2nd

DR-TB DRUGS UNDER THE MICROSCOPE Sources and prices for drug-resistant tuberculosis medicines 2nd Edition – November 2012

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 TB care for 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’s first MDR-TB programmes opened in 1999, and the organisation is now one of the biggest NGO providers of MDR-TB care.

In 2011, the organisation treated 26,600 patients with TB in 39 countries, 1,300 of whom had MDR-TB. Overall the success rate of treating MDR-TB within MSF is 53% and only 13% in XDR-TB patients.

The International Union Against Tuberculosis And Lung Disease The mission of the International Union Against Tuberculosis and Lung Disease (‘The Union’) is to bring innovation, expertise, solutions and support to address health challenges in low- and middle-income populations. With nearly 10,000 members and subscribers from 150 countries, The Union has its headquarters in Paris and offices serving the Africa, Asia Pacific, Europe, Latin America, Middle East, North America and South-East Asia regions. Its scientific departments focus on tuberculosis and HIV, lung health and non-communicable diseases, tobacco control and research.

The Union has been the leading international TB control and prevention agency since 1920. Each year, The Union works in close to 90 countries, providing technical assistance at the request of national tuberculosis control programmes; conducting operational research and clinical trials; organising conferences and courses; and publishing not only two peer-reviewed journals, but also a range of technical guides.

In addition, The Union regularly monitors MDR-TB project sites and provides technical assistance on all aspects of MDR-TB management in Europe, Africa, Asia, Latin America and the Middle East. The Union organises also comprehensive clinical MDR-TB courses in Africa, Asia and Latin America, as well as more than 15 national courses including most of the high-burden MDR-TB countries.

Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 Ta b l

Table of contents e

o f C f

Background ontents 2 DR-TB drugs under the microscope 3 How market insecurity impacts price and quality 6 Addressing these challenges 9 Research and development: needs and opportunities 11 Conclusions and recommendations 12 Case study: “Medicines have become my food” 13 Methodology

Drug Profiles Group two: Injectables 14 Amikacin 16 Kanamycin 18 Capreomycin

Group Three: Fluoroquinolones 20 Moxifloxacin 22 Levofloxacin 24 Ofloxacin

Group Four: Oral bacteriostatic second-line agents 25 Ethionamide 26 Prothionamide 27 Cycloserine 29 Terizidone 30 PAS and PAS-Sodium

Group five: Agents with unclear efficacy 32 Clofazimine 34 Linezolid

Annexes 36 Annex 1: Summary table of prices provided by pharmaceutical companies 38 Annex 2: Conditions of offer, as quoted by companies 39 Annex 3: Company contacts 40 References 43 Glossary and abbreviations

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

Tuberculosis (TB) is a curable disease that continues to kill nearly 1.4 million people across the globe each year, and is the main cause of death in people living with HIV/AIDS. In 2011, there were up to an estimated 400,000 cases of multidrug-resistant TB (MDR-TB) among notified TB patients; MDR-TB is a form of the disease that does not respond to at least two of the primary drugs used to treat the disease. Close to 10% of all MDR cases are in fact extensively drug-resistant (XDR-TB), meaning they are also resistant to two of the key drugs used as a part of second-line regimens.1

Yet the response to the epidemic measures are taken. These challenges, remains inadequate. With 94% of although considerable, lie beyond the patients at risk of MDR-TB (those scope of this report.

DR-TB DRUGS UNDER THE MICROSCOPE previously treated) not having access This report focuses on just some of the to tests capable of diagnosing MDR-TB, many factors that hamper the scaling and only 19% of people with MDR-TB up of DR-TB treatment – the limited having been enrolled on treatment availability and high cost of quality- in 2011, the full extent of the burden assured medicines for resistant strains is unknown and undertreated. The of the disease, owing to an insecure Global Drug Facility – the international market and insufficient demand; and pooled procurement mechanism the research questions that remain for TB medicines and diagnostics – unsolved with existing medicines. procured DR-TB treatments for less than 20,000 people in 2011.2 Finally, as the R&D pipeline prepares to deliver the first new compounds Given this alarming outlook, it is for TB in close to half a century, the imperative that DR-TB be considered report provides an initial assessment a public health emergency, one of the approaches to be taken in order that mobilises an appropriate to radically transform our ability to response from all stakeholders,

respond to this plague. © Andrea Stultiens including governments, the World Health Organization (WHO), the private sector, donors, civil society organisations, and affected DR, MDR, XDR: communities. the many faces of resistant TB

Treating DR-TB is complex: medicines Drug-resistant tuberculosis (DR-TB) second-line drugs (capreomycin, need to be taken for two years, and is used to describe strains of TB kanamycin and amikacin). regimens need to be tailored to the that show resistance to one or The phrase ‘totally drug-resistant individual patient, based on which more first-line drugs. TB’ has been used since late 2010 drugs are effective against that Multidrug-resistant tuberculosis to describe a group of patients person’s infection. Side effects are (MDR-TB) is defined by TB that is in India that have developed severe and incapacitating, so much resistant to at least isoniazid and resistance to all drugs for which so that programmes must devote rifampicin, the two most powerful they were tested. However, this is considerable resources to adherence anti-TB drugs. not accepted WHO terminology, counselling, managing side effects and and these cases are officially providing psychosocial care. From the Extensively drug-resistant defined as XDR-TB. programmatic perspective, significant tuberculosis (XDR-TB) is caused investments are required. Resources by strains of MDR-TB that are also All forms of resistance to more are needed, in human resources and resistant to second-line drugs, than one of the first-line drugs, training, investment in laboratory including at least one from the and which are neither MDR-TB nor infrastructure to diagnose infection class of fluoroquinolones, and XDR-TB, are defined as polydrug- and monitor treatment, as well as at least one of three injectable resistant TB (PDR-TB). ensuring adequate infection control

2 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 HO W

HOW MARKET INSECURITY M A R

IMPACTS PRICE AND QUALITY K ET INSECURIT ET

DR-TB medicines are expensive

Medicines are far from being the only TABLE 1: cost associated with treating DR-TB. The cost in US$ of a standard MDR-TB regimen lasting 24 months, including Programmes must devote considerable

cycloserine and eight months of injectable capreomycin, using quality-assured Y resources to adherence counselling, medicines, based on prices provided for this report. IMP managing side effects and providing psychosocial care, to infection control LOWEST HIGHEST A CTS PRICE PRICE CTS and laboratory support. QUALITY-ASSURED PRICE QUALITY-ASSURED PRICE Cost for Cost for Medicine Unit price Unit price The price of medicines adds to regimen regimen these costs. Whereas first-line TB capreomycin 1gr vial 5.34 1,281.6 8 1,920 treatment is affordable, costing only

US$22 per patient for a six-month cycloserine 250mg caps 0.58 1,252.8 0.8 1,728 A ND ND treatment course,1 DR-TB treatment is

considerably more expensive. ethionamide 250mg tab 0.07 151.2 0.1 216 Q U

The exact price varies considerably, moxifloxacin 400mg tab 1.68 1,209.6 1.85 1,332 AL as treatment must be individualised IT pyrazinamide 400mg tab* 0.02 57.6 0.02 57.6 according to a patient’s drug resistance Y profile. But the cost of a standard Total regimen cost 3,952.8 5,253.6 regimen for MDR-TB as recommended by the 2011 WHO treatment guidelines, *Price sourced from the GDF online catalogue at http://www.stoptb.org/gdf/drugsupply/ lasting 24 months and with eight months drugs_available.asp of injectable capreomycin, ranges between $4,000 and $6,000. TABLE 2: Four medicines in particular weigh heavily in the overall cost of a DR-TB The cost in US$ of a standard MDR-TB regimen lasting 24 months, including PAS regimen: capreomycin, moxifloxacin, and eight months of injectable capreomycin, using quality-assured medicines, PAS and cycloserine. Using kanamycin based on prices provided for this report. instead of capreomycin brings the LOWEST HIGHEST price down, but at $2,850, the cost QUALITY-ASSURED PRICE QUALITY-ASSURED PRICE of the medicines is still too high. Cost for Cost for Medicine Unit price Unit price regimen regimen

capreomycin 1gr vial 5.34 1,281.6 8 1,920

PAS / PAS Sodium 1.45 2,088 1.57 2,260.8

ethionamide 250mg tab 0.07 151.2 0.1 216

moxifloxacin 400mg tab 1.68 1,209.6 1.85 1,332

pyrazinamide 400mg tab* 0.02 57.6 0.02 57.6

Total regimen cost 4,788 5,786.4

*Price sourced from the GDF online catalogue at http://www.stoptb.org/gdf/drugsupply/ drugs_available.asp

Continued overleaf

DR-TB Drugs Under the Microscope 3 How market insecurity impacts price and quality continued

Y The market is small and fragmented IT For most DR-TB drugs, with the AL

U notable exceptions of linezolid and Q moxifloxacin, the medicines were developed so long ago that patents, ND

A which typically act to prevent competition and thereby keep prices higher for longer, have long run out, and do not act as a barrier.

These high prices are rather a reflection CTS PRICE

A of the fact that current market demand is low, due to limited capacity to

IMP diagnose and treat DR-TB, which Y does not provide a sufficient incentive to manufacturers. The global DR-TB market was estimated to be worth $300 million in 2010, with only $125 million procured through the public sector.3 ET INSECURIT

K Considering the current capacity to

R diagnose and treat DR-TB is limited, A the small international market size M is not appealing for manufacturers. W

Furthermore, there is still a high degree © Bithin Das

HO of variation between regimens used by country programs, which leads to a very fragmented market. For example, there is no general consensus Uncovering the epidemic of DR-TB between the use of ethionamide or While timely and accurate culture, phenotypic drug sensitivity prothionamide, between cycloserine or diagnosis of DR-TB remains a testing and line probe assay – are terizidone, nor between capreomycin significant challenge for most or other injectable drugs. Even key to uncovering the epidemic packaging requirements for DR-TB high-burden countries, recent of DR-TB. Moving forward, drugs differ between India and the diagnostic advances provide a developing more robust and less rest of the world. key opportunity to significantly sophisticated next-generation improve diagnosis of DR-TB and NAA-based tests which are As a result of these factors, manufacturers increase demand for DR-TB can not achieve economies of scale better suited to resource-limited medications. Introduction of nucleic necessary to bring prices down. environments, will also be crucial. acid amplification (NAA)-based Although greater market competition tests, such as Xpert MTB/RIF, are New tools must be developed that among multiple producers could help, expected to result in a three-fold will be less expensive, and will the impact would be limited; indeed 4 the greater challenge today is securing increase in the diagnosis of DR-TB allow diagnosis of paediatric or today’s fragmented and fragile market. and to significantly decrease time extra-pulmonary tuberculosis using Securing greater demand is therefore to DR-TB treatment initiation a range of sample types. Finally, critical to bringing prices down. (detection of TB and drug resistance a point of care TB diagnostic test takes about two hours with Xpert suitable for implementation in MTB/RIF, as opposed to more than most peripheral settings is also four weeks for conventional culture critical to ensuring adequate and drug sensitivity testing). access to TB diagnosis in settings Improving access to DR-TB where the majority of patients diagnosis through Xpert MTB/ are seen. But such a test is still RIF, optimizing its operating not available and research efforts characteristics, and ensuring access should be focused on achieving to confirmatory tests – including this important tool.

4 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 Supply of quality-assured sources is insecure HO W

The modest market size also has an A few other sources have received ceased production, because of falling M

effect on the security of supply of marketing authorisation by a stringent demand in wealthy countries. Of three A quality-assured sources. regulatory authority. quality-assured sources of kanamycin R K

globally, the first was forced to INSECURIT ET Compared to the first edition of this Nevertheless, the situation remains suspend production because its report, published in March 2011, the fragile and supply is vulnerable for active pharmaceutical ingredient (API) overall situation of DR-TB drugs has the market of quality assured DR-TB supplier relocated in 2009. The second slightly improved with more sources medicines. Thirty per cent of drugs also experienced a supply problem of quality-assured drugs now available profiled in this report – kanamycin, in 2010 and ceased production for a for procurement for TB treatment. terizidone, clofazimine and linezolid period of time, leaving programmes Three manufacturers have been – are still reliant on only one supplier. Y dependent on a third manufacturer IMP approved by the WHO Prequalification Even drugs for which at least two with limited capacity, so much so Programme for ofloxacin, two suppliers are available, are often reliant that the manufacturer dedicated its A

manufacturers for levofloxacin and PRICE CTS on the same manufacturer for the active production solely to GDF procurement, one source of PAS-Sodium. Others are pharmaceutical ingredient. For all of which left other DR-TB treatment in the process of having their products these medicines, supply is extremely programmes with no quality-assured evaluated by WHO. The joint Global vulnerable to disruption. source. While this situation is now Drug Facility / Global Fund Expert resolved, this experience serves as The past example of kanamycin Review panel, an additional mechanism A a cautionary tale. for assessment of drug quality, gave illustrates the risks associated with ND temporary purchase permission for relying on too few sources for a given Sources of API are also limited. A 2010 Q

two sources of prothionamide, one of medicine. Several manufacturers had study for the GDF noted that the supply of U moxifloxacin, one of ethionamide, one kanamycin registered for use in the API was vulnerable for amikacin, kanamycin, AL 5 of levofloxacin and one of cycloserine. US, although all but one subsequently prothionamide and clofazimine. IT Y

Getting medicines into bodies: additional difficulties

There are additional barriers faced The lack of a streamlined process to import them. Additionally, by treatment providers to getting between forecasting needs at many countries do not fast-track drugs into countries and to patients. country level, cost evaluation and registration procedures for planning of orders, the signature medicines that have been quality- One is lead times. Orders for DR-TB of agreements, and disbursements assured through the WHO drugs placed with GDF are often of donor funds all contribute Prequalification Programme. small and need to be pooled by to making lead times for DR-TB manufacturers before they produce Finally, for some DR-TB drugs, drug delivery excessively long. a new batch, leading to four to additional barriers prevent them National TB programmes also six months standard lead times, from reaching the DR-TB patients. need to fully pre-pay their orders from order placement to receipt in Neither linezolid nor clofazimine before they can be processed by country. In order to overcome this have an approved indication for GDF. If agreements with donors challenge, UNITAID has financed DR-TB. Access to clofazimine for and consequent disbursements are a stockpile so that more expedited the treatment of XDR-TB patients delayed, the process is blocked. shipments can be organised by GDF. has been denied on the basis of A revolving fund mechanism where 2 In 2011, this stockpile was used by unclear efficacy, while linezolid is money could be advanced to 60 national tuberculosis programmes extremely expensive. As a result, countries before donors funds and served mainly to complement while there is one quality-assured are made available could alleviate orders for which quantities were producer for both, accessing these this road-block. drugs at an affordable price is missing. Twenty national tuberculosis extremely difficult. For more details programmes placed 25 emergency Delays are also largely caused by refer to the drug profiles for orders in 2011, which were delivered national regulations: as DR-TB these medicines. with a median lead time of 31 days.6 drugs are often not registered in Unfortunately, 25 emergency orders countries where treatment projects with expedited delivery represent are located, MSF experience only a small proportion of shows that cumbersome special GDF orders. authorisation is frequently needed

DR-TB Drugs Under the Microscope 5 ADDRESSING ENGES

ALL THESE CHALLENGES

By diagnosing patients more effectively and more quickly with DR-TB, new diagnostic tests have the potential to increase demand for DR-TB drugs by helping expose the true scale of the crisis.

Aside from stimulating demand and encouraging countries to scale up treatment, other avenues should be explored:

DDRESSING THESE CH Pooled procurement A

By aggregating individual countries’ through the GDF, with the commitment demand, pooled procurement has the from the countries that GDF drugs “It’s the collective responsibility potential to bring a global solution to are used only in conjunction with of the TB community to act problems of supply disruption of API quality-assured drugs. In parallel, so that patients can get access and/or finished formulations. regional GLC offices have been to better treatment soon. concentrating on monitoring and Today, the Global Drug Facility (GDF) technical assistance in countries and The Union is trialling a shorter acts as a procurement mechanism are still involved in the approval process treatment regimen for MDR-TB. for DR-TB drugs by pooling demand of Global Fund-funded programmes.2 Other actors also need to act, generated through DR-TB programme and with two new drugs active grants made by the Global Fund to In a fragmented and volatile market, against TB potentially reaching Fight AIDS, Tuberculosis and Malaria. pooled procurement could facilitate In 2010, $40 million was channelled global solutions to supply disruptions, the market in 2013 – the first through this pooled procurement as very few countries have the capacity in decades – it needs to mechanism for TB medicines and or resources to identify new sources happen now. ” diagnostics.7 Since 2011, securing of quality-assured medicines on their Christophe Perrin, approval from the Green Light own. However, a pooled procurement Pharmacist, International Committee ceased to be a pre-condition mechanism on its own will not secure for procuring DR-TB drugs through and maintain a market of affordable Union Against Tuberculosis the GDF. Countries now have the quality-assured drugs, unless the size and Lung Disease possibility to procure partial regimens of the demand it covers is substantial. © Krisanne Johnson

6 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 A

The role of middle-income countries CH THESE DDRESSING

With the market for DR-TB drugs produced in China, largely due to its to increase access to quality-assured largely concentrated in the BRICS advanced fermentation technology TB treatment. While in Brazil, the countries – Russia, India and China and cost position for manufacturing.8 government has shown strong account for 60% of all notified India is a major producer of finished political will to control the TB drug DR-TB cases among the 22 high- TB formulations. Yet not all medicines market, with drugs to treat both burden countries – procurement produced and marketed in these drug-sensitive and drug-resistant TB decisions made in these countries will countries meet WHO standards.9, 10 available solely in the public sector, have a considerable impact on the and free of charge.14 Exposing large numbers of TB patients future shape of the market.1 If they ALL to non-quality-assured medicines In other countries, however, TB and committed to using DR-TB medicines

represents a serious threat to public DR-TB drugs are not channelled ENGES that meet WHO quality standards, health. Several initiatives have been through TB programmes and their global demand for these would be undertaken to address this threat and dispensing is not regulated. In India, consolidated, likely leading to more promote quality-assured DR-TB drugs for example, drugs to treat both drug- quality-assured suppliers of both API in these countries, whether in terms susceptible TB and DR-TB are available and finished formulations entering of production or procurement. over the counter in the private market.15 the market. For example, since 2009, initiatives and Patients are left to purchase such These countries also play a major technical assistance aimed at boosting drugs out of pocket, often not able role in manufacturing of both API the production of quality-assured to afford the all drugs in the regimen and finished formulations. 80-85% TB medicines in China have been or the full treatment course, which of active pharmaceutical ingredients, undertaken,11, 12, 13 but government can have a hugely negative impact, including for second-line drugs, are commitment is additionally needed fuelling further drug resistance.

Creating incentives for manufacturers

Part of the problem of too few quality- WHO Prequalification Programme or assured sources for international supply stringent regulatory authorities. To date, “Alarmingly, in some of our could be resolved by linking funding institutions, governments and WHO clinics in Central Asia, up to to procurement for quality-assured have not done enough in this regard. one third of patients who have medicines. While the Global Fund TB for the first time are coming One welcome step is that the GDF has requires the drugs procured by the DR-TB in with strains that are already had a clear quality assurance policy programmes it funds to meet WHO drug-resistant. While we’ve since 2010 that sends a signal to quality standards, thus contributing been able to scale up treatment manufacturers to invest in quality, by to pooled demand for quality-assured modestly within our projects, medicines, other donors such as the requiring products to be either quality- we struggle every day with the World Bank do not set specific assured by the WHO Prequalification inadequate tools and drugs to quality criteria. Programme, a stringent regulatory tackle the disease. With two authority (SRA), or to be approved by new drugs coming to market When weak regulatory authorities the GDF/Global Fund’s Expert Review in the next year, we have a allow marketing of products that do Panel. The Panel provides time-limited historic opportunity to improve not meet WHO quality standards approval for products that have fewer DR-TB treatment. These but are nevertheless procured by than three sources approved by either the drugs need to be introduced national tuberculosis programmes, WHO Prequalification Programme or SRA. effectively, so governments drug quality is clearly not being and treatment providers can prioritised enough. Efforts should The GDF has now published an scale up the response to this also be directed at manufacturers to overview of prices online;16 they have alarming crisis. ” encourage them to improve compliance also provided further information on Dr Teshome Ashagre, with internationally recognised quality products used for the purpose of this Medical Coordinator, standards and submit product dossiers publication, helping to increase price MSF Uzbekistan for quality assessment through the and quality transparency.

Continued overleaf

DR-TB Drugs Under the Microscope 7 Addressing these challenges continued ENGES ALL DDRESSING THESE CH A MSF / © Natalia Sergeeva

Securing the funding base “Multidrug-resistant tuberculosis Funding will also be required in order DR-TB. Additional restructuring at the is an escalating public health to consolidate the market and respond Global Fund may further restrict the emergency, yet the global to the demand for DR-TB drugs. amount of funding available for TB response is abysmal, with Overall, domestic funding accounts grants and also risks severely cutting levels of testing and treatment for 86% of total funding for TB control, the amount of money available to the remaining shockingly low. with the Global Fund accounting for BRICS countries, where most DR-TB With barely one in twenty TB 12% and grants from other agencies occurs. Although DR-TB is included patients being tested for drug for 2%.17 among the essential services to be resistance, we’re just seeing the funded under the ‘Transitional Funding tip of the iceberg. Even if you The value of grants for DR-TB from Mechanism’18 that was set up to ensure are diagnosed and lucky enough the Global Fund is progressing, the continuation of grants, the list of to receive treatment for drug- and reached $130 million in 2011. countries eligible for future grants has resistant TB, it is appalling that According to country reports, the been restricted, with middle-income you only have a 48% chance biggest grants are for India and countries with high MDR-TB burdens at of being cured. We need more China, at $36 million and $31 million 17 high risk of cuts in Global Fund support. testing, we need more treatment respectively. When only international Any future changes in the Global Fund and we need better drugs to funding is taken into consideration, need to take into account the huge costs make treatment more effective the Global Fund’s share represents 82% of scaling up MDR-TB care and ensure and more tolerable for patients” of the total spent – a figure that rises to 91% for MDR-TB.17 The Global Fund there are adequate funds allocated to Dr Grania Brigden, remains the predominant international addressing this. TB Advisor for Médecins Sans donor for access to DR-TB treatment. This vulnerability comes in a context of Frontières’ Access Campaign As a consequence, the financial woes at considerable need: WHO estimates that the Global Fund – which led to the an additional $3 billion are needed each agency having to cancel its 11th funding year to fill the funding gap for TB care, round in November 2011 – may lead a figure which does not even include to more restrictive grant-making for the research and development needs.19

8 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 RESEARCH AND DEVELOPMENT: RESE A NEEDS AND OPPORTUNITIES RCH A ND DE ND Neglected populations: children and people living with HIV/AIDS V E

To date, there has been very little purchase them through the GDF. co-infection with TB is now uncommon L OPMENT: NEEDS NEEDS OPMENT: research to even determine the best Treatment providers who attempt to in wealthy countries. This is particularly use of existing DR-TB drugs, with treat children therefore must do so problematic given that TB is the biggest today’s DR-TB treatment largely based by manipulating adult formulations, killer of people living with HIV today.22 on experience and expert opinion such as breaking or crushing tablets For many DR-TB medicines, crucial rather than randomised clinical trials, to approximate the required dose. research is lacking. For kanamycin, and many ‘grey areas’ where expert This carries a major risk of over- or amikacin and capreomycin, for opinions may be conflicting. under-dosing a child.

example, the potential for renal A

Children are particularly neglected. In addition, safety and efficacy data in toxicity when used with tenofovir (the OPPORTUNITIES ND At least 10-15% of total TB cases each children have not been established for backbone of the WHO-recommended year occur in children, and a similar the majority of the medicines used in first-line HIV treatment regimen) percentage can be assumed among DR-TB treatment. Only three medicines is unstudied. The medicines of the 20 new DR-TB cases in children. in this report have been licensed for use fluoroquinolone class – moxifloxacin, Yet the WHO programmatic guidelines in children. However one of those that is levofloxacin and ofloxacin – are released in 2011 did not provide licensed for paediatric use, levofloxacin, thought to interact with crucial guidance on dosing and use of DR-TB has not been approved beyond 14 days protease inhibitors like lopinavir and drugs in children and adolescents. atazanavir (both part of second-line of treatment, even though a child with And only three medicines featured HIV regimens). Drug interactions are DR-TB would need to take the medicine in this report (amikacin, levofloxacin also predicted between ethionamide for close to two years. and linezolid) have been developed as and prothionamide and ARVs such as paediatric formulations. These are not The interactions of DR-TB drugs with nevirapine and efavirenz. And there is widely available, with none included HIV medicines are also largely unknown.21 very little knowledge about possible in the GDF product catalogue, which This research has not been a priority interactions for other medicines, such means that treatment providers cannot for HIV drug developers because as cycloserine, terizidone and PAS.

Finally some good news after a half century of neglect

With treatment that is expensive, century of neglect, there is encouraging they be added to the existing regimen complex, toxic and, with success rates progress in recent years, with to optimise outcomes, or can entirely 23 at around just 50%, insufficiently ten drugs in clinical testing (four new regimens be devised? effective, many look to the research and repurposed, six new drugs and development (R&D) pipelines for a new three new classes of drugs).24 Most Access to these promising drugs regimen to address these problems. encouragingly, two completely should be accelerated in a way that R&D into TB drugs and diagnostics new compounds – bedaquiline and improves the effectiveness, shortens has been neglected for decades delamanid – have been submitted for the duration and reduces adverse because the disease primarily affects approval for MDR-TB treatment by effects of the current M/XDR-TB developing countries and therefore stringent regulatory authorities, the treatment regimen. There is an does not represent a lucrative market first for TB in half a century. opportunity to develop one or more for the pharmaceutical industry. There is an unprecedented opportunity regimens that achieve these goals as Compared to other disease treatment to start building a new approach to well as addressing the programmatic pipelines, TB’s drug pipeline remains treating DR-TB. How these drugs are barriers that the current treatments fairly limited. But after nearly a half used will be critical in that respect: will pose to implementers.

Continued overleaf

DR-TB Drugs Under the Microscope 9 Research and development: needs and opportunities continued Clinical trials, ongoing and planned

Clinical trials are being run with existing drugs to shorten the duration of today’s MDR-TB treatment. The Union, for example, is sponsoring the Evaluation of a Standardised Treatment Regimen of Anti-tuberculosis drugs for patients with MDR-TB (STREAM)

ND OPPORTUNITIES trial, which will assess a nine-month A standardised treatment regimen for MDR-TB that achieved excellent outcomes with a cure rate of 87% in a non-randomised observational 25 study in Bangladesh. Modelled MSF / on the Bangladesh regimen, the STREAM regimen uses moxifloxacin,

OPMENT: NEEDS clofazimine, ethambutol, and L pyrazinamide for nine months, © Natalia Sergeeva E

V supplemented by prothionamide, kanamycin, and isoniazid during an delamanid: A study has commenced bedaquiline: A Phase III trial comparing intensive phase of four months. looking at the safety and efficacy nine months of treatment with ND DE The aim of this study is to show that

A of delamanid for six months in bedaquiline versus placebo using the this shorter treatment regimen is patients with MDR-TB. It is a background regimen of the STREAM trial at least as effective as the current multicentre, randomised, double-

RCH is due to start recruiting patients toward lengthier treatments used throughout A blind, placebo-controlled, parallel the end of 2012.27 A subpopulation of the world to treat MDR-TB. 26 group trial, studying patients with HIV co-infected patients will be included.

RESE Looking to the pipeline, two Phase III culture-positive, pulmonary trials are underway involving the two MDR-TB, by adding delamanid to Other organisations are working on trials drugs that are close to market under the intensive phase of the current for new regimens, however the timelines conditional approval: WHO-recommended regimen. for outcomes may be several years away.28

Compassionate use: getting experimental “TB remains the main killer of treatments to patients without options people living with HIV, and in sub-Saharan Africa we have been Compassionate use provides potentially to secure compassionate use access to working to ensure people get life-saving experimental treatments bedaquiline in South Africa shows that treatment for both diseases at to patients suffering from a disease political will is required to ensure that the same time, at the same place, for which no satisfactory authorised this happens in a timely manner, so and from the same health worker. therapy exists and / or who cannot enter that patients left with few options can For DR-TB, we’ve developed a clinical trial. It is also called ‘expanded benefit from experimental treatments.30 strategies to deliver care to access’ or ‘special access,’ and became people in their communities, a standard approach over the years for The drug developer has the final decision which have shown some success. diseases such as cancer and HIV/AIDS. on whether the drug will be supplied But it’s extremely difficult to for compassionate use and under watch your patients try to cope WHO approved the application of this which conditions. with the horrendous side effects concept to DR-TB in 2008, taking into caused by this arduous two-year consideration new TB compounds With the results of the new drugs in treatment. We urgently need under clinical development.29 For phase III trials and other drugs in phase treatment for DR-TB that can compassionate use to be implemented, II studies now published, there are a cure people in less time and a necessary regulatory framework must number of drugs that offer the potential with fewer side effects.” be in place.29 Often in high-burden for compassionate use. There needs to Dr Kazi Arif Uddin, DR-TB countries, there is little experience be greater awareness of this option to Matsapha Comprehensive of compassionate use and the treat failing DR-TB patients, as well as Health Center TB Coordinator, necessary framework will need to be the necessary regulatory framework MSF Swaziland developed. MSF’s experience in trying to allow it.31

10 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 CONCLUSIONS AND CONC L RECOMMENDATIONS USIONS A

Left untreated, drug-resistant tuberculosis kills and further encourages the disease’s spread. RECOMMEND ND

But with inadequate ability to diagnose DR-TB and insufficient numbers of patients on treatment, demand for DR-TB drugs is low, not least for WHO quality-assured drugs. Therefore, there is little incentive either for new producers to enter the market or for existing producers to invest in meeting WHO quality standards or increase production capacity. This creates a vicious circle, as limited drug supplies and expensive medicines in turn contribute to hindering the scale up of DR-TB treatment. Supply insecurity due to delivery delay or interruption means that programmes have been cautious rather than ambitious

about the number of people they aim to treat – a direct disincentive to treatment scale-up. A TIONS

Demand should be encouraged, and new The Global Drug Facility: The World Health Organization: diagnostic methods that allow for easier Should continue to publish prices Should promote the use of quality- and speedier detection of DR-TB will help assured medicines at country level in this regard. However, it is crucial that of medicines on its website in order to improve transparency access to DR-TB diagnosis is strengthened Should keep a balance between with proper implementation of current Should work on the expansion stimulating an optimal offer of older diagnostics, including Xpert MTB/RIF. of the existing rotating stockpile second-line drugs and introduction This will help ensure a quicker time to to decrease the time it takes for of new compounds diagnosis and identify the true need countries to receive medicines for DR-TB treatment. Should support the evaluation of for all orders, and not only shorter treatment regimens and With two new drugs active against DR-TB emergency ones give timely advice on the use of about to come to market, the global TB new compounds Should further develop a strategic community must seize this opportunity revolving fund with international to make a real difference in DR-TB donors to provide manufacturers Donors: treatment, and actively work to assess the best way of introducing the new drugs. a financial guarantee to secure the Should support research to define a Only a far shorter treatment regimen with production and supply of second- better and shorter DR-TB treatment far fewer side effects will be up to the line TB drugs regimen with the inclusion of task of allowing treatment providers to newer drugs dramatically scale up DR-TB treatment. Should promote the use of quality- assured medicines at country level by harmonising quality criteria for medical procurement across donors

Should streamline supply chain mechanism both at country and global levels

Governments:

Should commit to use medicines which meet WHO standards

Should ensure patients have free access to a complete course of DR-TB treatment in quality programmes MSF

/ Should regulate DR-TB medicines in order to preserve their efficacy and avoid fuelling resistance

Should establish a framework for © Natalia Sergeeva compassionate use programmes

DR-TB Drugs Under the Microscope 11 ” “ Medicines Have Food Become My Food” My

DR-TB treatment requires people to take a course of up to six different medicines – as many

ecome as 20 pills per day for up to two years – plus, for the first six months, a painful daily injection.

B Patients often endure intolerable side effects. These can include nausea, severe vomiting, depression, e aggressive behaviour, hallucinations, vertigo, hearing loss, diarrhoea and lethargy. Additional medicines may be needed to mitigate these side effects. Hav People’s lives are interrupted by DR-TB treatment, and many find adhering to it too arduous to bear. As a result, many patients abandon treatment, which increases the risk of more extensively resistant forms of the disease developing, and spreading.

* edicines Shanti, from India, shared her story of life with DR-TB. M

“

Shanti grew up close to the beach in The side effects of the drugs made life Unfortunately, Shanti’s story is far from Mumbai, India. In 2006, she began very difficult for Shanti. unique. Patients who reach MSF’s clinic suffering from diarrhoea, and experienced often arrive in very bad condition and “ I am not able to eat properly. I vomit recurring bouts of fever and vomiting. some even die before they can start their all the time and feel drowsy the A year later, she was diagnosed with HIV treatment. A lot of them have already whole day long. My mind does not and put on antiretroviral treatment. been treated in the private sector with seem to work; I feel very distressed. inappropriate TB drug regimens. Often, At the same time, she was put on I feel giddy after taking my medicine, there is a lack of monitoring among treatment for drug-sensitive TB, but and also unbearably hot.” private practitioners to ensure that patients failed to respond to all three subsequent By the time Shanti had come to MSF, take their drugs continuously. The high treatment courses. Eventually, she she was very frail. She had spent much drug costs also force many patients discovered she was sick with drug- of her money getting tests that did in the private sector to discontinue resistant TB. In 2011, she was finally able not tell her what was wrong, and treatment before they have been cured. to start treatment for DR-TB through MSF. medicines that had failed to cure her – “ If the private market continues For TB alone, Shanti had to take six it had taken years to get the help she the casual over-the-counter sale of tablets in the morning and eight needed. Sadly, a few months after she drugs, we are going to see even tablets at night, in addition to her daily started treatment with MSF, she passed more cases of drug resistant TB HIV medicines. She often said that her away due to complications as a result developing” says Piero Gandini, medicines had become her food. of her far-gone illness. of MSF in India. “There is an urgent need for authorities to regulate the private sector so that patients are given treatment and support of an acceptable standard.”

India has the second highest MDR-TB burden in the world with nearly 66,000 new cases every year. Yet only five percent of people in India with MDR-TB are able to get the treatment they need to stay alive.1

“ It is really important that people with TB are correctly diagnosed at an early stage, and that appropriate care and treatment is provided. It’s very sad every time we are unable to save a patient’s life. But unless more is done by the authorities to address the growing problem of drug resistance, we are just going to see more cases like this” says Gandini.

© Bithin Das * Name has been changed to protect identity

12 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 M Methodology ethodo

This report looks at the sources and prices of anti-tuberculosis medicines classified Groups 2– 5 in the World l Health Organization’s 2011 Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis, for og 32 which there are particular problems of access and for which supply is problematic or vulnerable to disruption. y

Grouping Drugs

Group 1 – First-line oral agents isoniazid, rifampicin, ethambutol, pyrazinamide, rifabutin

Group 2 – Injectable agents amikacin, kanamycin, capreomycin

Group 3 – Fluoroquinolones gatifloxacin, moxifloxacin, levofloxacin, ofloxacin ethionamide, prothionamide, cycloserine, terizidone, Group 4 – Oral bacteriostatic second-line agents para-aminosalicylic acid (PAS) clofazimine, linezolid, amoxicillin/clavulanate, clarithromycin, Group 5 – Agents with unclear efficacy imipenem, thioacetazone

This report however does not include: • All first-line medicines in Group 1. For first-line medicines occasionally used in DR-TB treatment, such as pyrazinamide, price is not a barrier. Attention should of course be paid to the quality of the products selected. • Gatifloxacin in Group 3, which has not been included because of its controversial risk / benefit profile. The drug was not included in the July 2012 expression of interest of the joint Global Drug Facility / Global Fund Expert Review Panel33 and it was not on the June 2012 WHO prequalification expression of interest list for manufacturers.34 • Certain medicines in Group 5, which, although listed in the WHO guidelines, are very rarely used, such as imipenem injectable, the twice-daily administration of which is complicated for both patients and treatment providers. Additional Group 5 drugs excluded are those commonly used for other indications, such as clarithromycin and amoxicillin/ clavulanate, access to which is not problematic. Nevertheless, attention should be paid to these products’ quality.

Data collection Prices listed are ‘ex works’ except for authority, or that have been reviewed Questionnaires were sent to companies prices provided by Cipla (FOB, Mumbai) and listed by the Expert Review Panel that had at least one anti-tuberculosis and Macleods (FCA, Mumbai) – see (ERP) of the Global Fund, are listed in product either listed on the WHO List annex 2 for details. the price tables as ‘under evaluation’. of Prequalified Medicinal Products The prices listed in this publication are Submissions to WHO Prequalification or quality-approved by a stringent the ones provided by the manufacturers. are confidential and all companies regulatory authority (SRA), according The prices paid by the purchaser might mentioned that have the dossier to MSF or The Union’s knowledge. be higher because of add-ons (such as accepted for review have given MSF and The data were collected up to July 2012. import taxes and distribution mark-ups), The Union the permission to disclose this or may be lower after negotiations or information. Products that have not yet Price information as a result of effective procurement been submitted to WHO Prequalification procedures. The document should not Prices are listed where manufacturers or to a stringent regulatory authority be viewed as a manufacturers’ price list. agreed to share information. A number have not been included in the table. of manufacturers, including Aspen, Prices ‘ex works’ offered by the Global Products procured by the Global Drug Bayer, Mylan, Novartis, Pfizer, Teva and Drug Facility (GDF) pooled procurement Facility comply with the GDF’s Quality Vianex did not have prices available or mechanism are also listed according to the Assurance policy. This deems eligible did not agree to publish prices, and GDF catalogue available at http://www. for GDF procurement all products no responses were received from APP stoptb.org/gdf/drugsupply/drugs_available. that are included on the WHO List of Pharma, Glenmark, and Meiji. asp (accessed July 2012). Note that GDF Prequalified Medicinal Products, that Prices are given in US dollars (US$), prices can fluctuate during the year if, for are approved by a stringent regulatory rounded up to the nearest third example, a long-term agreement with authority, or that are approved by decimal point, and correspond to the different suppliers comes to an end. the joint GDF / ERP. The GDF quality lowest unit price (i.e. the price of one assurance policy can be found at: http:// Quality information tablet, capsule or vial). When prices that www.stoptb.org/gdf/drugsupply/quality_ Products that are either listed on the varied according to packaging (e.g. sourcing_process.asp blisters or bottle) were received from a WHO List of Prequalified Medicinal manufacturer for the same formulation, Products or approved by a stringent As the information on the WHO List the lowest price was selected. Prices regulatory authority are listed in the of Prequalified Medicinal Products is received in currencies other than US$ price tables as ‘approved’. Products that updated regularly, the list should be were converted on 2 July 2012 using the are undergoing review by either WHO consulted for up-to-date information, currency converter site www.oanda.com. Prequalification, by a stringent regulatory at: http://apps.who.int/prequal/

DR-TB Drugs Under the Microscope 13 AMIKACIN ( Am ) GROUP 2 ) GROUP 2

m A GENERAL INFORMATION

CIN ( • Therapeutic Class: Aminoglycoside • Presentations available: solution for • Approved indication in the US:

KA antibiotic. injection: 500mg / 2ml; 100mg / 2ml. Amikacin is indicated for the short-term

MI As powder for injection: 100mg, treatment of serious infections due to • ATC Code: J01GB06.32 A 500mg & 1g. susceptible strains of Gram-negative • Included in the WHO Guidelines bacteria, including bacterial • First approved by US Food and Drug as a Group 2 injectable agent.35 septicaemia (including neoatal sepsis), Administration (FDA): The date of the serious infections of the respiratory • Included in the 17th edition of original New Drug Application (NDA) tract, bones and joints, central nervous the WHO Model List of Essential is not publically available on the US system (including meningitis) and Medicines36 and in the 3rd edition FDA website. The first Abbreviated skin and soft tissue; intra-abdominal of the WHO Model List of Essential New Drug Application (ANDA) was infections (including peritonitis); 37 38 Medicines for Children. approved on 22 January 1981. burns and post-operative infections (including post-vascular surgery).39

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

AMIKACIN Cipla Medochemie GDF pooled procurement price

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

500mg/2ml 0.962 (Medochemie) solution for 3.250 0.990 2.950 (Cipla)* injection

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

14 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 A MI KA CIN ( CIN A

Spotlight on access issues m

GENERAL INFORMATION 2 GROUP ) There is no clinical difference between kanamycin and amikacin. As they have similar side effect profiles and show high levels of cross-resistance,35 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.35

Number of quality sources programmes, as qualified staff need HIV co-infection There are several stringent to administer the product, and on No antiretroviral interaction studies regulatory authority-approved the patient, who must undergo have been performed, but based on sources of amikacin, however there painful injections for eight months. pharmacokinetic profiles, the potential for drug interactions are low. are few sources that supply TB Amikacin is available in both programmes. In January 2011, the powder and liquid formulations; However, there is potential for first generic amikacin from Cipla the latter is more adaptable additive toxicities, in particular was prequalified by WHO; Indian to resource-limited settings as with antiretrovirals which may manufacturer Micro Labs is still reconstitution is not required. cause renal toxicity, such as expected to submit a dossier for tenofovir.41 Further studies are Paediatrics WHO prequalification. required to confirm this. Amikacin is licensed for use in Manufacturer Help S.A announced neonates, infants and children.40 that they have stopped production There is a smaller dosage of amikacin. (100mg / 2ml) available which Adaptability allows for more accurate dosing Amikacin, like other aminoglycosides in children. No prices were offered and capreomycin, cannot be for this product for this report administered orally. This imposes and the product is not available burdens both on treatment through the GDF.

DR-TB Drugs Under the Microscope 15 KANAMYCIN ( Km ) GROUP 2 ) GROUP 2

m K GENERAL INFORMATION CIN (

Y • Therapeutic Class: Aminoglycoside • Presentations available: solution • Approved indication in the US:

M antibiotic. for injection: 1g/4ml, 500mg/2ml, Kanamycin is indicated in the short- A

N 1g/3ml. As powder for injection: 1g. term treatment of serious infections • ATC Code: J01GB04.32 caused by susceptible strains of

KA • First approved by US Food and Drug 42 • Included in the WHO Guidelines Administration (FDA): The date of the micro-organisms. 35 as Group 2 injectable agent. original New Drug Application (NDA) • Included in the 17th edition of is not publically available on the US the WHO Model List of Essential FDA website. The first Abbreviated Medicines36 and in the 3rd edition New Drug Application (ANDA) was of the WHO Model List of Essential approved on 13 February 1973. The only currently registered Medicines for Children.37 product in the US 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)

KANAMYCIN Macleods Panpharma GDF pooled procurement price

Under evaluation by SRA approved / Quality status GDF Quality Assurance Policy WHO PQ ERP approved 1g powder for 1.510 0.748 0.790 (Panpharma)* injection

1g/4ml solution xx xx 2.580 (Meiji) for injection

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

16 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 KA N A M Y CIN ( CIN

Spotlight on access issues K m

There is no clinical difference between kanamycin and amikacin. As they have similar side effect profiles 2 GROUP ) and show high levels of cross-resistance,35 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.35

Number of quality sources Additional manufacturers exist in Kanamycin is available in both In the past, kanamycin formulations China, India, in countries from powder and liquid formulations; from several different manufacturers the former Soviet Union, and in the latter is more adaptable were registered in the US. However, other countries, but it is unknown to resource-limited settings as there are currently only three whether they comply with WHO reconstitution is not required. quality standards. kanamycin sources approved by Paediatrics a stringent regulatory authority: Active Pharmaceutical The safety and efficacy of kanamycin US manufacturer APP Pharma, Ingredient in children has not been established. Japan’s Meiji and Panpharma in Issues with the production of the While dosages are published in several France. APP Pharma and Meiji did active pharmaceutical ingredient guidelines, there is an urgent need for not respond to questionnaires for (API) have been a barrier in increasing further research (in pharmacokinetics, the purpose of this publication. the number of quality-assured pharmacodynamics, and safety data) sources for the finished product. No sources of kanamycin are into the use of this drug in younger WHO-prequalified, although one Kanamycin API is manufactured by a populations, in particular in children manufacturer (Macleods) has specialised process of fermentation. aged under five. submitted a dossier for WHO There are few manufacturers globally HIV co-infection prequalification and has been who have the capacity to produce No antiretroviral interaction studies accepted for evaluation. quality-assured API through this fermentation process, and the have been performed, but based on The supply of kanamycin remains complexity is further increased pharmacokinetic profiles, the potential vulnerable, with only two sources as the API should be sterile. The for drug interactions are low. available for TB procurement – quality assurance of the API is a However, there is potential for Panpharma and Meiji – both of key factor in the approval of the additive toxicities, in particular with which have experienced production finished product through WHO antiretrovirals which may cause renal limitations. Panpharma has resolved Prequalification or a stringent toxicity, such as tenofovir.41 Further issues with active pharmaceutical regulatory authority. studies are required to confirm this. ingredient (API) production which Adaptability had resulted in an interruption Kanamycin, like other aminoglycosides of supply to several national TB and capreomycin, cannot be programmes in 2010. Meiji was administered orally. This imposes identified by GDF as an alternative burdens both on treatment source in 2010; however their limited programmes, as qualified staff need production capacity means the to administer the product, and on price of their product is considerably patients, who must undergo painful higher than Panpharma’s. injections for eight months.

DR-TB Drugs Under the Microscope 17 CAPREOMYCIN (Cm) GROUP 2 ) GROUP 2 m

GENERAL INFORMATION CIN (C

Y • Therapeutic Class: Polypeptide • Presentations available: M. tuberculosis when the primary antibiotic. 1g powder for injection. agents (isoniazid, rifampicin, ethambutol, aminosalicylic acid, and • ATC Code: J01GB06.32 • First approved by US Food and Drug streptomycin) have been ineffective, PREOM 43

A Administration (FDA): 2 June 1971. • Included in the WHO Guidelines as or cannot be used because of toxicity C 35 43 a Group 2 injectable agent. • Approved indication in the US: or the presence of resistant bacilli. • Included in the 17th edition of Capreomycin is used concomitantly the WHO Model List of Essential with other appropriate anti-tuberculosis Medicines36 and in the 3rd edition agents; it is indicated for use in of the WHO Model List of Essential pulmonary infections caused by Medicines for Children.37 capreomycin-susceptible strains of

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

CAPREOMYCIN Akorn Macleods Vianex GDF pooled procurement price

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

1g powder for Manufacturer did not 8.000 (Akorn) 6.250 7.720 injection agree to publish prices 5.340 (Vianex)*

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

18 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 C A PREOM Y CIN (C CIN Spotlight on access issues

Capreomycin shows moderate cross-resistance to amikacin and kanamycin.35 m ) GROUP 2 GROUP ) 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 complexity is further increased However, with a new quality- Eli Lilly, the original licence-holder as the API should be sterile. The assured source identified and for capreomycin, has been actively quality assurance of the API is a three suppliers set to receive WHO engaged in technology transfer key factor in the approval of the prequalification, it is anticipated to three generic manufacturers finished product through WHO the price will eventually decrease. (Aspen, Hisun and SIA International) Prequalification or a stringent Adaptability since 2003. However, none of regulatory authority. these manufacturers has received Capreomycin, like DR-TB medicines approval by a stringent regulatory Eli Lilly transferred the technology from the aminoglycosides class, authority or WHO Prequalification. for capreomycin API to only one cannot be administered orally. manufacturer, Chinese generic This imposes burdens both on GDF have identified two quality- producer Hisun, which received treatment programmes, as qualified assured sources available for supply: US FDA approval in 2006. staff need to administer the product, Akorn – which had bought Eli Lilly’s and on patients, who must undergo US licence; and, in 2011, Vianex – a Other API manufacturers exist, painful injections for eight months. manufacturer based in Greece, which but have not been approved by has received stringent regulatory a stringent regulatory authority Paediatrics or by the WHO Prequalification authority approval in Spain. The safety and efficacy of Programme. With only two quality-assured capreomycin in children has sources currently available for Evolution in price not been established. TB procurement, the supply of For a number of years, Eli Lilly While dosages are published capreomycin is still considered subsidised the price of capreomycin in several guidelines, there vulnerable; however, three for GLC-approved programmes, is an urgent need for further companies, including Macleods charging US$1.02 per vial until a research (pharmacokinetics, and Aspen, have submitted a certain volume had been ordered, pharmacodynamics, safety data) dossier for WHO prequalification. and $4.00 thereafter. into the use of this drug in younger Active Pharmaceutical populations, in particular in Since transferring the technology Ingredient children aged under five. to other manufacturers, however, Issues with the production of the the price at which countries can HIV co-infection active pharmaceutical ingredient procure capreomycin has increased (API) have been a barrier in increasing No antiretroviral interaction studies considerably. With Eli Lilly’s stock the number of quality-assured have been performed, but based on now exhausted, the subsidised sources for the finished product. pharmacokinetic profiles, the potential price of $4.00 per vial is no longer for drug interactions are low. Capreomycin API is manufactured available. GDF procures the by a specialised process of Akorn product at a price of $8.00 However, there is potential for fermentation. There are few per vial, although the company additive toxicities, in particular with manufacturers globally who provided a price of $6.25 per vial antiretrovirals which may cause have the capacity to produce to this publication. Vianex-sourced renal toxicity such as tenofovir.41 quality-assured API through this capreomycin is available for GDF Further studies are required to fermentation process, and the procurement at $5.34 per vial. confirm this.

DR-TB Drugs Under the Microscope 19 3 MOXIFLOXACIN (Mfx) GROUP 3 roup ) G fx

GENERAL INFORMATION

CIN (M • Therapeutic Class: Fluoroquinolone. • Presentations available: 400mg tablet. acute bacterial exacerbation of

XA chronic bronchitis, uncomplicated 32

O • ATC Code: J01MA14. • First approved by US Food and and complicated skin and skin

FL Drug Administration (FDA): I • Included in the WHO Guidelines structure infection, and complicated 44 X as a Group 3 Fluoroquinolone.35 12 October 1999. intra-abdominal infections.45

MO • Not included in the 17th edition • Approved indication in the US: of the WHO Model List of Essential Moxifloxacin was initially approved Medicines36 nor in the 3rd edition for the indications of bacterial sinusitis of the WHO Model List of Essential and community-acquired pneumonia. Medicines for Children.37 This was further expanded to include

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

GDF pooled MOXIFLOXACIN Bayer Cipla Hetero Macleods procurement price Under evaluation Under evaluation GDF Quality Quality status SRA approved WHO PQ approved by WHO PQ by WHO PQ Assurance Policy Manufacturer 1.680 (Cipla) 400mg tab did not agree to 1.850 1.100 1.600 1.500 (Macleods)* publish prices

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

20 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 MO X I FL O XA CIN (M CIN Spotlight on access issues

Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, fx such as moxifloxacin and levofloxacin, are preferred to ofloxacin.35 ) G )

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

Number of quality sources Cipla provided a quality-assured Similarly, generic versions have 3 Bayer was the only quality-assured FOB price of $1.85 per tablet; GDF now been registered in South source of moxifloxacin available for reports an ex works price of $1.68 for Africa and are supplied for DR-TB many years. In November 2010, the same product. As more generic treatment through the National Cipla’s product became the manufacturers enter the market, it is TB programme as part of the first generic moxifloxacin to be expected the price will fall further. government tender awarded in prequalified by WHO and a second 2011. Generic versions are also Approved indication manufacturer (Macleods) has since marketed in the Russian Federation. While moxifloxacin has been shown submitted a dossier that has been Paediatrics to be effective against M. tuberculosis, accepted for evaluation. The safety and efficacy of moxifloxacin it has not yet received an approved in children has not been established. Meanwhile, the Macleods product TB indication by any stringent received joint GDF/Global Fund regulatory authority. While dosages are published in several Expert Review Panel approval in guidelines, there is an urgent need for Patents June 2012, making it eligible for further research (pharmacokinetics, Although the basic patent which procurement for Global Fund grants. pharmacodynamics, safety data) covered the moxifloxacin molecule into the use of this drug in younger Further sources of quality-assured 47 has now expired in most countries, populations, in particular in children moxifloxacin are also expected as a subsequent patent claiming aged under five. other approved indications of use exist a crystal monohydrate form of As there is no paediatric formulation for the drug. There are currently three moxifloxacin48 was filed which available, paediatric doses are generic manufacturers (Dr Reddy’s, blocks generic production in obtained by manipulating adult Teva, Torrent Pharms) that have countries where the patent is tentative US FDA approval, waiting formulations to achieve target granted. An addition, a patent on doses. This requires a certain level of to enter the US market when the 49 the tablet oral formulation appears training, supervision and resources, patent expires in 2019. to stand in the way of generic which may not be available in many Although price remains a barrier, the production in the US market until settings where DR-TB is prevalent. supply of moxifloxacin will therefore 2019 (see box on US patents). HIV co-infection be relatively secure in the near future. The following patents are listed No antiretroviral interaction Additional manufacturers exist in by the US FDA for moxifloxacin studies have been performed, but China, India, in countries from 400mg tablet:50 based on the metabolism rate of the former Soviet Union, and in moxifloxacin, levels of the drug US patent number. Expiry date other countries, but it is unknown may be reduced by use of ritonavir 4990517 8 December 2011 whether they comply with WHO and increased by atazanavir. 5607942 4 March 2014 quality standards. Further research is needed to 5849752 5 December 2016 assess this. Evolution in price 6610327 29 October 2019 After the arrival of a quality-assured Protease inhibitors and efavirenz generic onto the market, the price In India, where the patent on the may prolong QT interval, so caution is advised in concomitant use with has reduced considerably. Prior to this, crystal monohydrate form was moxifloxacin, with electrocardiogram the only option available was Bayer; rejected after a pre-grant opposition, monitoring recommended. prices for this product reported in additional patents on other the Global Fund Price and Quality pharmaceutical forms have been Oral absorption of fluoroquinolones Reporting (PQR) tool have ranged granted, but these do not block is reduced by buffered drugs, so between US$3.97 and $5.03 per generic manufacturing of the doses should be separated from tablet in the last four years.46 tablet formulation. didanosine-buffered tablets.41

DR-TB Drugs Under the Microscope 21 3 LEVOFLOXACIN (Lfx) GROUP 3 roup ) G fx L GENERAL INFORMATION CIN ( • Therapeutic Class: Fluoroquinolone. • Presentations available: 250mg, community-acquired pneumonia, XA 500mg and 750mg tablets; 25mg / ml uncomplicated skin and skin O • ATC Code: J01MA12.32 oral solution. structure infections, complicated FL

O urinary tract infections (UTI), and • Included in the WHO Guidelines • First approved by US Food and Drug V 35 acute pyelonephritis. This was further E as a Group 3 Fluoroquinolone. Administration (FDA): 20 December L expanded to include uncomplicated 1996. The paediatric formulation • Included in the 17th 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 2004.51 Medicines36 and in the 3rd edition (post-exposure).51 of the WHO Model List of Essential • Approved indication in the US: Medicines for Children.37 Levofloxacin Levofloxacin was initially approved is considered a better alternative to for the indications of acute ofloxacin, based on availability and maxillary sinusitis, acute bacterial 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 LEVOFLOXACIN Cipla Hetero Macleods Micro Labs procurement price Under evaluation SRA approved / by WHO PQ / Under evaluation by GDF Quality Quality status WHO PQ WHO PQ approved Under evaluation by WHO PQ Assurance Policy approved SRA / ERP approved

250mg tab 0.061 0.060 0.060 0.090 0.050 (Cipla)

500mg tab 0.085 0.092 0.075 0.160 0.080 (Cipla)

Manufacturer did not agree 750mg tab xx xx xx xx to publish prices

22 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 L E V O FL O XA CIN ( CIN Spotlight on access issues L

Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, 3 Group fx) such as moxifloxacin and levofloxacin, are preferred to ofloxacin.35

Number of quality sources indication approved by any stringent available in many settings where Levofloxacin 250mg and 500mg oral regulatory authority.35 DR-TB is prevalent. Paediatric formulations produced by Micro Labs formulations need to be made Patents and Cipla are prequalified by WHO. more widely available. Patents in the US and in several Hetero (250mg and 500mg) and European countries claiming HIV co-infection Macleods have submitted their levofloxacin expired in June 2011. No antiretroviral interaction studies dossiers for WHO prequalification. have been performed, but based on Paediatrics In addition, Hetero has received joint the metabolism rate of levofloxacin, The US FDA has approved levofloxacin GDF/Global Fund Expert Review no interactions are expected. However, for use in children aged over six Panel approval, making their 250mg further research is needed to assess this. and 500mg products eligible for months, but only for acute infections. Global Fund procurement. The safety of levofloxacin in children Protease inhibitors and efavirenz treated for more than 14 days has may prolong QT interval, so caution With patents in the US having expired not been studied; as this drug may is advised in concomitant use with in June 2011, there are currently 13 be taken for up to two years, there levofloxacin, with electrocardiogram manufacturers that have 250mg, is an urgent need for more safety monitoring recommended. 500mg or 750mg formulations data on the use of levofloxacin for registered with the US FDA. These Oral absorption of fluoroquinolones extended periods of time in children. is reduced by buffered drugs, so manufacturers could be potential doses should be separated from suppliers to GDF and national TB While there are two manufacturers didanosine-buffered tablets.41 programmes in the future. of the paediatric formulation (25mg/ml oral solution) available The price of levofloxacin does in the US, these are not widely not appear to be an issue. available elsewhere. Currently, Approved indication the majority of DR-TB programmes The 2011 WHO programmatic prepare paediatric doses by guidelines for DR-TB recommend use manipulating adult formulations to of later generation fluorquinolones, achieve target doses. This requires including levofloxacin. However, a certain level of training, supervision levofloxacin does not have a TB and resources, which may not be

DR-TB Drugs Under the Microscope 23 3 OFLOXACIN (Ofx) GROUP 3 roup ) G fx o GENERAL INFORMATION

CIN ( • Therapeutic Class: Fluoroquinolone. of the WHO Model List of Essential • Approved indication in the US:

XA 37 Ofloxacin is approved for the indications 32 Medicines for Children. O • ATC Code: JJ01MA01. of acute bacterial exacerbations of FL • Presentations available: chronic bronchitis, acute uncomplicated

O • Included in the WHO Guidelines as a Group 3 Fluoroquinolone.35 200mg, 300mg, 400mg tablet. uretheral and cervical gonorrhea, non- gonococcal urethritis and cervicitis, • Included in the 17th edition of • First approved by US Food and acute pelvic inflammatory disease, the WHO Model List of Essential Drug Administration (FDA): and uncomplicated skin and skin Medicines36 and in the 3rd edition 28 December 1990.44 structure infections.52

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

GDF pooled OFLOXACIN Cipla Macleods Medochemie Micro Labs procurement price WHO PQ SRA approved / GDF Quality Quality status WHO PQ approved WHO PQ approved approved ERP approved Assurance Policy

200mg tab 0.055 0.060 0.095 0.060 0.050 (Cipla)

400mg tab 0.099 xx xx 0.110 0.090 (Cipla)

Spotlight on access issues

Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, such as moxifloxacin and levofloxacin, are preferred to ofloxacin.35

Number of quality sources Approved indication formulations to achieve target doses. Ofloxacin formulations produced The 2011 WHO DR-TB programmatic This requires a certain level of training, by Cipla, Macleods and Micro Labs guidelines recommend use of later supervision and resources, which have received WHO prequalification. generation fluoroquinolones. As with may not be available in many settings Micro Labs has also received joint other Group 3 drugs, ofloxacin does where DR-TB is prevalent. not have a TB indication approved by GDF / Global Fund Expert Review HIV co-infection any stringent regulatory authority. Panel approval, making it eligible No antiretroviral interaction studies for Global Fund procurement. Paediatrics have been performed, however As the patent for ofloxacin The safety and efficacy of ofloxacin in one source suggests there may be has expired, other generic children has not been established. potential interactions with atazanavir and lopinavir.53 manufacturers (including Teva While dosages are published in several and Dr. Reddy’s) have now guidelines, there is an urgent need for Protease inhibitors and efavirenz entered the market, with products further research (pharmacokinetics, may prolong QT interval, so caution available in the US and Europe. pharmacodynamics, safety data) is advised in concomitant use with into the use of this drug in younger ofloxacin, with electrocardiogram populations, in particular in children monitoring recommended. aged under five. Oral absorption of fluoroquinolones is As there is no paediatric formulation reduced by buffered drugs, so doses available, paediatric doses are should be separated from didanosine- obtained by manipulating adult buffered tablets.41

24 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 ETHIONAMIDE (Eto) ETHION GROUP 4 A MIDE (E MIDE

GENERAL INFORMATION to

• Therapeutic Class: Carbothionamides • Included in the 17th edition of the WHO • Approved indication in the US: 4 GROUP ) group, derivative of isonicotinic acid.35 Model List of Essential Medicines36 and ethionamide is primarily indicated for in 3rd edition of the WHO Model List of the treatment of active tuberculosis • ATC Code: J04AD03.32 Essential Medicines for Children.37 in patients with M. tuberculosis • Included in the WHO Guidelines resistant to isoniazid or rifampicin, • Presentations available: 250mg tablet. or where the patient is intolerant as a Group 4 oral bacteriostatic to other drugs.54 second-line agent.35 • First approved by US Food and Drug Administration (FDA): 30 April 1965.44

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

GDF pooled procurement ETHIONAMIDE Cipla Lupin Macleods Micro Labs Pfizer price Under Under WHO PQ evaluation WHO PQ GDF Quality Quality status evaluation SRA approved approved by WHO PQ / approved Assurance Policy by WHO PQ ERP approved

Manufacturer Manufacturer 0.080 (Cipla) 250mg tab 0.091 did not agree to 0.095 0.078 did not agree to 0.073 (Macleods)* publish prices publish prices 0.079 (Lupin)*

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

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.55

Number of quality sources expected in the future, the supply and formulations to achieve target doses. As of December 2011, there were number of sources of ethionamide This requires a certain level of three quality-assured sources of is gradually improving. training, supervision and resources, which may not be available in many ethionamide, with Cipla 250mg The price of ethionamide does not tablets having received WHO appear to be an issue. settings where DR-TB is prevalent. prequalification; Macleods and Paediatrics HIV co-infection Wyeth Pharm – under licence The safety and efficacy of ethionamide While no antiretroviral interaction from Pfizer – also produce quality- in children has not been established. studies have been performed, assured products. pharmacokinetic profiles suggest that While dosages are published in several In addition, Lupin and Micro Labs drug interactions with ethionamide guidelines, there is an urgent need for have submitted their dossiers are possible. further research (pharmacokinetics, for WHO prequalification, while pharmacodynamics, safety data) There is the possibility of additive Lupin has also received joint GDF/ into the use of this drug in younger toxicities with antiretrovirals which Global Fund Expert Review Panel populations, in particular in children may cause hepatotoxicity, including approval, making it eligible for aged under five. efavirenz and nevirapine.41 Global Fund procurement. As there is no paediatric formulation With the potential for interactions with With an additional quality-assured available, paediatric doses are some classes of antiretrovirals, there is source now approved and more are obtained by manipulating adult an urgent need for further studies.

DR-TB Drugs Under the Microscope 25 4 PROTHIONAMIDE (Pto) GROUP 4 roup ) G to GENERAL INFORMATION

• Therapeutic Class: Carbothionamides of the WHO Model List of Essential • Approved indication in Germany: MIDE (P 35 37 A group, derivative of isonicotinic acid. Medicines for Children. Treatment of all forms and stages of pulmonary and extra-pulmonary • ATC Code: J04AD01.32 • Presentations available: 250mg tablet. tuberculosis as second-line drug in the • Included in the WHO Guidelines • First approved by German Federal case of proven multidrug-resistance of as a Group 4 oral bacteriostatic Institute for Drugs and Medical Devices the pathogens against first-line drugs; 35 PROTHION second-line agent. (BfArM): First marketed in Germany treatment of diseases caused by so-called • Not included in the 17th edition in the 1970s but registered in the ubiquitous (atypical) mycobacteria; of the WHO Model List of Essential framework of posterior registration treatment of leprosy in the context Medicines36 nor in the 3rd edition process in Germany on 14 June 2005.56 of modified therapy regimens.57

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

PROTHIONAMIDE Fatol Lupin Micro Labs Olainfarm GDF pooled procurement price

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

Manufacturer did not 0.127 (blister) (Fatol) 250mg tab 0.126 0.080 0.140 agree to publish prices 0.080 (bottle) (Lupin)

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.55

Number of quality sources is gradually improving its supply, This requires a certain level of training, Only two sources of prothionamide and the price of prothionamide is supervision and resources, which have received stringent regulatory expected to fall further. may not be available in many settings authority approval (Germany’s where DR-TB is prevalent. Paediatrics Fatol and Latvia’s Olainfarm), while The safety and effectiveness of HIV co-infection none have been WHO-prequalified. prothionamide in children has not While no antiretroviral interaction However, Lupin and Micro Labs been established. studies have been performed, have submitted their dossiers for pharmacokinetic profiles suggest WHO prequalification. While dosages are published in several that drug interactions with guidelines, there is an urgent need for Lupin and Micro Labs have also prothionamide are possible. received joint GDF/Global Fund further research (pharmacokinetics, Expert Review Panel approval, pharmacodynamics, safety data) There is the possibility of additive making them eligible for Global into the use of this drug in younger toxicities with antiretrovirals which Fund procurement, while Olainfarm populations, in particular in children may cause hepatotoxicity, including is likewise considered eligible for aged under five. efavirenz and nevirapine.41 procurement under the Global Fund As there is no paediatric formulation With the potential for interactions quality assurance policy. available, paediatric doses are with some classes of antiretrovirals, The increasing number of quality- obtained by manipulating adult there is an urgent need for assured sources of prothionamide formulations to achieve target doses. further studies.

26 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 C Y

CYCLOSERINE (Cs) C L

GROUP 4 (C OSERINE

GENERAL INFORMATION s ) GROUP 4 GROUP ) • Therapeutic Class: Analog of D-alanine.35 Medicines36 and in 3rd edition • Approved indication in the US: of the WHO Model List of Essential Cycloserine is indicated in the • ATC Code: J04AB01.32 Medicines for Children.37 treatment of active pulmonary • Included in the WHO Guidelines and extra-pulmonary tuberculosis as a Group 4 oral bacteriostatic • Presentations available: (including renal disease), when the second-line agent.35 250mg capsule. causative organisms are susceptible to this drug and when treatment with the • First approved by US Food and Drug • Included in the 17th edition of primary medications (streptomycin, 44 the WHO Model List of Essential Administration (FDA): 29 June 1964. isoniazid, rifampicin and ethambutol) has proved inadequate.58

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

CYCLOSERINE Aspen Chao Center / Purdue Lupin Macleods GDF pooled procurement price

Under evaluation WHO PQ WHO PQ Quality status SRA approved by WHO PQ / ERP GDF Quality Assurance Policy approved approved approved Manufacturer Manufacturer 0.580 (blister) (Macleods) did not agree 250mg cap 0.580 did not agree to 0.593 0.780 (bottle 100) (Aspen) to publish publish prices prices 0.800 (bottle 40) (Chao Center)

Continued overleaf

DR-TB Drugs Under the Microscope 27 ) GROUP 4 s 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. OSERINE (C

L Number of quality sources The company completed a There is an urgent need for further C

Y Eli Lilly, the original licence holder of technology transfer for the API to research (pharmacokinetics, C cycloserine, has actively engaged in Indian manufacturer Shasun, in pharmacodynamics, safety data) technology transfer to three generic 2006. Shasun API was subsequently into the use of this drug in younger manufacturers (Aspen, Chao Center/ US FDA approved in June 2008. populations, in particular in children Purdue GMP and SIA International) Evolution in price aged under five. and ceased production in 2008. Since 2001, the GDF-sourced price As there is no paediatric formulation There are currently three quality- of cycloserine has risen, from an available, paediatric doses are assured sources of cycloserine, with Eli Lilly-subsidised price of US$0.14 per obtained by manipulating adult Macleods and Aspen sources now capsule to $0.58 per capsule in the formulations to achieve target WHO-prequalified, and Chao Center/ wake of technology transfers.59 doses. This requires a certain level of Purdue having stringent regulatory With a number of quality-assured training, supervision and resources, authority approval. sources, and more expected in which may not be available in many Four other manufacturers, including the future, the price of cycloserine settings where DR-TB is prevalent. Lupin and Cipla, have submitted is expected to fall with increased HIV co-infection dossiers for WHO prequalification, competition. meaning the supply of quality-assured The metabolism of cycloserine Paediatrics cycloserine is relatively secure. is not completely understood, The British National Formulary and therefore interactions with Active Pharmaceutical provides doses for children aged antiretrovirals are unpredictable.41 Ingredient two to 18, while the US FDA states Until 2006, the only quality-assured that the safety and effectiveness There is a need for more research source for the active pharmaceutical of cycloserine in children has not into potential interactions between ingredient of cycloserine was Eli Lilly. been established. antiretrovirals and cycloserine.

28 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 TERIZIDONE (Trd) (T TERIZIDONE GROUP 4

GENERAL INFORMATION rd ) G ) • Therapeutic Class: Analog Medicines36 nor in 3rd edition of in the 1970s and is still in the process roup of D-alanine.35 the WHO Model List of Essential of the posterior registration process in 37 Germany. The filing date for this process 32 Medicines for Children.

• ATC Code: J04AK03. 4 was 1 January 1978.56 • Included in the WHO Guidelines • Presentations available: • Approved indication in Germany: 250mg capsule. as a Group 4 oral bacteriostatic Treatment of tuberculosis in adults second-line agent.35 • First approved by German Federal and adolescents aged 14 or older.56 • Not included in the 17th edition Institute for Drugs and Medical Devices of the WHO Model List of Essential (BfArM): First marketed in Germany

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

TERIZIDONE Fatol GDF pooled procurement price

Quality status SRA approved GDF Quality Assurance Policy

250mg cap 1.489 1.494 (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,57 and, in some countries, the drug is used instead of cycloserine.

Number of quality sources While dosages are published in several HIV co-infection Germany’s Fatol is currently the sole guidelines, there is an urgent need for As terizidone is a combination of quality-assured source of terizidone. further research (pharmacokinetics, two molecules of cycloserine and Currently no manufacturers pharmacodynamics, safety data) the metabolism of cycloserine is have submitted dossiers for into the use of this drug in younger not completely understood, WHO prequalification. populations, in particular in children interactions with antiretrovirals aged under five. are unpredictable.41 Additional manufacturers exist, but it is unknown whether they comply As there is no paediatric formulation There is a need for more research with WHO quality standards. available, paediatric doses are obtained into potential interactions between by manipulating adult formulations antiretrovirals and terizidone. Paediatrics to achieve target doses. This requires The safety and effectiveness of a certain level of training, supervision terizidone in children has not and resources, which may not be been established. available in many settings where DR-TB is prevalent.

DR-TB Drugs Under the Microscope 29 PARA-AMINOSALICYLIC ACID (PAS) and PARA-AMINOSALICYLATE SODIUM (PAS-Sodium) GROUP 4

GENERAL INFORMATION

A S- Sodium ) G roup 4 • Therapeutic Class: Salicylic acid of the WHO Model List of Essential Currently, only PAS is available in the anti-folate.35 Medicines for Children.37 PAS-Sodium US, with the product registered on is not included in either document. 30 June 1994.60 • ATC Code: for PAS: J04AA01; for PAS-Sodium: J04AA02.32 • Presentations available: PAS: 4g sachet. • Approved indication in the US: PAS-Sodium: 60% weight for weight PAS is indicated for the treatment of • Included in the WHO Guidelines: TE SODIUM (P granules 9.2g sachet and 100g jar; tuberculosis in combination with other PAS: as a Group 4 oral bacteriostatic powder for solution 5.52g sachet active agents. It is most commonly second-line agent; PAS-Sodium: (equivalent to PAS 4g sachet). used in patients with multidrug- not included.35 • First approved by US Food and resistant TB or in situations when • PAS is included in the 17th edition Drug Administration (FDA): therapy with isoniazid and rifampicin of the WHO Model List of Essential PAS-Sodium was first registered in a is not possible due to a combination Medicines36 and in the 3rd edition tablet formulation on 8 March 1950. of resistance and / or intolerance.60 A R - MINOS AL IC YLA

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

PAS Jacobus GDF pooled procurement price

Quality status SRA approved GDF Quality Assurance Policy

4g sachet 1.567 1.530 (Jacobus)

PAS-SODIUM Macleods Olainfarm GDF pooled procurement price

WHO PQ GDF Quality Quality status SRA approved approved Assurance Policy

60% w/w granules A R - MINOS AL IC YL CID (P 1.510 xx 1.450 (Macleods) P – 9.2g sachet

60% w/w granules 16.270 16.000 (Macleods) xx – 100g jar (1.497 for 9.2g) (1.472 for 9.2g)

Powder for solution xx 1.550 1.500 (Olainfarm) – 5.25g sachet

30 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 P A R - MINOS AL IC YL CID (P

Spotlight on access issues

Para-aminosalicylate sodium (PAS-Sodium) is the sodium salt of para-aminosalicylic acid (PAS), with 1.38g of PAS-Sodium equivalent to approximately 1g of PAS.61

With none of the quality-assured sources of either PAS or PAS-Sodium presented in the same formulation – the concentration of PAS varies between product and manufacturer61 – dosing can be can be particularly confusing if multiple formulations exist in one treatment programme. A S) a nd P With moxifloxacin, capreomycin and cycloserine, PAS is one of the four medicines which weigh heavily in the overall cost of a DR-TB regimen.

Number of quality sources While PAS-Sodium products do not As there is no paediatric formulation A R - MINOS AL IC YLA There is currently only one quality- require any special storage conditions, available, paediatric doses are assured source of PAS (Jacobus), PAS is required to be stored in a cold obtained by manipulating adult and just two quality-assured sources chain below 15°C. This is problematic formulations. With all adult of PAS-Sodium (Macleods and for many settings where DR-TB is formulations varying in strength Olainfarm), with no other sources prevalent, as maintaining a functional and in either granule or powder in the pipeline. cold chain requires a certain level presentations, measuring the exact of investment both in infrastructure The Macleods PAS-Sodium received dose for a child is difficult and and human resources. WHO prequalification in 2009, but requires calibrated scales to be

the unexpectedly large demand However, the latest PAS stability available at the point of dispensing. TE SODIUM (P for this product led to capacity data states that PAS can be kept in Some manufacturers are now problems, resulting in long lead conditions below 40°C and 75% times for orders. This was humidity for one month without supplying a graduated dosage resolved in 2011. risk of degradation, if required. scoop for PAS which allows for a more accurate paediatric dosage, or With three quality-assured sources Paediatrics

measuring spoons for PAS-Sodium, A S-S odium ) G roup 4 of PAS and PAS-Sodium now The safety and effectiveness of PAS but these methods are still not available for procurement, supply and PAS-Sodium in children has not completely accurate. has improved, but is still considered been established. vulnerable, particularly as the HIV co-infection While dosages are published in several different formulations available guidelines, there is an urgent need for No antiretroviral interaction studies are not easily interchangeable. further research (pharmacokinetics, have been performed, but based Adaptability pharmacodynamics, safety data) on the pharmacokinetic profile of The various formulations have different into the use of this drug in younger PAS, drug interactions are unlikely. storage conditions, which can present populations, in particular in children Studies should be performed to issues for treatment programmes. aged under five. confirm this.41

DR-TB Drugs Under the Microscope 31 CLOFAZIMINE (cfz) GROUP 5 ) GROUP 5 fz GENERAL INFORMATION

• Therapeutic Class: Phenazine • Included in the 17th edition of • First approved by US Food and 35

ZIMINE (C Derivative. the WHO Model List of Essential Drug Administration (FDA): 62

FA Medicines (as an anti-leprosy 15 December 1986. • ATC Code: J04BA01.32 O medicine)36 and in the 3rd edition L • Approved indication in US: Clofazimine C • Included in the WHO Guidelines of the WHO Model List of Essential is indicated in the treatment of as a Group 5 medicine; agents Medicines for Children (as an lepromatous leprosy, including with unclear efficacy.35 anti-leprosy medicine).37 dapsone-resistant lepromatous leprosy • Presentations available: 50mg and and lepromatous leprosy complicated 100mg soft-gel capsules. by erythema nodosum leprosum.62

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

Clofazimine is a Group 5 medicine which is used in patients with XDR-TB, currently a very small market. This medicine does not exist in the GDF product catalogue.

CLOFAZIMINE Novartis GDF pooled procurement price

Quality status SRA approved xx

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

32 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 C L O FA ZIMINE (C ZIMINE

Spotlight on access issues fz Clofazimine was first synthesised in 1954 as an anti-TB compound, but was subsequently thought to be ineffective ) GROUP 5 GROUP ) against TB. In 1959, clofazimine demonstrated effectiveness against leprosy and, after clinical trials, was launched by Novartis for use in leprosy in 1969.

In late 1999, Novartis signed a Memorandum of Understanding with the WHO leprosy programme for a donation of clofazimine. In the past few years, the GLC and the GDF were able to source small quantities of clofazimine through the Leprosy Program at WHO – which procures the medicine through Novartis – and supply a few countries. As the programmes’ demand for this drug increased, this supply channel could no longer support the volumes needed by MDR-TB projects. Together with GLC partners, the GDF therefore approached Novartis in an attempt to secure clofazimine, but so far no agreement has been reached.63

Clofazimine has no official indication for the treatment of DR-TB, and as its effectiveness has not 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 / XDR-TB, when there are no other options available. A systematic review published in October 2012 suggests that clofazimine could be considered as an additional therapeutic option in the treatment of DR-TB.64

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. For these reasons, Novartis chose not submit a price for this publication.

WHO is currently in discussion with Novartis to address the liability for off-label use and patient safety of clofazimine for TB use, and hopes to have the drug available for MDR and XDR-TB treatment as soon as possible.2

Number of quality sources of Interest for product evaluation pharmacodynamics, safety data) Clofazimine produced by Sandoz for issued by the Expert Review Panel. into the use of this drug in Novartis is currently the sole quality- younger populations, in particular As demand for clofazimine is expected assured source of the drug. Additional to increase, there is a need for alternative in children aged under five. manufacturers exist in India and sources of the drug other than the A 50mg soft-gel capsule is currently Europe, but it is unknown whether they existing Novartis product, which is available, but this formulation comply with WHO quality standards. not easily available. makes it impossible to fraction With no market for clofazimine in the dose. This puts clinicians in a developed countries, there is no reason For patients who require this drug, difficult position, with risks of for manufacturers to seek stringent it can be purchased through certain regulatory authority approval. private pharmacies. The GDF catalogue either over-dosing the child and does not list clofazimine, but it can increasing the risk of side effects, In order to send a clear message to be procured at a price of US$1.12 per or under-dosing and increasing manufacturers that clofazimine is 100mg capsule through a supplier in the risk of amplification of the needed, a call to include the drug in 65 Switzerland. child’s resistance profile. the WHO Prequalification Expression of Paediatrics Interest (EoI) was issued. However, in HIV co-infection The safety and effectiveness of June 2012, the drug was not included Clofazimine may have a significant clofazimine in children has not in the 11th Invitation to Manufacturers drug-drug interaction with some been established. to submit expressions of interest for antiretrovirals. No studies have been WHO prequalification. Meanwhile, While dosages are published performed, but clofazimine is a weak clofazimine continues to be included in in several guidelines, there inhibitor of the CYP3A4 metabolism the joint GDF / Global Fund Invitation to is an urgent need for further pathway and may increase levels of Manufacturers to submit an Expression research (pharmacokinetics, protease inhibitors and etravirine.41

DR-TB Drugs Under the Microscope 33 LINEZOLID (Lzd) GROUP 5 ) GROUP 5 zd L GENERAL INFORMATION ID ( L • Therapeutic Class: • Not included in the 17th edition • Approved indication in US: Oxazolidinone antibiotic. of the WHO Model List of Essential Linezolid is indicated for treatment Medicines36 nor in the 3rd edition of susceptible strains of designated INEZO • ATC Code: J01XX08.32 L of the WHO Model List of Essential microorganisms for nosocomial • Included in the WHO Guidelines Medicines for Children.37 pneumonia; and complicated and as a Group 5 medicine; agents uncomplicated skin and skin structure • Presentations available: 600mg tablet, with unclear efficacy.35 infections. It is not indicated for 100mg / 5ml powder for suspension. the treatment of Gram-negative • First approved by US Food and Drug infections and community-acquired Administration (FDA): 18 April 2000.66 pneumonia.67

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

Linezolid is a Group 5 medicine which is used in patients with XDR-TB, currently a very small market. This medicine does not exist in the GDF product catalogue.

LINEZOLID Hetero Pfizer GDF pooled procurement price

Quality status Under evaluation by SRA SRA approved xx

Manufacturer did not agree 600mg tab 2.500 xx to publish prices 100mg/ml powder Manufacturer did not agree xx xx for susp. to publish prices

34 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 L INEZO L ID ( ID L Spotlight on access issues zd ) GROUP 5 GROUP ) Although linezolid has no official indications for DR-TB treatment, clinical data on use in TB has been published. The 2011 WHO programmatic guidelines recommend the use of linezolid for patients with MDR or XDR-TB. In April 2012, a systematic review outlined the efficacy of linezolid in DR-TB treatment.68

Linezolid has a relatively high number of adverse side effects, including myelosuppression, anaemia, and irreversible peripheral and optical neuropathies. Nonetheless, linezolid plays an important role in patients with XDR-TB.

Number of quality sources Due to patents covering linezolid countries including Argentina, Brazil, Currently, only one manufacturer – in the US and a number of other China, Colombia, Mexico, Ukraine Pfizer – is approved by a stringent countries, the cost of the drug is and South Africa. These patents regulatory authority. extremely high. For example, the could also impede the introduction price of Pfizer-produced linezolid in of generic versions. A further four manufacturers (Teva, the South African private sector is Mylan, Glenmark and Gate Pharma) In India the basic compound patent US$81.00 per tablet63. At this price, have tentative approval from the could not be filed as in 1993, the the cost of linezolid alone for one local patent law did not allow US FDA; however, there appears patient is nearly $60,000 for two pharmaceutical product patenting. to be no willingness to produce years’ treatment. Patients failing The generic version is now available linezolid and supply the DR-TB conventional DR-TB treatments in India. market with quality-assured drugs but who could have a chance to before the patents expire in 2021. survive through the use of linezolid, Paediatrics Despite the call for linezolid to be are denied this option due to the Pharmacokinetic studies have been completed in children from birth, included in the WHO Prequalification prohibitively expensive cost. and dosages are approved by the Expression of Interest for product The search for more alternative US FDA exclusively for infections evaluation, the drug was not included quality-assured sources is critical with gram-positive bacteria resistant in the 11th Invitation to Manufacturers to ensure price reductions. to other antibiotics. issued in July 2012. However, linezolid Patents is included in the joint GDF / Global A paediatric formulation exists as a The basic patent claiming linezolid Fund Invitation to Manufacturers to powder for suspension, produced by was filed by Upjohn Company submit an Expression of Interest for Pfizer. The reconstituted product can in the US in 1993 and will expire be stored at room temperature. product evaluation issued by the on 18 November 2014.70 Upjohn Expert Review Panel (ERP). Company also filed patents in There is a need for further safety and Macleods subsequently submitted the US on a crystalline form71 and efficacy data on the use of linezolid 72 a dossier for evaluation to the ERP. on a tablet formulation in 2002; for extended periods in children Indian generic manufacturer Hetero these patents will impede generic with DR-TB. competition in the US until 2021. has also submitted a dossier for HIV co-infection linezolid to the US FDA. The following patents are listed by No antiretroviral interaction 50 Additional manufacturers exist in the US FDA for linezolid: studies have been performed but interactions are unlikely. There India, but it is unknown whether they US patent number. Expiry date may, however, be an increased comply with WHO quality standards. 5688792 18 November 2014 risk of myelosuppression and 6514529 15 March 2021 Evolution in price mitochondrial toxicities with 6559305 29 January 2021 No price was supplied for linezolid long-term use in combination 6610327 29 October 2019 from GDF for this publication, and with certain antiretrovirals there are no entries in the Global The patents claiming crystal forms (zidovudine, stavudine, Fund Price and Quality Reporting and the tablet formulation have also didanosine).41 Further studies (PQR) tool. been granted in many developing are required to confirm this.

DR-TB Drugs Under the Microscope 35 Annex 1: Summary table of prices provided by pharmaceutical companies nies a The price corresponds to the price of one unit (tablet, capsule, etc.)

Products included in the WHO List of Prequalified Medicinal Products and/or approved by a stringent regulatory authority comp (SRA) are in bold. al Products that are under evaluation by WHO prequalification and/or SRAs, and/or approved by ERP are underlined.

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

ceutic Please refer to Annex 2 for the conditions of eligibility set by individual companies, and for the incoterms a associated with these prices. rm a GDF pooled Companies Drug procurement ph price y

b AMIKACIN GDF Cipla Medochemie

0.962 (Medochemie) 500mg/2ml solution for injection 3.250 0.990

ided 2.950

v (Cipla)*

KANAMYCIN Macleods Panpharma

pro 0.790

1g powder for injection 1.510 0. 748 (Panpharma)*

2.580 1g/4ml solution for injection (Meiji)

prices CAPREOMYCIN Akorn Macleods Vianex

f 8.000 Manufacturer o (Akorn) 1g powder for injection 6.250 7.720 did not agree to e 5.340 publish prices l (Vianex)* b MOXIFLOXACIN Bayer Cipla Hetero Macleods a

t 1.680 Manufacturer y (Cipla) 400mg tablet did not agree to 1.850 1.100 1.600 r 1.500 publish prices a (Macleods)*

LEVOFLOXACIN Cipla Hetero Macleods Micro Labs

umm 0.050 250mg tablet 0.061 0.060 0.060 0.090 (Cipla)

0.080 500mg tablet 0.085 0.092 0.075 0.160

x 1: S (Cipla)

Manufacturer 750mg tablet did not agree to publish prices Anne OFLOXACIN Cipla Macleods Medochemie Micro Labs

0.050 200mg tablet 0.055 0.060 0.095 0.060 (Cipla)

0.090 400mg tablet 0.099 0.110 (Cipla)

ETHIONAMIDE Cipla Lupin Macleods Micro Labs Pfizer

0.080 (Cipla) Manufacturer Manufacturer 0.073 250mg tablet 0.091 did not agree to 0.095 0.078 did not agree to (Macleods)* publish prices publish prices 0.079 (Lupin)*

PROTHIONAMIDE Fatol Lupin Micro Labs Olainfarm

0.127 (blister) (Fatol) Manufacturer 250mg tablet 0.080 (bottle) 0.126 did not agree to 0.080 0.140 (Lupin) publish prices

36 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 Anne x 1: S 1: x umm a r y y t a b l e

o

GDF pooled f Companies Drug procurement prices price

Chao Centre/ CYCLOSERINE GDF Aspen Lupin Macleods Purdue

0.580 (blister) (Macleods) pro 0.780 (bottle 100) Manufacturer Manufacturer 250mg capsule (Aspen) did not agree to 0.580 did not agree to 0.593 v publish prices publish prices 0.800 (bottle 40) ided (Chao Center/ Purdue)

TERIZIDONE Fatol b

1.494 y

250mg capsule (Fatol) 1.489 ph a

PAS Jacobus rm

1.530 a

4g sachet (Jacobus) 1.567 ceutic

PAS-SODIUM Macleods Olainfarm

1.450 60% w/w granules – 9.2g sachet (Macleods) 1.510 al comp 60% w/w granules – 16.000 16.270 (1.472 for 9.2g) 100g jar (Macleods) (1.497 for 9.2g) a

1.500 nies Powder for solution – 5.25g sachet (Olainfarm) 1.550

CLOFAZIMINE Novartis

Manufacturer Not included in the 50mg soft-gel capsule did not agree to GDF catalogue publish prices

LINEZOLID Hetero Pfizer

Manufacturer Not included in the 600mg tablet 2.500 did not agree to GDF catalogue publish prices

Manufacturer Not included in the 100mg/ml powder for suspension did not agree to GDF catalogue publish prices

DR-TB Drugs Under the Microscope 37 Annex 2: Conditions of offer, as quoted by companies nies a Definitions of eligibility vary from company to company. The conditions detailed in the table below were those quoted by companies. comp

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

AKORN No restrictions No restrictions Akorn is the sole US manufacturer for capreomycin Ex works uoted 1g powder for injection and is FDA approved in the

q United States. Akorn has the capacity to produce s 2 million units annually , a CHAO CENTER No restrictions No restrictions Ex works er (Purdue) ff o

f CIPLA No reported restrictions but No restrictions Prices for larger quantities are negotiable FOB o

higher prices have been (Mumbai, India) negotiated separately for ten Latin American countries

FATOL No restrictions No restrictions Ex works

Ex works onditions HETERO

JACOBUS No restrictions unless by US MSF, WHO, GDF All other organisations will be handled on a Ex works Government case-by-case basis x 2: C MACLEODS FCA (Mumbai)

MEDOCHEMIE No restrictions No restrictions Ex works Anne MICRO LABS No restrictions except India No restrictions Ex works

OLAINFARM No restrictions No restrictions Ex works

PANPHARMA Cambodia, Latvia, Lithuania WHO, ICRC, Ex works IDA, MSF

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

38 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 Annex 3: Company contacts Anne x 3: 3: x This section reports the contact details of companies that have been contributing

with price information to this publication. comp

Akorn Hetero Olainfarm www.akorn.com www.heterodrugs.com http://olainfarm.lv/en/ a

Lake Forest, Illinois, USA 7-2-A2, Industrial Estates, Sanath Nagar, n

5 Rupnicu Street, Olaine LV-2114, Latvia y Sean Brynjelsen Hyderabad-500 018, A.P., India Mrs. Elena Vasilevskaya cont Vice President, New Business Development Mr. M. Srinivas Reddy Business Development Tel: +1 847 279 6149 Tel: +91 40 23704923/24/25 Tel: +371 67013701/67013745 E-mail: [email protected] E-mail: [email protected] E-mail: [email protected] a cts Chao Center (Purdue) Jacobus PanPharma www.thechaocenter.com Princeton, New Jersey, USA www.panpharma.fr Laura R Jacobus 3070 Kent Ave, West Lafayette, Indiana, USA Tel: +1 (609) 799-8221 ex 207 Fougères, France Sarah Witwer E-mail: [email protected] Michel le Bellego Legacy Products Coordinator Head of Sales & Contract-Manufacturing Tel: +1 765 464 8414 ext 307 Macleods Tel: +33 2 99 97 92 12 E-mail: [email protected] www.macleodspharma.com E-mail: [email protected] Cipla 304 Atlanta Arcade, Marol Church Road, www.cipla.com Andheri East, Mumbai, India Vijay Agarwal 289, Belasis Road, Mumbai Central, Business Development Director Maharashtra, India Tel: +91 22 66762800 Raul Lande E-mail: [email protected] Manager-Exports Tel: +91 22 23025387 (Direct) Medochemie +91 22 23070013 / 23070393 / 23070385 www.medochemie.com E-mail: [email protected] or [email protected] Limassol, Cyprus Phaedon Ellinas FATOL Arzneimittel Tel: +357 25 867 618 www.fatol.de E-mail: [email protected] Production Facility of RIEMSER Arzneimittel AG, Micro Labs Schiffweiler, Germany www.microlabsltd.com Elke Rinkes International Business Coordinator No.11 Bank Street, Kilpauk, Tel: +49 (0) 68 21/ 96 05 17 Chennai 600 010, India E-mail: [email protected] N.K.Kothari Executive Vice President International Tel: +91 44 26450789, 26471205 E-mail: [email protected]

DR-TB Drugs Under the Microscope 39 References erences

f 1. World Health Organization. Global 9. Barber SL, Smid M, Hennig C, Huang B, 17. World Health Organization. Global e

R Tuberculosis Report 2012. [Online] WHO, Arifaj D. Multidrug-resistant tuberculosis Tuberculosis Report 2011. [Online] WHO, Geneva, 2012 October [cited 2012 October and quality-assured medicines. The Lancet Geneva, 2011 October [cited 2012 October 17] Available from: http://www.who.int/tb/ 2009; vol 374: 292 17] Available from: http://www.who.int/tb/ publications/global_report/en/index.html publications/global_report/2011/en/ 10. Laserson KF, Kenyon AS, Kenyon 2. World Health Organization. Global TA, Layloff T, Binkin NJ. Substandard 18. The Global Fund. Global Fund Green Light Committee meeting report tuberculosis drugs on the global market and Information Note: Transitional Funding Mechanism [Online] 2011 December 12 [Online] WHO, Geneva; February 2012 their simple detection. International Journal [cited 2012 October 11] Available from: [cited 2012 October 17] Available of Tuberculosis and Lung Disease. 2001 www.theglobalfund.org/documents/tfm/ from: http://www.who.int/tb/ May; 5(5):448-54 TFM_Request_InfoNote_en/ challenges/mdr/greenlightcommittee/ 11. Bill and Melinda Gates Foundation. Meetingreport2ndgGLCmeeting.pdf Stop TB Partnership/World Health Tuberculosis Strategy Overview, 2009 19. Organization. It’s airborne and can kill; 3. Cambridge Economics Policy Associates [Online] 2009 November [cited 2012 it’s curable at low cost; so why aren’t we (CEPA) LLP. Market Dynamics Study October 8] Available from: http://www. stopping it? [Online] Stop TB Partnership/ gatesfoundation.org/global-health/ produced for the Global Fund to Fight AIDS, WHO, Geneva; 2012 October 17 [cited Documents/tuberculosis-strategy.pdf Tuberculosis and Malaria, Phase I Report. 2012 October 22] Available from: http:// 2011 January 14. 12. United States Pharmacopeia. PQM www.stoptb.org/assets/documents/news/ Technical Assistance for Manufacturers of TB_CurableA4folded.pdf 4. World Health Organization. Tuberculosis Second-line TB Medicines. [Online] USAID/ diagnostics: Xpert MTB/RIF Test – WHO 20. Marais B J, Gie R P, Schaaf H S, Beyers N, USP, Washington DC, 2012 February [cited endorsement and recommendations. Donald P R, Starke J R. Childhood pulmonary 2012 October 9] Available from: http:// [Online] WHO, Geneva, 2012 May [cited tuberculosis: old wisdom and new www.usp.org/sites/default/files/usp_pdf/EN/ 2012 October 18] Available from: challenges. American Journal of Respiratory aroundTheWorld/PQM/pqm_ta_to_tb_mfrs- http://www.who.int/tb/features_archive/ and Critical Care Medicine 2006; 173: pqm060f_gdf_2012-02-feb_2012.pdf factsheet_xpert_may2011update.pdf 1078–1090. 13. The Global Fund. Grant number 5. Dalberg. Analysis of the second-line TB 21. Mukadi YD, Maher D, Harries A. CHN-S10-G14-T; China: Reduce the drugs market and the feasibility of advanced Tuberculosis case fatality rates in high HIV morbidity and mortality of tuberculosis in purchase market commitments. 2010 prevalence populations in sub-Saharan China. [Online] 2012 June 28 [cited 2012 Africa. AIDS 2001;15:143-52. November. October 10] Available from: http://portfolio. 22. World Health Organization. 6. Ditiu, L and Moore, T. GDF Vision For theglobalfund.org/en/Grant/Index/CHN- Tuberculosis (Fact Sheet no. 104) [Online]. SLD Supply Chain. Stop TB Partnership S10-G14-T WHO, Geneva 2012, October [cited 2012, Global Drug Facility. [Online] Institute of 14. Keravec, J. Brazil’s Model for SLDs October 10]. Available from: http://www. Medicines meeting presentation notes, Quality Assurance and Management: who.int/mediacentre/factsheets/fs104/en/ Washington DC, 2012 July 31. [cited A Country Perspective. SIAPS [Online] 2012 October 10] Available from: http:// 23. Ahuja SD, Ashkin D, Avendano M, Institute of Medicines meeting presentation www.iom.edu/~/media/Files/Activity%20 Banerjee R, Bauer M, et al. (2012) Multidrug notes, Washington DC, 2012 July 31. [cited Resistant Pulmonary Tuberculosis Treatment Files/Research/DrugForum/2012-JUL-31- 2012 October 10] Available from: http:// Regimens and Patient Outcomes: AUG-01/731%20%20Session%20I%20%20 www.iom.edu/~/media/Files/Activity%20 An Individual Patient Data Meta-analysis of Ditiu%20Lucicia.pdf Files/Research/DrugForum/2012-JUL-31- 9,153 Patients. PLoS Med 9(8): e1001300. AUG-01/731%20%20Session%20II%20%20 7. Cambridge Economics Policy Associates doi:10.1371/journal.pmed.1001300 Keravec%20Joel.pdf (CEPA) LLP. Market Dynamics Study 24. Working Group on New TB Drugs. produced for the Global Fund to Fight AIDS, Divakaran B, JM Myalil, Sreedharan J, 15. Drug Pipeline [Online] Stop TB Partnership, Tuberculosis and Malaria, Phase I Report. Surendranath D. Sale of anti-tuberculosis 2012 [cited 2012 October 12] Available 2011 January 14. drugs through private pharmacies: a cross from: newtbdrugs.org/pipeline.php sectional study in Kerala, India. [Online] 8. Lukulay, P. MDR-TB Drug Quality: The Italian Journal of Public Health 2011, Vol 25. Van Deun A, Maug AK, Salim MA, Urgent Need for Action. USAID. [Online] 8, No. 1 [cited 2012 October 12] Available Das PK, et al. Short, highly effective, and Institute of Medicines meeting presentation from: http://ijphjournal.it/article/view/5639 inexpensive standardized treatment of notes, Washington DC, 2012 July 31. [cited multidrug-resistant tuberculosis. [Online] 2012 October 10] Available from: http:// 16. The Global Drug Facility. GDF Product The American Journal of Respiratory and www.iom.edu/~/media/Files/Activity%20 Catalogue. [Online] Stop TB Partnership Critical Care Medicine 2010, September 1, Files/Research/DrugForum/2012-JUL-31- 2012 [cited 2012 October 11] Available vol. 182 no. 5 684-692 [cited 2012 October AUG-01/731%20%20Session%20II%20%20 from: http://www.stoptb.org/gdf/ 9] Available from: http://ajrccm.atsjournals. Lukulay%20Patrick.pdf drugsupply/drugs_available.asp org/content/182/5/684.abstract

40 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 R e f erences

26. ClinicalTrials.gov. Safety and Efficacy 34. World Health Organization. 42. Drugs.com. Kantrex official FDA Trial of Delamanid for 6 Months in Patients 11th Invitation to manufacturers of information, side effects and uses. [Online] With Multidrug Resistant Tuberculosis. antituberculosis medicines to submit an 2006, March [cited 2012, September 7] [Online] US National Institutes of Health, Expression of Interest (EOI) for product Available from: http://www.drugs.com/ 2012 October 25 [cited 2012 October 29] evaluation to the WHO Prequalification pro/kantrex.html Available from: http://clinicaltrials.gov/ct2/ Programme. [Online] WHO, Geneva, 2012 show/NCT01424670 June [cited 2012 October 24] Available 43. US FDA. Approved product label: 27. Haxaire-Theeuwes M, the TMC207 from: http://apps.who.int/prequal/info_ USFDA Capastat. [Online] United States Team, Diacon AH, et al. Phase 2 open-label applicants/eoi/EOI-Tuberculosis_V11.pdf Food and Drug Administration. 2008, trial of TMC207 in an MDR-TB treatment January 14. [cited 2012, September 14]. 35. World Health Organization. Guidelines regimen. [Online] Presented at: 42nd Available from: http://www.accessdata. Union World Conference on Lung Health, for the programmatic management of fda.gov/scripts/cder/drugsatfda/index. Lille, France; 2011 October 26–30 [cited drug-resistant tuberculosis: Emergency cfm?fuseaction=Search.DrugDetails 2012 October 12] Available from: http:// Update 2011. [Online] WHO; Geneva, www.worldlunghealth.org/confLille/ 2011. [cited 2012 September 18] 44. US FDA. Cycloserine drug product images/stories/AbstractBook2011_Web.pdf Available from: http://whqlibdoc.who.int/ details. [Online] United States Food also http://uwclh.conference2web.com/ publications/2011/9789241501583_eng.pdf and Drug Administration. [cited 2012, content/1108 36. World Health Organization. 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October 26] Available from: http://www. quinolone- and -naphthyridonecarboxylic Overview&DrugName=AMIKACIN%20 msf.org.za/publication/bedaquiline-tmc207- acid derivatives as antibacterial agents should-be-prioritised-drug-resistant-tb- SULFATE and feed additives. [Online] European patients-south-africa 39. Drugs.com. Amikacin official FDA Patent Office, 2012 September 24 31. Horsburgh Jr. CR, Haxaire-Theeuwes M, information, side effects and uses. [Online] [cited 2012, October 11] Available Lienhardt C, Wingfield C, et al. Compassionate 2007, December. [cited 2012, September 5] from: http://worldwide.espacenet.com/ use and Expanded Access to new drugs for Available from: http://www.drugs.com/pro/ publicationDetails/biblio?DB=worldwide. Drug-Resistant Tuberculosis. International amikacin.html espacenet.com&II=0&ND=3&adjacent=tru Journal of Tuberculosis and Lung Disease e&locale=en_EP&FT=D&date=19910205& 40. Costello, I. British National (IJTLD) 2012, forthcoming publication. CC=US&NR=4990517A&KC=A Formulary for Children 2006, Cdr edition. 32. World Health Organization/Norwegian Pharmaceutical Press. 2007, April 30 48. Espacenet. Crystal modification of Institute for Public Health. ATC/DDD Index CDCH a process for its preparation and 2011. [Online] World Health Organization 41. Coyne K.M, Pozniak A.L, Lamorde pharmaceutical formulations comprising Collaborating Centre for Drug Statistics M, Boffito M. Pharmacology of second- this modification. [Online] European Methodology; Geneva, 2010, December 12. line antituberculosis drugs and potential [cited 2012, September 14] Available from: for interactions with antiretroviral agents. Patent Office, 2012 September 24 http://www.whocc.no/atc_ddd_index/ [Online] AIDS. 2009, February 20, Vol [cited 2012, October 11] Available from: http://worldwide.espacenet.com/ 33. The Global Fund. Quality Assurance 23 (4): 437-446 [cited 2012, September Policy for Pharmaceutical Products. [Online] 14] Available from: http://journals.lww. publicationDetails/biblio?DB=worldwide. 2012 [cited 2012 October 24] Available com/ aidsonline/fulltext/2009/02200/ espacenet.com&II=0&ND=3&adjacent=tru from: http://www.theglobalfund.org/en/ pharmacology_of_second_line_ e&locale=en_EP&FT=D&date=19981215& procurement/information/ antituberculosis_drugs.1.aspx CC=US&NR=5849752A&KC=A

Continued overleaf

DR-TB Drugs Under the Microscope 41 References continued

49. Espacenet. Pharmaceutical 58. The Chao Center. Seromycin; Cycloserine 67. US FDA. Zyvox drug details.

erences moxifloxacin preparation. [Online] capsules USP. [Online] 2005, April 28 (revised) [Online] United States Food and Drug f [cited 2012, September 18] Available from: Administration. 2010, June (revised) [cited e European Patent Office, 2012 September

R http://www.thechaocenter. com/seromycin/ 2012, September 18] Available from: http:// 24 [cited 2012, October 11] Available product_insert.pdf www.accessdata.fda.gov/scripts/cder/ from: http://worldwide.espacenet.com/ drugsatfda/index.cfm publicationDetails/biblio?DB=worldwide. 59. Gupta R, Kim J.Y, Espinal M.A, Caudron espacenet.com&II=0&ND=3&adjacent=true J-M, Pecoul, Farmer P.E, et al. Responding 68. Sotgiu G, Centis R, D’Ambrosio &locale=en_EP&FT=D&date=20030826&C to Market Failures in Tuberculosis Control. L, Alffenaar J, et al. Efficacy, safety and tolerability of linezolid containing regimens C=US&NR=6610327B1&KC=B1 [Online] Science, 2001, August 10: 1049-1051. Published online 2001, July 19 [cited 2012, in treating MDR-TB and XDR-TB: systematic 50. US FDA. Orange Book: Approved Drug September 6] Available from: http://www. review and meta-analysis. Eur Respir J. Products with Therapeutic Equivalence sciencemag.org/content/293/5532/1049. 2012 Apr 10. summary?sid=296cc982-def8-4a77-b4ec- Evaluations [Online] United States Food and 69. South African Medicine Price Registry. a7c4cc474993 Drug Administration [cited 2012 October Database of Medicine Prices [Online] 17] Available from: http://www.accessdata. 60. US FDA. Paser drug details. 2012 August 30 [cited 2012 October 16] fda.gov/scripts/cder/ob/docs/queryai.cfm [Online] United States Food and Drug Available from: http://www.mpr.gov.za/ Administration. [cited 2012, September PublishedDocuments.aspx#DocCatId=21 51. US FDA. Levofloxacin drug details. 18] Available from: http://www.accessdata. 70. Espacenet. Substituted oxazine and [Online] United States Food and Drug fda. gov/scripts/cder/drugsatfda/index. thiazine oxazolidinone antimicrobials. Administration [cited 2012, September 7] cfm?fuseaction=Search.DrugDetails [Online] European Patent Office. [cited Available from: http://www.accessdata.fda. 61. Sweetman, S.C. Martindale Complete 2012 July 31] Available from: http:// gov/scripts/cder/drugsatfda/index.cfm Drug Reference Guide, 33rd Edition. v3.espacenet.com/publicationDetails/biblio? DB=EPODOC&adjacent=true&locale=en_EP 52. US FDA. Floxin Tablets (oxfloxacin Pharmaceutical Press, 2002. pp148-3 &FT=D&date=19950316&CC=WO&NR=95 tablets). [Online] United States Food and 62. US FDA. Lamprene drug details. 07271A1&KC=A1 Drug Administration 2008, September [Online] United States Food and Drug 71. Espacenet. Linezolid-crystal form II. [cited 2012, September 7] Available from: Administration. 2002, July (revised) [cited [Online] European Patent Office. [cited http://www.accessdata.fda.gov/drugsatfda_ 2012, September 18] Available from: 2012, July 31] Available from: http:// docs/label/2008/019735s059lbl.pdf http://www.accessdata.fda.gov/scripts/cder/ v3.espacenet.com/publicationDetails/biblio? drugsatfda/index.cfm DB=EPODOC&adjacent=true&locale=en_EP 53. HIV Drug Interactions. Drug Interaction 63. Green Light Committee Initiative. &FT=D&date=20010809&CC=WO&NR=01 charts - interactions with anti-HIV and other Annual Report 2008. [Online] World Health 57035A1&KC=A1 drugs. [Online] The University of Liverpool. Organization/Stop TB Partnership. 2009 72. Espacenet. Oxazolidinone tablet 2010 [cited 2012, September 18] Available [cited 2012, September 21]. Available from: formulation. [Online] European Patent from: http://www.hiv-druginteractions.org/ http://whqlibdoc.who.int/hq/2009/WHO_ Office. [cited 2012, July 31] Available from: Interactions.aspx HTM_TB_2009.421_eng.pdf http://v3.espacenet.com/publicationDetails/ 54. US FDA. Trecator (ethiomanide tablets, 64. Dey T, Brigden G, Cox H, Shubber Z, biblio?DB=EPODOC&adjacent=true&locale =en_EP&FT=D&date=20010927&CC=WO& USP). [Online] United States Food and Drug Cooke G, Ford N. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: NR=0170225A2&KC=A2 Administration. 2005, December (revised) a systematic review and meta-analysis. [cited 2012, September 10] Available from: Journal of Antimicrobial Chemotherapy. 2012 http://www.accessdata.fda.gov/drugs October 10. [E-pub ahead of print] atfda_docs/label/2006/013026s024lbl.pdf 65. Stop TB Partnership. Global Drug 55. Wang F, Langley R, Gulten G, Dover LG, Facility Drug Supply – Clofazimine 100mg Besra GS, Jacobs WR Jr, et al. Mechanism of capsules Product Information [Online] 2012 thioamide drug action against tuberculosis [cited 2012 October 15] Available from: and leprosy. [Online] J Exp Med. 2007, http://www.stoptb.org/gdf/drugsupply/ January 22, Vol 204 (1): 73-8. Published pc3.asp?PID=562

online 2007, January 16 [cited 2012, 66. US FDA. Linezolid drug details. September 18] Available from: http://www. [Online] United States Food and ncbi.nlm.nih.gov/pubmed/17227913 Drug Administration. [cited 2012, September 18] Available from: http:// 56. Terizidone product specifications www.accessdata.fda. gov/scripts/cder/ provided to MSF by RIEMSER Arzneimittel drugsatfda/index.cfm?fuseaction=Search. AG, Germany, 2011, June 6 Overview&DrugName=LINEZOLID

42 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 Gl Glossary and oss a r Abbreviations a y nd

ANDA: ‘Abbreviated New Drug Culture: Bacterial culture is a laboratory FCA: ‘Free Carrier’. A commerical Abbre Application’. An Abbreviated New method used to grow and multiply (Incoterm 2010) term meaning that Drug Application (ANDA) contains bacteria in order to determine their the seller hands over the goods, data that, when submitted to the presence or otherwise in a sample; it is cleared for export, into the disposal v

US FDA, provides for the review the gold standard test to diagnose TB. of the first carrier (named by the i a and ultimate approval of a generic buyer) at the named place. The seller tions Drug resistance: Bacteria (in TB, drug product. These applications are pays for carriage to the named point typically M. tuberculosis) which resist a ‘abbreviated’ because they generally of delivery, and risk passes when the drug’s curative or bacteria-killing power. are not required to include preclinical goods are handed over to the (animal) and clinical (human) data to Drug-susceptible/drug-sensitive TB: first carrier. establish safety and efficacy. Instead, Bacteria are said to be sensitive to a drug First-line drugs: The drugs used as the a generic applicant must scientifically when the drugs are effective in killing or first choice to treat a disease. In the demonstrate that its product is stopping the multiplication of bacteria in the case of TB, the following four drugs are bioequivalent (i.e. performs in the body and can therefore clear the infections. usually chosen: isoniazid (H), rifampicin same manner as the innovator drug). Strains of TB which are sensitive to all first- (R), ethambutol (E), pyrazinamide (Z). Once approved, an applicant may line drugs are called drug-susceptible. manufacture and market the generic These drugs are highly effective in drug product to provide a safe, Ex works : A commercial term (Incoterm drug-susceptible TB and patients usually effective, low-cost alternative in the US. 2010) meaning that the seller delivers tolerate them well. Streptomycin (S) when the goods are placed at the disposal injectable is used in first-line treatment API: ‘Active pharmaceutical ingredient’. of the buyer, at the seller’s premises or of TB meningitis. Any substance or mixture of substances another named place (i.e. works, factory, intended to be used in the manufacture of a warehouse etc.), not cleared for export FOB: ‘Free on board’. A commerical pharmaceutical dosage form and that, when and not loaded on any collecting vehicle. (Incoterm 2010) term meaning that so used, becomes an active ingredient of the seller delivers when the goods pass ERP: ‘Expert Review Panel‘. An independent that pharmaceutical dosage form. the ship’s rail at the named port of technical body composed of external shipment. This means that the buyer Clinical trials: Sets of tests in medical technical experts, hosted by the WHO has to bear all costs and risks of loss or research and drug development Department of Essential Medicines and damage to the goods from that point. that generate safety and efficacy Pharmaceutical Policies. Their purpose The FOB term requires the seller to data (including information about is to review the potential quality risk clear the goods for export. adverse drug reactions and adverse of using antiretroviral, anti-TB and effects of other treatments) for health antimalarial products which are not yet GDF: ‘Global Drug Facility’. A mechanism interventions (e.g., drugs, diagnostics, WHO prequalified or authorised by a hosted by WHO to expand access to, devices, therapy protocols). stringent regulatory authority, and to give and availability of, quality-assured anti-TB advice to the Global Fund and the Global drugs and diagnostics through pooled Compassionate use: The terms Drug Facility whether procurement of procurement. Products procured comply ‘compassionate use,’ ‘expanded access ‘ such products can be authorised. with the GDF’s Quality Assurance policy. or ‘special access’ programmes all refer This deems eligible for GDF procurement to programmes that are intended to Extemporaneous preparation/ all products that are included on the provide potentially lifesaving experimental formulation: Preparation of a drug WHO List of Prequalified Medicinal product according to a physician’s treatments to patients suffering from Products, that are approved by a prescription, a drug formula, or a a disease for which no satisfactory stringent regulatory authority, or that recipe. Extemporaneous preparations authorized therapy exists, and/or who are approved by the Expert Review are used when the needs of individual cannot enter a clinical trial. The terms Panel also used by the Global Fund. refer to programmes that make medicinal patients cannot be met by the use of products available either on a named an approved commerical drug product. Global Fund: The Global Fund to Fight patient basis or to cohorts of patients. AIDS, Tuberculosis and Malaria is an Extensively drug-resistant TB: Compassionate use needs to be framed international financing institution that see XDR-TB within a national legislation which establishes invests government and private money the conditions under which the drug is Extra-pulmonary TB: Form of TB where in HIV, TB and malaria treatment made available. Refer to Annex 5 (Use M. tuberculosis bacteria infect parts of programs. It supports large-scale of experimental drugs outside of clinical the body other than the lungs. The most prevention, treatment and care trials, “compassionate use”) of the common forms of extra-pulmonary TB programs against the three diseases WHO Guidelines for the programmatic affect the lymph nodes, bones, central in 150 countries and it channels 82% management of drug-resistant TB, nervous system, and cardiovascular of the international financing for TB. Emergency Update 2008. and gastrointestinal systems. www.theglobalfund.org

Continued overleaf

DR-TB Drugs Under the Microscope 43 Glossary and Abbreviations continued

GLC: ‘Green Light Committee’. Pharmacokinetic (PK): Branch of resistant strains, be compatible with The GLC Initiative was created in pharmacology, which studies the antiretroviral therapies for those HIV-TB 2001 to help countries gain access to mechanisms of absorption and patients currently on such therapies, and tions

a quality-assured second-line anti-TB distribution of an administered drug;

i improve treatment of latent infection.

v the rate at which a drug action drugs so they can provide treatment The TB Alliance is committed to begins and the duration of the for people with MDR-TB in line with ensuring that approved new drug effect; the chemical changes of WHO guidelines, the latest scientific regimens are affordable, widely the substance in the body (e.g. Abbre evidence and country experiences. by metabolic enzymes); and the adopted and available to those who The Initiative consisted of a secretariat, need them. nd effects and routes of excretion of the Green Light Committee (an the metabolites of the drug. expert review and WHO advisory Tentative FDA approval: Tentative y a

r body) and the Global Drug Facility Pharmacodynamic (PD): Branch FDA approval is awarded by the a (the drug procurement arm of the of pharmacology, which studies US FDA to a drug product that has the biochemical and physiological

oss Initiative). Since 2011, there is no met all required quality, safety and need for GLC approval to procure effects of drugs on the body, or on efficacy standards, but is not eligible Gl microorganisms or parasites within quality-assured second-line TB drugs for marketing in the US because of or on the body, and the mechanisms through GDF. GLC was restructured in existing patent protection. of drug action and the relationship June 2011 into a Global GLC (gGLC) between drug concentration and effect. and regional GLC (rGLC) to focus on Totally drug-resistant (see XDR-TB): monitoring and technical assistance to Point-of-Care testing (POC): Testing The term ‘totally drug-resistant TB’ national TB programmes in countries at the point-of-care means that was used in 2011 for a group of and WHO. diagnosis is carried out as close as patients in India who presented with possible to the site of patient care. resistance to all known TB drugs they Microscopy: Currently the most The driving notion behind point- were tested for. It is a term widely by commonly used technique to diagnose of-care testing is having a test as the media, but is not recognised by TB. Two to three sputum samples convenient to the patient as possible WHO, after a decision taken during a are taken from the patient, with the which gives immediate results that can meeting in 2012 to discuss the term. sample stained and later read under lead to prompt initiation of treatment. the microscope. If TB bacilli are These cases are defined as extensively Pulmonary TB: Form of TB where present, they will appear highlighted drug-resistant tuberculosis (XDR-TB), M. tuberculosis bacteria infect the lungs. from the rest of the sample. according to WHO definitions. QT Interval: In cardiology, the QT MDR-TB: ‘Multidrug-resistant TB’. US FDA: United States Food and Drug interval is a measure of the time Strains of TB that are resistant to (at Administration. between the start of the Q wave and least) the two most powerful first- the end of the T wave in the heart’s WHO Prequalification (PQ): The line drugs used to treat TB, namely electrical cycle. This represents the Prequalification Programme, set up rifampicin and isoniazid, are said to total duration of electrical activity of in 2001, is a service provided by the be multidrug-resistant TB, or MDR-TB. the ventricles. A prolonged QT interval World Health Organization (WHO) to is a biomarker of life-threatening Mycobacteria: Types of bacteria, of facilitate access to medicines that meet ventricular tachyarrhythmias – the genus Mycobacterium, which including torsdes de pointes. unified standards of quality, safety cause diseases such as TB and leprosy. and efficacy for HIV/AIDS, malaria and Second-line drugs: Second-line drugs M. Tuberculosis: A pathogenic bacterial tuberculosis. Please consult are used when first-line drugs are no http://apps.who.int/prequal/ species of the genus Mycobacterium longer effective to cure a patient. In and the causative agent of most cases the case of tuberculosis, they are less w/w – Percentage weight/weight: of TB. First discovered in 1882 by effective and have many more side- A form of measurement written as Robert Koch. effects than first-line drugs. x% w/w that indicates the amount of New Drug Application (NDA): An Stringent regulatory authority solute (as liquid, granules, powder, etc) application to the US FDA to register (SRA): A regulatory authority that needs to be dissolved – usually in a new drug for marketing approval; which meets criteria principally 100mg or mL amounts – to achieve this can only occur once the drug through membership of, or links the desired solution strength. For meets requirements on quality, to, the International Conference of example, a solution written as 20% safety, and efficacy. The application Harmonization (ICH). Please consult w/w will mean 20g or 20mL dissolved http://www.ich.org must contain data from specific in 100mL of water. technical viewpoints for review, TB Alliance: The TB Alliance is a XDR-TB (Extensively drug-resistant TB): including chemistry, pharmacology, not-for-profit, product development medical, biopharmaceutics, and partnership accelerating the discovery Strain of MDR-TB that also shows statistics. If the NDA is approved, and development of new TB drugs resistance to second-line drugs, the product may be marketed (sold) that will shorten treatment, be including at least one fluoroquinolone in the United States. effective against susceptible and drug and one injectable drug.

44 Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease | November 2012 Acknowledgements:

MSF and The Union wish to thank manufacturers and the Global Drug Facility (particularly Tom Moore) for sharing price information for this publication.

Front cover photo: © Natalia Sergeeva / MSF

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 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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