised. establish under which condition the drug (http://www.theglobalfund.org/en/ Global Fund: The Global Fund to Fight is made available. Refer to Annex 5 procurement/quality/pharmaceutical/). AIDS, Tuberculosis and Malaria is an

54 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 G lossar international financing institution that Pharmacokinetic (PK): Branch of European Free Trade Association invests the world’s money to save lives. pharmacology, which studies the (EFTA) as represented by Swiss It invests in 150 countries to support mechanisms of absorption and Medic, Health Canada and World large-scale prevention, treatment distribution of an administered drug, Health Organization (WHO); or (c) and care programs against the three the rate at which a drug action begins a regulatory authority associated with y diseases and it channels 82 percent of and the duration of the effect, the an ICH member through a legally the international financing for TB. chemical changes of the substance in binding mutual recognition agreement the body (e.g. by metabolic enzymes) including Australia, Norway, Iceland Green Light Committee (GLC): and the effects and routes of excretion and Liechtenstein. Please consult The GLC Initiative was created in 2001 of the metabolites of the drug. http://www.ich.org to help countries gain access to quality- assured second-line anti-TB drugs so Pharmacodynamic (PD): Branch TB Alliance: The TB Alliance is a they can provide treatment for people of pharmacology, which studies not-for-profit, product development with multidrug-resistant tuberculosis the biochemical and physiological partnership accelerating the discovery in line with the WHO guidelines, the effects of drugs on the body or on and development of new TB drugs latest scientific evidence and country microorganisms or parasites within that will shorten treatment, be experiences. The Initiative consisted of a or on the body and the mechanisms effective against susceptible and secretariat, the Green Light Committee of drug action and the relationship resistant strains, be compatible with (an expert review and WHO advisory between drug concentration and effect. antiretroviral therapies for those HIV-TB body) and the Global Drug Facility (the patients currently on such therapies, Point-of-Care testing (POC): drug procurement arm of the Initiative). and improve treatment of latent Testing at the point-of-care means Since 2011, there is no need anymore infection. The TB Alliance is committed that diagnosis is carried out as close to get GLC approval to procure quality- to ensuring that approved new drug as possible to the site of patient care. assured second line TB drugs through regimens are affordable, widely The driving notion behind point- GDF. GLC has been also restructured adopted and available to those who of-care testing is having a test as in June 2011 into a Global GLC (gGLC) need them. and regional GLC (rGLC) to focus on convenient to the patient as possible monitoring and technical assistance to and giving immediate results that can Tentative FDA approval: Is awarded National TB programmes in countries lead to prompt initiation of treatment. by the US FDA to a drug product that has met all required quality, and WHO. Pulmonary TB: Form of TB where safety and efficacy standards, but is M. tuberculosis bacteria are infecting Microscopy: Microscopy is currently not eligible for marketing in the US the lungs. the most commonly used technique because of existing patent protection. to diagnose TB. Two to three sputum QT Interval: In cardiology, the QT Tentative approval does make the samples are taken from the patient interval is a measure of the time product eligible for purchase outside and the sample will be stained and between the start of the Q wave and the US under the US President’s later read under the microscope. If TB the end of the T wave in the heart’s Emergency Plan for AIDS Relief bacilli are present, they occur in the electrical cycle. This represents the (PEPFAR) programme. form of small red rods, while the rest total duration of electrical activity of the Totally drug-resistant (see XDR-TB): of the sample is blue. ventricles. A prolonged QT interval is a The term “totally drug-resistant TB” was biomarker of life-threatening ventricular Multidrug-resistant TB (MDR-TB): used in 2011 for a group of patients in tachyarrhythmias – including torsdes Patients infected with strains of TB India presenting resistance to all drugs de pointes. that are resistant to (at least) the two that they were tested for. It is now most powerful first-line antibiotics used Second-line drugs: Second-line drugs widely by the media. The term “totally to treat TB, namely rifampicin and are used when the first-line drugs are drug-resistant” tuberculosis is not isoniazid, are said to have multidrug- no longer effective to cure a patient. recognised by the WHO, after they held resistant TB, or MDR-TB. In the case of tuberculosis, they are a meeting in 2012 to discuss the term. Mycobacteria: Types of bacteria, of less effective and have many more These cases are defined as extensively the genus Mycobacterium, that cause side-effects than first-line drugs. drug-resistant tuberculosis (XDR-TB), diseases such as TB and leprosy. This report looks at the sources and according to WHO definitions. prices of second-line anti-tuberculosis M. Tuberculosis: Mycobacterium WHO Prequalification medicines classified in World Health Tuberculosis: A pathogenic bacterial (PQ) Programme: Organization Groups 2 (injectable species of the genus Mycobacterium and The Prequalification Programme, set agents), 3 (fluoroquinolones), 4 (oral the causative agent of most cases of TB. up in 2001, is a service provided by bacteriostatic second-line agents) First discovered in 1882 by Robert Koch. the World Health Organization (WHO) and 5 (agents with unclear efficacy), to facilitate access to medicines that New Drug Application (NDA): When as well as new drugs like bedaquiline. meet unified standards of quality, the sponsor of a new drug believes Staircase pricing: Global Drug safety and efficacy for HIV/AIDS, that enough evidence on the drug’s Facility prices occasionally depend malaria and tuberculosis. Please consult safety and efficacy has been obtained to volume, with lower prices per unit http://apps.who.int/prequal/ meet FDA’s requirements for marketing if larger quantities are ordered. The approval, the sponsor submits to US XDR-TB (Extensively drug-resistant TB): GDF refers to this pricing structure FDA a new drug application (NDA). Patients, who have MDR-TB and also as ‘staircase pricing’. The application must contain data from show resistance to second-line drugs, specific technical viewpoints for review, Stringent regulatory authority including at least one from the class including chemistry, pharmacology, (SRA): Is a regulatory authority which known as fluoroquinolones and one medical, biopharmaceutics, and statistics. ‘is (a) a member of the International of the injectable drugs, are described If the NDA is approved, the product Conference of Harmonization (ICH); as suffering from extensively may be marketed in the United States. or (b) an ICH Observer, being the drug-resistant TB or XDR-TB.

DR-TB Drugs Under the Microscope 55 Abbreviations

ANDA – Abbreviated New Drug ERP – Expert Review Panel PDR-TB – Polydrug-resistant Application tuberculosis EU – European Union A bbre v iations API – Active pharmaceutical PQ – Prequalification GLI – Global Laboratory Initiative ingredient R&D – research and development GDF – Global Drug Facility API PQ – Active Pharmaceutical SRA – Stringent regulatory authority Ingredient-Prequalification GFATM – Global Fund to Fight ARIPO – African Regional AIDS, Tuberculosis, and Malaria TAC – Treatment Action Campaign Intellectual Property Organization GLC – Green Light Committee TB – Tuberculosis

ATC - Anatomical Therapeutic HIV – Human immunodeficiency TDR-TB – Totally drug-resistant Chemical virus tuberculosis BfArM – Bundesinstitut für LIC – Low-income countries TRIPS – Trade-Related Aspects Arzneimittel und Medizinprodukte of Intellectual Property Rights (German Federal Institute for Drugs MDR-TB – Multidrug-resistant (Agreement) and Medical Devices) tuberculosis USAID – US Agency for BRICS – Brazil, Russia, India, China MCC - Medicines Control Council International Development and South Africa (South Africa) US FDA – US Food and Drug CEWG – Consultative Expert MIC – Middle-income countries Administration Working Group MRC – Medical Research Council (UK) WHO – World Health Organization CIF – Cost, insurance and freight MSF – Médecins Sans Frontières WHO PQ – World Health DR-TB – Drug-resistant tuberculosis NDA – New Drug Application Organization Prequalification DS-TB – Drug-sensitive tuberculosis Programme NGO – Non-governmental EBA – Early Bactericidal Activity organisation w/w – weight for weight

EMA – European Medicines Agency OAPI – Organisation Africaine de XDR-TB – Extensively drug-resistant la Propriété Intellectuelle tuberculosis EoI – WHO Prequalification Expression of Interest PAS – Para-aminosalicylic acid ZAR – South African rand

56 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | October 2013 Acknowledgements:

Médecins Sans Frontières and The Union wish to thank manufacturers and the Global Drug Facility (particularly Joel Keravec and Kaspars Lunte) for sharing price information for this publication.

Front cover photo: © Siddharth Singh

Back cover photo: © Jose Cendon

Design/artwork/print: ACW Ltd +44 (0)20 8392 4330 www.acw.uk.com

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 (MSF) 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.

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