DR-TB DRUGS UNDER THE MICROSCOPE SOURCES AND PRICES FOR DRUG-RESISTANT TUBERCULOSIS MEDICINES 4th Edition – March 2016

www.msfaccess.org THE MSF ACCESS CAMPAIGN In 1999, on the heels of Médecins Sans Frontières (MSF) being awarded the Nobel Peace Prize – and largely in response to the inequalities surrounding access to HIV/AIDS treatment between rich and poor countries – MSF launched the Access Campaign. Its sole purpose has been to push for access to, and the development of, life-saving and life-prolonging medicines, diagnostics and vaccines for patients in MSF programmes and beyond.

MSF has been involved in tuberculosis (TB) care for 30 years, often working alongside national health authorities to treat patients in a wide variety of settings, including chronic conflict zones, urban slums, prisons, refugee camps and rural areas. MSF’s first programmes to treat multidrug-resistant TB opened in 1999, and the organisation is now one of the largest NGO treatment providers for drug-resistant TB. In 2014, the organisation treated over 23,000 patients with TB, including 1,800 patients with drug-resistant TB.

LATEST RESOURCES FROM MSF ON TB Out of Step (2015): TB policies in 24 countries Out of Step presents the results of a survey of 24 countries conducted by Stop TB Partnership and MSF, tracking the latest TB policies, guidelines and tools across five areas. The results of this survey provide a snapshot of the world’s readiness to defeat the TB epidemic.

www.msfaccess.org/content/report-out-step-2015-tb-policies-24-countries

Ready, set, slow down The first new TB drugs in decades have received conditional regulatory approval, but remain largely out of the reach of patients. MSF looks at accessibility of five key drugs: bedaquiline, delamanid, imipenem/cilastatin, clofazimine and linezolid.

www.msfaccess.org/content/ready-set-slow-down

Out Of Step (2014): Deadly implementation gaps in the TB response Based on a survey of eight high TB burden countries, MSF’s research reveals that efforts to control the epidemic are dangerously out of step with international recommendations and proven best practices, leaving drug-resistant forms of TB to spread unabated.

www.msfaccess.org/content/out-step-deadly-implementation-gaps-tb-response

Médecins Sans Frontières | March 2016 TABLE OF CONTENTS TABLE OF CONTENTS

DR-TB DRUGS UNDER THE MICROSCOPE Sources and prices for drug-resistant tuberculosis medicines 4th Edition – March 2016

SUMMARY ANALYSIS 2 Introduction 3 DR-TB drug and regimen pricing trends 6 Barriers to access for key DR-TB drugs 9 The road to better treatment and new regimens 12 Policy recommendations

13 Methodology

DRUG PROFILES GROUP TWO: INJECTABLES 14 Amikacin 16 Kanamycin 18 Capreomycin

GROUP THREE: FLUOROQUINOLONES 20 Moxifloxacin 22 Levofloxacin

GROUP FOUR: ORAL BACTERIOSTATIC SECOND-LINE AGENTS 24 Ethionamide 25 Prothionamide 26 Cycloserine 28 Terizidone 30 PAS and PAS-sodium

GROUP FIVE: AGENTS WITH UNCLEAR EFFICACY 32 Clofazimine 34 Linezolid

NEW DRUGS: 36 Bedaquiline 38 Delamanid

ANNEXES 40 Annex 1: Summary table of all prices 41 Annex 2: Conditions of offer, as quoted by companies 42 Annex 3: Company contacts 43 References 46 Abbreviations 47 Glossary

DR-TB Drugs Under the Microscope 1 INTRODUCTION

This report – now in its fourth edition – analyses the barriers and factors affecting access to treatment regimens for drug-resistant tuberculosis (DR-TB), including new and repurposed drugs. We provide detailed pricing profiles of key DR-TB drugs, using manufacturer responses INTRODUCTION to standardised questionnaires and the Global TB Drug Facility website.

Access to successful DR-TB additional barriers to accessing DR-TB DR-TB markets by streamlining the treatment remains low. World Health drugs beyond their prices, including a number of second-line drug options Organization (WHO) reports that lack of registration in many countries, recommended, in line with medical only half of notified MDR-TB patients not being included on national outcomes, so that the market isn’t were successfully treated and cured Essential Medicine Lists (EML) and unnecessarily split. Data from ongoing in 2014, using routine treatment.1 a lack of appropriate country-level and pending clinical trials should help Encouragingly, early results from MSF guidance for programmatic use.3 inform decisions to cull certain drugs and other implementers’ operational Even when it is possible to procure that have onerous side effects while research in treating extensively drug- the needed drugs, they may not be offering little benefit to patients, and resistant (XDR) TB using the new indicated for TB use (e.g. linezolid and should help with fast-tracking other drugs, bedaquiline and delamanid, clofazimine), which contributes to a new and repurposed drugs that can in combination with promising reluctance on the part of national TB improve patient outcomes. GDF could repurposed drugs, indicate that much programmes to incorporate the drugs better consolidate demand if there higher cure rates can be achieved into national protocols that would were fewer second-line drug options. than with existing regimens (culture enable wider access. WHO and experts should also work conversion rates between 75% and with manufacturers to better forecast 97% are seen2, compared to 26% demand of streamlined drug options. with existing regimens1). However, a With more countries relying upon few years after these two new drugs STOP PRESS domestic funds to purchase TB and – bedaquiline and delamanid, the first This report went to print just DR-TB medicines, the Global Fund new drugs in nearly half a century – before the Global Drug Facility to Fight AIDS, Tuberculosis and were conditionally approved to treat was due to update its prices for Malaria (GFATM) should implement TB, barely two percent of those who DR-TB drugs by 1 April 2016, clear transition strategies to ensure could benefit from these treatments once the yearly manufacturer countries can secure the purchase have access to them.2 WHO also consultation was finalised. For of quality-assured first- and second- reports on a deadly and persistent the most up-to-date information line TB medicines, even after they diagnostic gap: among estimated on GDF prices for DR-TB drugs, graduate from support. The GDF DR-TB cases, only about a quarter of please consult the Global Drug should explore ways to evolve its people were diagnosed in 2014.1 Facility, www.stoptb.org/gdf/ business model in order to bid in TB is now the leading infectious drugsupply/drugs_available.asp national public tenders for countries disease killer worldwide and there is that purchase outside of the GDF. For a critical need for more effective and countries purchasing outside of the more affordable DR-TB treatment To increase the chance of a cure for GDF, the importance of continuing to regimens. Despite individual drug people with DR-TB, the deadly gaps procure and use quality-assured drugs price decreases, overall regimen in diagnosis and access to effective, is vital. By publishing pricing data in prices remain a barrier to sufficient affordable, tolerable treatment options this report, we hope to contribute treatment scale up. The price for to countries’ ability to negotiate the must be closed. DR-TB regimens that can be obtained lowest procurement price possible from the Global Drug Facility (GDF), A smarter DR-TB medicines market for quality-assured DR-TB drugs. range from US$1,023a – $4,646b can help. This requires having Countries that are able to obtain for the lowest-priced regimens, as enough quality-assured suppliers to affordable, sustainable access to of February 2016. The full price of meet demand and to foster price- needed DR-TB drugs have a better preferred DR-TB regimens range from lowering competition. WHO and chance of reducing the growing about $1,800c to $4,600d. There are experts can contribute to smarter number of DR-TB cases.

a. Regimen of 8 months with amikacin, ethionamide, cycloserine, levofloxacin and 16 months of ethionamide, cycloserine, levofloxacin. b. Regimen of 12 months capreomycin, prothionamide, cycloserine, moxifloxacin, PAS and 12 months prothionamide, cycloserine, moxifloxacin, PAS. c. Regimen of 8 months capreomycin and 24 months of cycloserine, ethionamide, moxifloxacin and pyrazinamide. d. Regimen of 8 months capreomycin and 24 months of PAS, ethionamide, moxifloxacin and pyrazinamide.

2 Médecins Sans Frontières | March 2016 DR-TB DRUG AND DR-TB DRUG AND REGIMEN PRICING TRENDS REGIMEN PRICING TRENDS

CURRENT PRICES: IMPROVEMENTS, BUT CHALLENGES PERSIST

Recent reductions in the prices of most A key factor in DR-TB drug price are now more manufacturers of the DR-TB drugs have brought preferred decreases is the joint GFATM-GDF active pharmaceutical ingredients (API), regimen prices down to a range of Expert Review Panel mechanism, contributing to the drug’s lower price. about $1,800-$4,600 per treatment which since 2009 has been successfully Notable exceptions to the trend of course (without any Group 5 or new attracting new manufacturers of drugs included) (see Table 1). This is quality-assured DR-TB medicines to decreasing drug prices are clofazimine, a marked improvement compared to the market. Competition from generic amikacin, prothionamide and our first Under the Microscope report in manufacturers of quality-assured finished ethionamide, whose prices have 2011, when drugs procured through products has reduced prices for linezolid, remained steady, and kanamycin the Green Light Committee (GLC)/ capreomycin, and levofloxacin (See and PAS-sodium, whose prices have GDF cost between $4,400 and almost Table 2). Additional drivers of price increased since 2013. Additionally, $9,000 per patient for a standard 18- reductions of DR-TB drugs over the some countries – especially middle- 24 month treatment course.4 However, past three years vary. For example, income countries – that purchase at up to $4,600 per treatment course, higher order volumes helped reduce outside of the GFATM-GDF mechanism DR-TB treatment regimens are still the lowest global price of DR-TB drug may still lack the competitive markets unaffordable, limiting countries’ linezolid. In the case of cycloserine, while of multiple manufacturers needed to abilities to respond to the growing the number of manufacturers of the access similarly low prices. (See Box: spread of drug resistance. finished product remains the same, there Spotlight on linezolid in South Africa.)

TABLE 1: 2015 PRICES FOR DR-TB DRUG REGIMENS*

Lowest unit price Highest unit price Lowest cost for Highest cost for Regimen dose for a quality-assured for a quality-assured regimen (US$) regimen (US$) source (US$) source (US$) 1 pill a day for Capreomycin 1g vial 3.80 912.00 8.00 1920.00 8 months 3 pills a day for Cycloserine 250mg capsule 0.19 403.92 0.60 1296.00 24 months 3 pills a day for Ethionamide 250mg tablet 0.06 133.92 0.10 211.68 24 months 1 pill a day for Moxifloxacin 40mg tablet 0.44 314.64 0.66 475.20 24 months 4 pills a day for Pyrazinamide 400mg tablet** 0.02 55.58 0.02 67.68 24 months

Total cost 1820.06 3970.56

By replacing cycloserine with PAS, the price changes to…

PAS 4g sachet / 2 sachets a day PAS-sodium 60% w/w 1.31 1919.52 1.69 1919.52 for 24 months granules 9.2g sachet

Total cost 3335.66 4595.08

* Prices sourced from MSF questionnaire sent to manufacturers, September 2015, and from the April 2015 GDF catalogue for TB drugs. **  Price obtained from GDF catalogue

DR-TB Drugs Under the Microscope 3 TABLE 2: KEY DR-TB DRUGS PRICE TRENDS

Change in lowest identified Drug Presentation Change in # of manufacturers from 2013 price from 2013 to 2015 ▲ number of finished product manufacturers by 3 Capreomycin 1g powder vial ▼by 24% (5 manufacturers in 2015) ▲ number of finished product manufacturers by 1 (3 manufacturers in 2015. In January 2016, this figure Linezolid 600mg tablet ▼by 22% went back to 2, awaiting the final assessment of the WHO Prequalification Programme for one source) No change in number of finished product Levofloxacin 250mg tablet ▼by 16% manufacturers (5 manufacturers in 2015) * No change in number of finished product Levofloxacin 500mg tablet ▼by 25% manufacturers (5 manufacturers in 2015) * ▲ number of API sources by 2 (3 sources for Cycloserine 250mg capsule ▼by 52% cycloserine API in 2015)

* The cause(s) of price drops for levofloxacin are unknown, but it is possible that these result from an increased demand for the drugs, either for a TB indication or for other uses. DR-TB DRUG AND REGIMEN PRICING TRENDS

SPOTLIGHT ON ACCESS TO LINEZOLID IN SOUTH AFRICA

Multiple studies have shown that Control Council (MCC), registered $62 (ZAR855) per pill, while Hetero’s inclusion of linezolid in the treatment pharmaceutical company Hetero’s product cost about $47 (ZAR655) of XDR-TB, including for people co- generic linezolid. The Hetero per pill.7 Public sector prices offered infected with HIV, improves culture product is marketed in South Africa by the two suppliers are discounted, conversion rates and treatment through an arrangement with but remain too high to have been 5,6 outcomes. However in South Sanofi. Pharmaceutical company accepted by national tenders. Africa, high prices charged by a Pfizer’s linezolid product had Further competition is needed to duopoly of suppliers have restricted previously held a monopoly on bring prices down. access, keeping linezolid out of reach the market. However, this limited of many XDR-TB patients. In South Africa, it is significantly competition has not resulted in less expensive for MSF to import In late 2014, at the urging of significant price reductions. As of Hetero’s linezolid through our own patients, clinicians, and civil society November 2015, in the private supply channels, at a price of $7.90 organisations, South Africa’s market, Pfizer was selling a 600mg per pill (ZAR109), than to source regulatory body, the Medicines daily tablet of linezolid for about linezolid at the Sanofi and Pfizer prices offered to South African provinces, which cost 46% to 96% more, respectively.7 South Africa receives support from the Global Fund to Fight AIDS, Tuberculosis and Malaria, has one of the largest TB burdens in the world, and has a high demand for linezolid8; the South African government should be offered prices comparable to the GDF, where linezolid costs between $5.35 and $5.48 per pill.

© MSF Note: All rand to dollar conversions calculated at November 2015 rates.

NOW CURED OF XDR-TB, SIYABULELA QWAKA, 30, WAS AN EARLY RECIPIENT OF A STRENGTHENED TREATMENT REGIMEN CONTAINING LINEZOLID, THROUGH AN MSF-SUPPORTED PILOT PROGRAMME IN KHAYELITSHA, SOUTH AFRICA.

4 Médecins Sans Frontières | March 2016 TARGET PRICES: DR-TB DRUG AND REGIMEN PRICING TRENDS OPPORTUNITIES FOR DRAMATIC FUTURE PRICE DECREASES

MSF believes that the total price for a the Global Fund and other © Lana Abramova full treatment course should be no more non-governmental organisations than $500. However, DR-TB who provide TB care – in providing regimen costs remain high and variable technical support at country level to despite the fact that prices could develop forecasts for DR-TB medicines. potentially be universally much lower Other price-decreasing measures could if they were based on production costs include promoting more competition plus profit margins. A recent study for linezolid suppliers, encouraging developed target price ranges for DR- new generic manufacturers for TB drugs based on estimated costs of clofazimine, and measures to active pharmaceutical ingredients (API), encourage generic production of excipients, formulation, packaging, delamanid and bedaquiline, whether and a reasonable profit margin (a via voluntary licences negotiated by ‘cost-plus’ model).9 The study notes the Medicines Patent Pool or through that treatment courses such as the the use of public health safeguards one used in the nine-month STREAM by governments seeking to foster regimen, also known as the ‘Bangladesh production or access to low-cost regimen’ (see Glossary) (see Box: generic versions. Clinical trials landscape), are currently In February 2016, Otsuka and the priced between just over $800 to more GDF announced a price of $1,700 than $1,800 per treatment course, per treatment course, available to JAYNA, WHO IS 28 AND but could be priced as low as $100- Global Fund-eligible countries through A MOTHER OF THREE, $400 per treatment course based IS BEING TREATED FOR the GDF.31 Given that delamanid on a ‘cost-plus’ model (see Table 3). XDR-TB IN THE RUSSIAN is just one drug that needs to be For the individual drugs clofazimine, FEDERATION. FIRST combined with multiple other drugs linezolid, bedaquiline, delamanid, and DIAGNOSED WITH TB to form a DR-TB regimen, this price is IN 2008, JAYNA HAS moxifloxacin, the estimated ‘target’ prohibitively expensive for most high- HAD SEVERAL RELAPSES prices per patient per month (pppm) burden MDR-TB countries and not SINCE. THIS TIME, HER that could be achievable with robust all high burden countries are eligible TREATMENT INCLUDES generic competition are listed below, BEDAQUILINE, AND for this price. In addition to the high along with the current price available AFTER JUST ONE WEEK, price, the registration of delamanid from GDF. SHE STARTED TO remains an issue; without broad FEEL BETTER. SHE To move closer to these targets we registration and an affordable price IS TOLERATING THE need better drug forecasting at country by the company, it will be difficult for TREATMENT WELL AND level. WHO and GDF could play a countries to scale up treatment of DR- IS EXPERIENCING NO leading role in promoting harmonised TB and ensure the people who need SIDE EFFECTS. approaches across actors – including this drug can receive it.

TABLE 3: TARGET VS. CURRENT PRICES FOR KEY DR-TB DRUGS

Clofazimine Linezolid Bedaquiline Delamanid Moxifloxacin Target price range 6.20-16.40 4.90-12.80 8.80-16.40 3.50-8.60 3.50-9.40 (pppm US$)* Current lowest GDF 66 161 150 283.33 13 price (pppm US$)

* Price per patient per month. Source: Gotham D et al. Target generic prices for novel treatments for drug-resistant tuberculosis. 15th European AIDS Conference, Barcelona, abstract PS2/4, October 2015.

DR-TB Drugs Under the Microscope 5 BARRIERS TO ACCESS FOR KEY DR-TB DRUGS

In addition to price barriers, several other factors impede access to new TB drugs and repurposed drugs developed for other indications that have been proven, or are thought to be, effective against TB. Barriers include a lack of clinical data, a lack of registration in countries, and a lack of a TB indication.

NEW DR-TB DRUGS

LONG-AWAITED CLINICAL TRIAL RESULTS

Bedaquiline (marketed by Janssen) and STREAM trial10 looking at the efficacy has not started despite being planned delamanid (marketed by Otsuka) were of shorter treatment regimens, has yet since 2014.11 To compensate for conditionally approved in 2012 and to commence. the lack of manufacturer-initiated, 2013 respectively based on their phase regimen-based clinical research, IIb clinical data, but completion and Also of great importance are the a number of trials run by NGOs, results of a long-awaited drug-drug BARRIERS TO ACCESS FOR KEY DR-TB DRUGS publication of phase III data are still including MSF, and other non-profit critically important. Delamanid’s phase interaction study (AIDS Clinical Trials product development partnerships are III clinical trial completed enrolment in Group’s A5343 trial), to examine underway or planned to test new DR- November 2013, with results expected possible effects of the two new drugs TB regimens containing bedaquiline in 2017. Bedaquiline’s phase III clinical on the heart (QT prolongation, see or delamanid12 (see Box: MDR-TB trial, which expands on the existing Glossary for additional details), which Clinical Trial Landscape).

MSF OPERATIONAL EXPERIENCE MSF reports positive clinical patient outcomes with bedaquiline-containing regimens and repurposed drugs in Armenia and Chechnya, Russian Federation, where we are supporting some of the largest cohorts of XDR-TB patients receiving bedaquiline in the world. Between April 2013 and March 2015, 60 patients received bedaquiline from MSF in Armenia. In the cohort of 38 patients who started before July 2014, 24 (80%) displayed sputum culture © Lana Abramova conversion at six months; in Chechnya, 27 out of 36 (75%) MSF patients who have completed six months of treatment are culture negative. Serious I don’t know why I got tuberculosis, adverse events were reported in four patients in people here in the mountains don’t get the Armenian cohort, one attributed to bedaquiline tuberculosis. I could hardly tolerate the QT effects without clinical consequences for the treatment. I was nauseous, I vomited patient, who completed bedaquiline treatment. and couldn’t eat. I survived by miracle, I Similarly successful culture conversion rates were thought I was going to die. But after eight reported for non-MSF compassionate use cohorts months the new drugs appeared and Dr in France and South Africa (97% and 77%, Animesh said: ‘You should take these respectively).13 Additional information from the drugs, you won’t die’. He’s a good doctor. cohort in South Africa demonstrated similar safety Thanks to all of them I recovered. and efficacy even when bedaquiline was given in SAPIKHAT, 53, TALKS ABOUT HER TREATMENT FOR combination with antiretroviral therapy (ART) to XDR-TB, WHICH INCLUDED BEDAQUILINE. SHE LIVES TB/HIV co-infected people (59.3% of the cohort WITH HER HUSBAND, A TEACHER, AND THEIR THREE were TB/HIV co-infected), another sign that CHILDREN IN A REMOTE MOUNTAIN VILLAGE IN CHECHNYA. SAPIKHAT PREVIOUSLY ENDURED MULTIPLE bedaquiline has the potential to transform DR-TB HOSPITALISATIONS AND LUNG SURGERY TO TREAT HER treatment in the coming years.14 TB; SHE NOW RECEIVES AMBULATORY CARE.

6 Médecins Sans Frontières | March 2016 BARRIERS TO ACCESS FOR KEY DR-TB DRUGS

SLOW SCALE UP OF ROUTINE AND COMPASSIONATE USE OF NEW DRUGS

Outside of clinical trials, approximately be affordable and available in country. DR-TB patients on bedaquiline- 700 patients have accessed bedaquiline These are not insurmountable hurdles containing regimens, the 3,000-patient through compassionate use and about and a number of countries are taking target should be achievable in 2016, 2,300 have received bedaquiline as strides to ensure that patients have the with even more ambitious numbers part of routine use as of January 2016. opportunity to access the new drugs, feasible in the future. Only about 180 patients have received particularly bedaquiline. Bedaquiline has been granted delamanid outside clinical trials.15 South Africa has committed to treating conditional or full marketing It is critical that new drugs 3,000 DR-TB patients per year with authorisation by the National Medicine be incorporated into routine, regimens including bedaquiline;16 Regulatory Agency (NMRA) in nine of programmatic DR-TB treatment however, this target was not met the 27 high MDR-TB burden countries, protocols. There is clear guidance from in 2015, with just 1,009 patients and submission is pending in nine WHO regarding how to incorporate starting treatment with bedaquiline others. In the case of delamanid, bedaquiline and delamanid into the during the year, as of November Otsuka has received conditional routine management of patients with 2015. This is in part due to a delayed approval or full marketing authorisation DR-TB. For this to become a reality, transition between Janssen’s national in Japan, South Korea, and in Europe there are some important barriers compassionate use programme, by the European Medicines Agency, that need to be addressed: the drugs which ended in December 2014, and but delamanid is not registered in need to be registered in country, with standard procurement by provinces. any high burden countries, including countries allowing import waivers Free access to bedaquiline through four countries considered to have a in the meantime; countries need to compassionate use ended before high burden of MDR-TB where Otsuka update their treatment guidelines to provinces had managed to adequately carried out clinical trials with the reflect the WHO recommendations; plan for the cost of bedaquiline in drug. To date, it has not been possible adequate pharmacovigilance systems annual budgets,17 leading to several for countries to plan for widespread need to be introduced; and the months’ delay in starting new patients programmatic use of delamanid due to accompanying drugs needed to form on treatment. As more facilities in a lack of registration and the lack of a a regimen with the new drugs need to South Africa gain experience initiating system to procure the drug for use.

DRUG DONATION PROGRAMMES FOR BEDAQUILINE AND DELAMANID Janssen and Otsuka have announced drug donation programmes for bedaquiline and delamanid, respectively. In December 2014, USAID and Janssen Therapeutics announced a donation programme for bedaquiline, with the official agreement signed in March 2015. The terms of this agreement specify that 30,000 treatment courses will be donated over a four-year period to more than 100 Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-eligible low- and middle-income countries through Stop TB Partnership’s Global Drug Facility (GDF).18 In October 2015, USAID announced Georgia as the first recipient of donated bedaquiline.19

Not all countries are eligible for these donations, however. For example, South Africa is ineligible, and there appears to be a quota on the number of treatments to be supplied to Commonwealth of Independent States (CIS) countries through the drug donation programme.

In April 2015, Otsuka announced its “FighTBack Initiative” to provide donations of delamanid to 20% of diagnosed MDR-TB patients by 2020.20 Despite requests for additional details about the programme, little information is publicly available eleven months later. Based on the joint announcement with GDF at the end of February 201631, it remains unclear how Otsuka will implement this donation.

MSF advocates for fair commercial terms for medicines and avoids medical products donations wherever possible. However, faced with a lack of an alternative source of delamanid for patients in our TB treatment programmes, MSF exceptionally accepted a donation of 400 treatments of delamanid from Otsuka. MSF maintains that medical product donation programmes are not a solution to access challenges and present a number of complications for sustainable access to essential medicines.21

DR-TB Drugs Under the Microscope 7 DRAWBACKS OF MEDICAL PRODUCTS DONATION PROGRAMMES

There are a number of reasons why excluded from programmes for preventing competitive generic donations fail to ensure sustainable reasons that are irrelevant to markets from emerging. access to medical products, which is public health needs. Temporary ‘solution’: widely acknowledged by medicines Burdensome requirements Donations may temporarily purchasers like MSF, international for recipients: Programmes reduce public pressure around organisations like WHO, and in may impose added logistical the underlying access problems, academic literature. Below are some of the key points of concern and operational burdens to making it harder to expand regarding drug donations: strained health systems with access to the drug in the future. onerous requirements concerning Additionally, donations are Unsustainability: Continued pharmacovigilance, monitoring, usually time-limited, so they are donations are entirely dependent evaluation, etc. inherently not durable solutions. on the choices of the donor. Time delays: Lengthy donation Potential distortion of rational Insufficient scale: In general, negotiations may prolong the use: Donated, but less effective, donations can only meet a fraction period in which patients cannot medicines may be used over more of a country’s disease burden. access the medicine. effective medicines. Indication restrictions: Drug

BARRIERS TO ACCESS FOR KEY DR-TB DRUGS Costs incurred by recipient Market priming: Donor recipients indications may be overly narrow, countries: Recipients often must may be pressured to purchase a preventing countries from using bear the costs of sorting, storing, drug from the donor once the drugs in ways that meet public distributing, and potentially donation has ended. health objectives. destroying expired donated Disincentivising future Inadequate consultation with medicines, ironically making biomedical R&D: Other firms recipient countries: Donations ostensibly free drugs quite costly. may be disincentivised from may not meet the public health Anti-competitive impacts engaging in future research and needs of recipients. on drug markets: Generic development to create improved Country eligibility concerns: manufacturers may be dissuaded medicines for lack of a viable Potential recipients may be from entering a recipient country, commercial market.

REPURPOSED DR-TB DRUGS Group 5 drugs (clofazimine, linezolid, not listed on the WHO EML as a TB in any country due to the lack of imipenem/cilastatin) show promise medicine, it is included in the WHO official indication. Clofazimine is in treating DR-TB but still lack DR-TB Prequalification Programme’s invitation not registered anywhere with a indications and conclusive clinical to manufacturers of API and Finished TB indication23, although it may data, which leads to problems Pharmaceutical Products in reference be registered by 2020 in the US, registering, procuring, importing, to second-line anti-tuberculosis following the US Food and Drug and dispensing these drugs for medicines.22 This should be understood Administration’s review of an orphan off-label use.13 by generic manufacturers as an drug filing and specific clinical trials incentive to develop clofazimine by Novartis. Without a registered TB MDR-TB INDICATED DRUGS products, and to pursue WHO indication, countries may be reluctant ON THE WHO ESSENTIAL prequalification or registration by a to incorporate Group 5 drugs into MEDICINES LIST stringent regulatory authority (SRA), national TB management guidelines, as required by the GFATM. and may even face challenges In April 2015, WHO released the purchasing the drug for DR-TB use. 19th edition of its Essential Medicines Both of these medicines should be List (EML). For the first time, this INDICATION AND REGISTRATION registered with TB indications as EML includes MDR-TB indications for CHALLENGES soon as possible, with a particular bedaquiline, delamanid, and linezolid, emphasis on registration in high MDR- which should spur governments Another major access problem is the TB burden countries. In the interim, to update their national EMLs.13 A severely limited national registration countries should consider granting thorough literature review allowed of repurposed DR-TB drugs. For import waivers for these medicines experts to justify the addition of example, while linezolid may be that are still unregistered nationally, linezolid to the WHO EML with a registered in some countries for whenever manufacturers obtain either TB indication, despite the lack of other antibiotic-resistant Gram- WHO Prequalification Programme registered indication for this particular positive bacterial infections, it cannot approval or registration by a stringent disease. Although clofazimine is still be registered with a TB indication regulatory authority (SRA).

8 Médecins Sans Frontières | March 2016 THE ROAD TO BETTER THE ROAD TO BETTER TREATMENT AND NEW REGIMENS TREATMENT AND NEW REGIMENS

Treatment of DR-TB is on the cusp of manufacturers to ensure sufficient For example, Group 4 contains drugs change, with multiple new drug trials supply for clofazimine, linezolid and from the same class, prothionamide and planned or underway (see Box: MDR- other promising drugs. ethionamide, which are both thioamides24 TB Clinical Trial Landscape). Given the and for which there is very little evidence opportunity for improvement, WHO There are numerous potential regimens to support the use of one over the other. should further improve regimens by to treat DR-TB using drugs from four This same issue occurs with Group 4 drugs streamlining recommended treatment groups (Groups 2–5). While some level cycloserine and terizidone which are also options, moving away from using of customisation is needed to ensure in the same class of antibiotic. Both drugs injectable agents and drugs with that the patient receives the best are recommended in the WHO guidance poor side effect profiles (such as regimen for their resistance pattern, too but there is a note that terizidone has PAS, ethionamide and cycloserine), much variation leads to fragmentation limited programme and effectiveness data and proactively working with of an already small market.e compared to cycloserine.

MDR-TB CLINICAL TRIAL LANDSCAPE

A number of clinical trials are month regimen replaces kanamycin South Africa, Tanzania and Uganda. planned or underway to assess with bedaquiline to give an all-oral Recruitment has been completed.26 combinations of repurposed and regimen for MDR-TB. Enrolment is STAND Trial: A phase III study new TB drugs for optimal treatment expected to begin in March 2016. to assess the efficacy, safety regimens.12 These include: NEXT Trial: This phase III trial is and tolerability of a six-month STREAM I Trial: This is a USAID- currently enrolling participants combination of moxifloxacin, funded, Union-sponsored and in South Africa to evaluate a new pretomanid and pyrazinamide in Medical Research Council treatment regimen for patients with subjects with MDR-TB. Also has a UK-implemented randomised MDR-TB through an open-label, DS-TB arm with the same regimen, clinical trial looking at a nine- randomised, controlled trial of a six- but for a shorter duration. Recruitment month combination of existing to nine-month injection-free regimen is currently suspended.27 TB drugs for the treatment of containing bedaquiline, linezolid, MDR-TB.25 The study regimen levofloxacin, ethionamide/high dose TB-PRACTECAL Trial: MSF is is ethambutol, pyrazinamide, isoniazid, and pyrazinamide. sponsoring this phase II-III trial, which intends to evaluate the safety moxifloxacin and clofazimine NiX TB Trial: This phase III open-label and efficacy of short treatment throughout, supplemented study assessing the safety and efficacy regimens containing bedaquiline by kanamycin, prothionamide of bedaquiline given only with other and pretomanid in combination and high-dose isoniazid in the new drugs (pretomanid and linezolid) with existing and repurposed TB first four months. Participating to patients with XDR-TB or treatment drugs for adults with MDR-TB, in patients are randomised to the intolerant/non-responsive MDR-TB, partnership with the London School STREAM regimen or the optimised including patients co-infected with of Hygiene and Tropical Medicine background MDR-TB regimen. The HIV, is recruiting participants in trial includes patients co-infected South Africa. and other leading international with HIV. Trial countries include research organisations. Recruitment Ethiopia, Mongolia, Vietnam and GATB NC-005 Trial: This phase II is planned for spring 2016, South Africa25 and the results may open-label partially randomised beginning in Uzbekistan.28 be ready by 2018. trial to evaluate the efficacy, safety and tolerability of combinations endTB Trial: MSF is collaborating STREAM II Trial: This phase III trial of bedaquiline, pretomanid and with Partners in Health (PIH) and compares six-month and nine-month pyrazinamide during eight weeks Interactive Research & Development bedaquiline-containing regimens of treatment in adults with newly (IRD) as part of the ‘endTB project’, against the WHO recommended diagnosed drug-sensitive TB (DS-TB), which will evaluate five experimental and STREAM I regimens. The six or bedaquiline, moxifloxacin, regimens containing bedaquiline month regimen adds bedaquiline to pretomanid and pyrazinamide for and/or delamanid by enrolling 750 the STREAM I regimen and the nine MDR-TB recruited participants, in participants in five countries.29

e. This fragmentation may be further exacerbated by duplicative options. In these cases, if the clinical evidence for these drugs is similar, there may be a positive market impact on recommending only one drug, thereby consolidating the market and allowing economies of scale that may help to reduce prices.

DR-TB Drugs Under the Microscope 9 3P PROJECT

Today, finally, there is a relatively with unaffordable single drug end incentivises R&D through the robust late-stage TB drug pipeline products. For TB this means that promise of financial rewards if certain with several drugs showing the early pipeline is weak and large objectives are met (i.e. through promising results. Nevertheless, companies are withdrawing from prizes); and 3. The project pools the TB research and development TB R&D due to a perceived lack resulting intellectual property (IP) to (R&D) pipeline’s potential to of a market. This is why MSF and ensure open collaborative research deliver therapeutic solutions for TB partners propose the 3P (Push-Pull- and fair licensing for competitive and DR-TB remains insecure. The Pool) Project, to deliver affordable, production and affordability of the challenges of TB drug and regimen effective new TB treatment regimens final products. Changing the model 30 development persist, in large part, faster. The 3P Project uses an open by which TB drugs are promoted and due to the way that drugs are collaborative approach to drug paid for can result in major public financed and incentivised. development, and novel approaches health gains with more efficiently to financing and coordinating R&D and affordably developed treatment Relying on monopoly-based rewards through three key features: 1. The regimens of new drugs, which can to spur innovation discourages project pushes upfront funding to be used in combination and without information sharing, promotes finance R&D activities (i.e. through deadly delays. Learn more about the inefficient duplication and leaves us grants); 2. The project pulls or 3P Project at: www.msfaccess.org/3P

I was told that if THE ROAD TO BETTER TREATMENT AND NEW REGIMENS THE ROAD TO BETTER TREATMENT I followed treatment, I would get cured. So I tried to follow treatment, I took medicines, I had intravenous fluids. I followed treatment strictly. But the medicines produced side effects, all my bones ached because of these pills, I had an allergy.

MOVSAR, 49, FROM NOVYE ATAGI, CHECHNYA, DESCRIBES HIS STRUGGLES WITH MDR-TB TREATMENT. DESPITE BEING TREATED FOR TB IN 2010 AND MDR- TB IN 2011, MOVSAR WAS DIAGNOSED WITH XDR-TB IN 2014. HE WAS ONE OF MSF’S FIRST PATIENTS TO BE TREATED WITH BEDAQUILINE. DESPITE BEING DIABETIC, MOVSAR TOLERATES THE NEW TREATMENT WELL AND HAS © Lana Abramova IMPROVED CONSIDERABLY.

10 Médecins Sans Frontières | March 2016 THE ROAD TO BETTER TREATMENT AND NEW REGIMENS

TABLE 4: ACCESS STATUS AND RECOMMENDATIONS FOR KEY DR-TB DRUGS

Bedaquiline Delamanid Clofazimine Linezolid Yes, but for leprosy (WHO has been WHO EML Yes for DR-TB Yes for DR-TB in discussion with Yes for DR-TB Novartis since 2008 to address indication) • Conditional approval • Conditional approval • Broader recommendation • Restricted use than Bdq (includes pre-XDR/XDR Not registered for TB Not registered for TB in Registration MDR-TB with an increased in any country any country • Registered in 9, risk of poor outcome) pending in 9, of 27 • Reg. in Japan, Europe, high burden countries S. Korea Indication limited Indication DR-TB DR-TB No TB indication to leprosy $66 (procured on a Lowest $150 per patient, per $283.33 pppm named-patient basis $161 pppm global price month (pppm) only) 100mg pppm • Donation programme launched April 2015 • International donation through USAID/GDF programme (FighTBack) for 30,000 treatment announced in April 2015 courses over 4 years to give access to 20% for all GFATM-eligible of all diagnosed and • Single producer countries. Quota for treated MDR-TB patients of quality-assured CIS countries by 2020; details remain clofazimine • Access in Russia and unclear; • In April 2014, • Secondary patents could select CIS countries via • Access to Global Fund- US FDA agreed preclude importation of low-cost Pharmstandard (ex. eligible countries at one to review a filing under orphan drug generics until 2021 in some Access conditions at $1,351/treatment single public price designation by countries, although likely that course, Feb 2016 for an • Patent barriers Novartis for phase II generic producers will challenge order in Uzbekistan) (compound and clinical trial of Cfz; or ignore the secondary patents • IP barriers until 2029 secondary patents) in could possibly that limit generic place until 2031 that limit lead to registration competition or generic competition or with TB indication development of FDCs development of FDCs by 2020 • Not clear if Janssen will • Slow discussions with engage in bilateral or generic companies Medicines Patent for potential voluntary Pool-led voluntary licence licence negotiations • Otsuka to clarify future • Novartis should • Pfizer, Hetero register Lzd in donation plan(s) in • Proactive plan to move continue pursuing a all high-burden TB countries as the framework of the from donation to TB indication for Cfz a priority FighTBack initiative sustainable, affordable (current outcomes • Quality-assured suppliers offer price ASAP, especially • Otsuka to publish an expected 2020) prices on par with GDF prices to all access plan for non- for MICs • A better price offered high-burden countries that procure Global Fund eligible • A lower, single price to countries linezolid outside of GDF channels countries (e.g. Russian offered to all LICs and • Tech transfer for • Macleods pursue the assessment MICs Federation) and those of its linezolid with WHO PQ transitioning out from API production to • Reduction of IP • Countries update their national Global Fund support (e.g. allow sustained barriers through use of EML with Lzd for TB based on the Georgia) availability; prioritise TRIPS flexibilities or a reformulation to a April 2015 WHO EML update • Reduction of IP barriers voluntary licence that presentation more • Manufacturers pursue a TB through use of TRIPS is negotiated through suited to hot and indication for this drug using the flexibilities or a voluntary Recommendations the MPP humid environments, literature review gathered by the licence that is negotiated • High-burden TB and allowing dosing WHO EML expert committee through the MPP countries’ NMRAs must adaptation • New generics companies (US FDA • Otsuka rapidly pursues prioritise registration • Current and tentatively approved) register Lzd registration in high- • Janssen must prioritise future generic in high burden TB countries burden TB countries and high-burden country manufacturers clinical trial countries; • Civil society and GDF push for registration of active until then Dlm should more competitors to improve pharmaceutical • Rapidly commence be widely accessible affordability and price transparency ingredients and trials looking at through compassionate • A better price offered to countries finished product combining Bdq with use or other early access • Use TRIPS flexibilities to remove of Cfz should other new drugs and in programmes secondary patents in countries pursue WHO shorter regimens where treatment scale up is • Rapidly commence trials prequalification • Rapidly start phase III looking at combining Dlm needed and where secondary • Inclusion on the and paediatric trials with other new drugs and patents may interfere with entry WHO EML for TB in shorter regimens of generics

DR-TB Drugs Under the Microscope 11 POLICY RECOMMENDATIONS

People affected by TB and their treatment providers need affordable access to medicines in the most effective, safe, and tolerable regimens possible. Drug pricing, indication, registration, inclusion in the EML and national treatment guidelines, clinical data gaps, and insufficient R&D persist as barriers to improved and more affordable treatment of this centuries-old, but curable, infectious disease that kills 1.5 million people per year. Governments, donors, drug companies and health actors should be working to solve these challenges for sufficient TB and DR-TB treatment scale up.

AFFECTED COUNTRY THE GLOBAL DRUG PHARMACEUTICAL

POLICY RECOMMENDATIONS POLICY RECOMMENDATIONS GOVERNMENTS SHOULD: FACILITY SHOULD: COMPANIES SHOULD: Scale-up optimal TB and Push for alternative quality-assured Submit for registration Group 5 TB DR-TB treatment, including use supplier(s) for clofazimine (2015-2016); medicines (linezolid, clofazimine, of Group 5 medicines, per WHO imipenem/cilastatin) and new drugs Promote more competition for recommendations; bedaquiline and delamanid in all linezolid suppliers; Register Group 5 TB medicines (linezolid, high-burden countries; Promote best practices on drug clofazimine, imipenem/cilastatin) and Pfizer and Sanofi should immediately new drugs bedaquiline and delamanid, forecasting at country level, in order offer more affordable prices for and in the meantime allow import to provide manufacturers with clearer linezolid in South Africa; waivers for these medicines; volumes to be ordered with the TB Alliance should develop a Update national treatment guidelines objective of driving down prices of compassionate use program for and national EML to match the latest DR-TB medicines; and pretomanid; WHO recommendations; Explore options allowing GDF Offer affordable, sustainable Ensure adequate planning and bidding to national public tenders. funding so that all diagnosed drug- commercial prices, not limited to countries’ income tiers, and where resistant patients (MDR- and XDR-TB) WORLD HEALTH are started on treatment with DR-TB applicable, negotiate non-exclusive, medicines that are compliant with ORGANIZATION SHOULD: broad voluntary licences with the WHO quality standards; Pursue data collection which could Medicines Patent Pool. Problematic donation programmes are not a Set-up adequate regulations for lead to the addition of clofazimine to sustainable answer to access to compassionate use or expanded the WHO EML list (Q1 2017); drugs; and access programmes for new Promote fast track registrations of pre-registered drugs; and Group 5 medicines for TB (e.g. WHO Refer to Table 4 for additional Exercise full use of public health PQ collaborative registration for drug-specific recommendations. flexibilities enshrined in prequalified medicines but also for international intellectual property those registered by SRAs); and CIVIL SOCIETY SHOULD: rules for pharmaceuticals, as well Provide guidance on whether as other measures available to Ensure countries are procuring promote competition and improve Group 4 drugs can be streamlined, quality-assured medications for access and affordability for key such as recommending only one DR-TB programmes; and drug from each class where there DR-TB medicines. Pressure governments to upgrade are currently two drugs in the national policies, including same class. (e.g prothionamide/ THE GLOBAL FUND ensuring that treatment guidelines ethionamide, terizidone/cycloserine). TO FIGHT AIDS, and EML are in line with WHO TUBERCULOSIS AND recommendations. MALARIA SHOULD: DONORS SHOULD: Support countries’ upgrading of Encourage countries to upgrade ALL STAKEHOLDERS national guidelines to meet WHO national TB programmes’ guidelines SHOULD: and national EML to meet WHO recommendations; and Support the 3P Project, an alternative recommendations; and Allow countries to carry on procuring model of TB drug development quality-assured TB medicines at Ensure that DR-TB drugs procured that promotes more efficient, more the lowest possible price once they with donor funding are compliant effective and more affordable TB transition out from GFATM support. with WHO quality standards. treatment regimens.

12 Médecins Sans Frontières | March 2016 METHODOLOGY METHODOLOGY

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

DATA COLLECTION for details, and the Glossary for an Submissions to WHO Prequalification explanation of incoterms. Questionnaires were sent to are confidential and all companies companies listed on the Global Fund mentioned that have a dossier accepted The prices listed in this publication List of Tuberculosis pharmaceutical for review have given MSF the are the ones provided by the products,i producing at least one permission to disclose this information. manufacturers. The prices paid by the anti-tuberculosis product either listed As the information on the WHO List purchaser might be higher because on the WHO List of Prequalified of Prequalified Medicinal Products is of add-ons (such as import taxes and Medicinal Products or approved updated regularly, the list should be distribution mark-ups), or may be iii by a stringent regulatory authority consulted for up-to-date information. (SRA) or temporarily approved by lower after negotiations or as a result Products procured by GDF comply the Expert Review Panel (ERP) of the of effective procurement procedures. with the GDF’s Quality Assurance Global Fund. The data were collected Prices offered by the Global Drug policy.iv This deems eligible for up to September 2015. Facility (GDF) pooled procurement GDF procurement all products that PRICE INFORMATION mechanism are also ‘ex-works’ and are included on the WHO List of correspond to the lowest and highest Prequalified Medicinal Products, Prices are listed where manufacturers prices referenced per medicine on that are approved by a stringent agreed to share information. GDF website.ii Note that prices in the regulatory authority, or that are A number of manufacturers, including: GDF price catalogue can fluctuate approved by the joint GDF/Global • Bayer, Glenmark, Ipca did not wish during the year if, for example, a Fund Expert Review Panel (ERP). to contribute to the publication; long-term agreement with different The ERP is an independent technical • Hisun, Lupin, Meiji, Microlabs, suppliers comes to an end. In body whose purpose is to review Mylan, Novartis, Pfizer, Panpharma, addition, this year a range of prices the potential quality risk of using Reimser-Fatol, Otsuka and Teva did is provided per medicine without medicines which are not yet WHO- not have prices available or did not specific figures per manufacturer. prequalified or authorised by a agree to publish prices; QUALITY INFORMATION stringent regulatory authority, and • no response was received from give advice to the Global Fund and Products that are either listed on the Medochemie; and the Global Drug Facility whether WHO List of Prequalified Medicinal • no contact for Biocom was available. time-limited procurement of such Products or approved by a stringent products can be authorised. The Prices are given in US dollars (US$), regulatory authority are listed in the list of ERP reviewed products for rounded up to the nearest third price tables as ‘approved’. Products tuberculosis can be consulted on decimal point, and correspond to the that are undergoing review by either The Global Fund website.v lowest unit price (i.e. the price of one WHO Prequalification, by a stringent tablet, capsule or vial). When prices regulatory authority, or that have that varied according to packaging been reviewed and listed by the ERP (e.g. blisters or bottle) were received of the Global Fund, are listed in the STOP PRESS from a manufacturer for the same price tables as ‘under evaluation’. This report went to print just formulation, the lowest price was Products that have not yet been before the Global Drug Facility selected. Prices listed are ‘ex-works’ submitted to WHO Prequalification was due to update its prices for except for prices provided by Apotex or to a stringent regulatory authority DR-TB drugs by 1 April 2016, (CIF, Toronto, Canada) - see Annex 2 have not been included. once the yearly manufacturer consultation was finalised. For the most up-to-date information i. http://www.theglobalfund.org/en/procurement/quality/pharmaceutical/ on GDF prices for DR-TB drugs, ii. http://www.stoptb.org/gdf/drugsupply/drugs_available.asp please consult the Global Drug iii. http://apps.who.int/prequal/ Facility, www.stoptb.org/gdf/ iv. http://www.stoptb.org/gdf/drugsupply/quality_sourcing_process.asp drugsupply/drugs_available.asp v. http://www.theglobalfund.org/en/procurement/quality/pharmaceutical/#A_B

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

GENERAL INFORMATION

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

AMIKACIN ( A m As powder for injection – 100mg, treatment of serious infections due to • ATC Code: J01GB06.36 500mg & 1g. susceptible strains of Gram-negative • Included in the WHO Guidelines bacteria, including bacterial septicaemia • First approved by US FDA: The as a Group 2 injectable agent.37 (including neonatal sepsis), serious date of the original New Drug infections of the respiratory tract, • Included in the 19th edition of Application (NDA) is not publicly bones and joints, central nervous the WHO Model List of Essential available on the US FDA website. system (including meningitis) and Medicines23 and in the 5th edition The first Abbreviated New Drug skin and soft tissue; intra-abdominal of the WHO Model List of Essential Application (ANDA) was approved infections (including peritonitis); Medicines for Children.38 on 22 January 1981.39 burns and post-operative infections (including post-vascular surgery).40

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Cadila Cipla Pharmatex Vianex GDF pooled procurement

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

500mg/2ml solution for 0.980 1.600 0.678 2.500 0.678 - 0.805 injection

14 Médecins Sans Frontières | March 2016 MKCN ( A m AMIKACIN

SPOTLIGHT ON ACCESS ISSUES

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

Capreomycin should be used if aminoglycosides are contra-indicated or poorly tolerated; may be effective in cases showing resistance to amikacin and kanamycin.

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

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

GENERAL INFORMATION

• Therapeutic Class: • Presentations available: solution for • Approved indication in the US: Aminoglycoside antibiotic. injection – 1g/4ml. As powder for Kanamycin is indicated in the injection – 1g/vial. short-term treatment of serious 36 • ATC Code: J01GB04. infections caused by susceptible KANAMYCIN ( K m • First approved by US FDA: The date strains of micro-organisms.41 • Included in the WHO Guidelines of the original New Drug Application as a Group 2 injectable agent.37 (NDA) is not publicly available on the US FDA website. The first Abbreviated • Included in the 19th edition of New Drug Application (ANDA) was the WHO Model List of Essential approved on 13 February 1973. 23 Medicines and in the 5th edition The only currently registered of the WHO Model List of Essential product in the US was approved Medicines for Children.38 on 17 November 2002.

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Macleods Meiji Panpharma GDF pooled procurement

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

1g powder for Manufacturer did not 1.000 xx 1.000- 1.721 injection agree to publish prices

1g/4ml solution Manufacturer did not xx xx 2.560 for injection agree to publish prices

16 Médecins Sans Frontières | March 2016 AAYI ( K m KANAMYCIN

SPOTLIGHT ON ACCESS ISSUES

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

Capreomycin may be effective in cases showing resistance to kanamycin.

Number of quality sources GDF as an alternative source in 2010; Suitability for use in In the past, kanamycin formulations however their limited production developing country settings from several different manufacturers capacity means availability of Kanamycin, like other were registered in the US. However, kanamycin is insufficient to cover aminoglycosides and capreomycin, as Fresenius Kabi has discontinued global needs. Further challenges cannot be administered orally and production, only two kanamycin in the production of the active is usually given intramuscularly sources are currently approved by a ingredient occurred in 2015 requiring (IM) but can be given intravenously stringent regulatory authority: Meiji extra manufacturing steps to ensure (IV). This imposes burdens both on (in Japan) and Panpharma (approved the sterility of the API, leading to patients and treatment programmes, in Latvia and Lithuania). Panpharma delays in supply and a 21% increase as qualified staff need to administer and Meiji did not agree to having in the price of the finished product. the product. their prices published. Meiji noted Additional manufacturers exist in Kanamycin is available in both that all supply goes through GDF. China, India, in countries from powder and liquid formulations; the former Soviet Union, and in No sources of kanamycin are the latter is more adaptable other countries, but it is unknown WHO-prequalified, although one to resource-limited settings as whether they comply with WHO manufacturer (Macleods) disclosed reconstitution is not required. that they have submitted a dossier quality standards. Paediatrics for WHO prequalification for the Active Pharmaceutical The safety and efficacy of kanamycin 1g/vial and 500mg/vial formulations Ingredient in children has not been established. which are currently under review. Issues with the production of the A price was available in September API remain a barrier in increasing While dosages are published in several 2015 from Macleods only for the the number of quality-assured guidelines 42,43, there is need for 1g/vial. Two additional sources for sources for the finished product. further research (in pharmacokinetics, 1g/vial and three additional sources Kanamycin API is manufactured pharmacodynamics and safety data) of 500mg/vial are undergoing by a specialised process of into the use of this drug in younger WHO prequalification.33 fermentation. There are few populations, in particular in children The supply of kanamycin remains manufacturers globally who aged under five years. vulnerable, with only two sources have the capacity to produce HIV co-infection (Panpharma and Meiji) available for quality-assured API through this No antiretroviral interaction studies TB procurement, both of which have fermentation process, and the have been performed, but based on experienced production limitations. complexity is further increased pharmacokinetic profiles, the potential Panpharma resolved issues with as the API should be sterile. The for drug interactions are low. active pharmaceutical ingredient quality assurance of the API is a key (API) production which had resulted factor and is often what prevents However, there is potential for in an interruption of supply to several companies from securing approval additive toxicities, in particular with national TB programmes in 2010, of the finished product through antiretrovirals which may cause renal although production only resumed WHO Prequalification or a stringent toxicity, such as tenofovir. Further in late 2011. Meiji was identified by regulatory authority. studies are required to confirm this.

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

GENERAL INFORMATION

• Therapeutic Class: • Presentations available: capreomycin-susceptible strains of Polypeptide antibiotic. 1g powder for injection. M. tuberculosis when the primary agents (isoniazid, rifampicin, • ATC Code: J04AB30.36 • First approved by US FDA: ethambutol, aminosalicylic acid, and 2 June 1971.43 • Included in the WHO Guidelines streptomycin) have been ineffective, CAPREOMYCIN (C m 37 or cannot be used because of as a Group 2 injectable agent. • Approved indication in the toxicity or the presence of resistant US: Capreomycin is to be used • Included in the 19th edition of tubercle bacilli.43 the WHO Model List of Essential concomitantly with other Medicines23 and in the 5th edition appropriate anti-tuberculosis of the WHO Model List of Essential agents; it is indicated for use in Medicines for Children.38 pulmonary infections caused by

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Akorn Aspen Hisun Macleods Vianex GDF pooled procurement

Under evaluation WHO PQ WHO PQ by WHO PQ GDF Quality Quality status SRA approved SRA approved approved approved (ERP approved Assurance Policy until 31/10/2016) Manufacturer 1g powder for did not agree 8.000 8.100 4.150 6.000 3.800 - 4.700 injection to publish prices

18 Médecins Sans Frontières | March 2016 CAPREOMYCIN (C m

SPOTLIGHT ON ACCESS ISSUES

Capreomycin shows moderate cross-resistance to amikacin and kanamycin and can be used when there is resistance to either one of these drugs. ) GROUP 2

With PAS and linezolid, capreomycin remains one of the three medicines which weigh heavily in the overall cost of a DR-TB regimen.

Number of quality sources per vial thereafter. The price at which Paediatrics There are currently five quality- countries can procure capreomycin The safety and efficacy of assured sources available: Akorn, increased considerably since Eli Lilly capreomycin in children has who bought Eli Lilly’s US licence; stopped production and transferred not been established. Vianex, a manufacturer based in technology to other companies While dosages are published in Greece, received stringent regulatory (Aspen, Hisun, and SIA International). several guidelines, there is need for authority approval in Spain in 2011; GDF currently procures further research (pharmacokinetics, Hisun, a China-based manufacturer, capreomycin at $3.80 to $4.70 per pharmacodynamics, safety data) received WHO prequalification in vial. Even with new quality-assured into the use of this drug in younger 2014; Macleod’s, which received ERP sources having entered the market, populations, in particular in children approval in 2014; and Aspen, which the price of capreomycin remains aged under five years. received WHO prequalification in higher than the Eli Lilly-subsidised December 2015. HIV co-infection product, despite a price decrease No antiretroviral interaction With five quality-assured sources now of 24% since 2013. studies have been performed, but available for TB procurement, the Suitability for use in based on pharmacokinetic profiles, supply of capreomycin has improved developing country settings the potential for drug interactions and the price has decreased by nearly Capreomycin, similar to amikacin is low. a quarter (24%) since 2013. Two and kanamycin from the further companies have submitted a However, there is potential for aminoglycosides class, cannot be dossier for WHO prequalification. additive toxicities, in particular with administered orally and is usually antiretrovirals which may cause Evolution in price given intramuscularly (IM), but renal toxicity such as tenofovir. For a number of years, Eli Lilly can also be given intravenously Further studies are required to subsidised the price of capreomycin (IV). This imposes burdens confirm this. for GLC-approved programmes, both on patients and treatment charging US$1.02 per vial until a set programmes, as qualified staff volume had been ordered, and $4.00 need to administer the product.

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

GENERAL INFORMATION

• Therapeutic Class: Fluoroquinolone. Essential Medicines.23 Not included in • Approved indication in the US: the 5th edition of the WHO Model List Moxifloxacin was initially approved for • ATC Code: J01MA14.36 of Essential Medicines for Children.38 the indications of bacterial sinusitis and community-acquired pneumonia. This • Included in the WHO Guidelines • Presentations available: 400mg tablet. as a Group 3 Fluoroquinolone.37 was further expanded to include acute • First approved by US FDA: bacterial exacerbation of chronic bronchitis, MOXIFLOXACIN (M fx ) GROUP 3 • Mentioned as an alternative to 12 October 1999.45 uncomplicated and complicated skin and levofloxacin for tuberculosis in the skin structure infection, and complicated 19th edition of the WHO Model List of intra-abdominal infections.46

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

GDF pooled Cipla Hetero Macleods Microlabs Sunpharma procurement

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

Manufacturer 400mg tablet 0.600 0.660 0.580 did not agree to 0.510 0.437-0.540 publish prices

20 Médecins Sans Frontières | March 2016 MOXIFLOXACIN (M fx ) GROUP 3

SPOTLIGHT ON ACCESS ISSUES

Moxifloxacin use is increasing due to the key role that fluoroquinolones play in the treatment of drug-resistant forms of tuberculosis. Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, such as moxifloxacin and levofloxacin, are preferred to ofloxacin (inferior performance and higher risk of resistance). There is, however, potential for cross-resistance between the later generation fluoroquinolones.

Number of quality sources with the Indian Central Drugs obtained by manipulating adult Bayer was the only quality-assured Standard Control Organisation, a formulations to achieve target source of moxifloxacin available number of whom have filed and doses. This requires a certain level of for many years. In November obtained WHO pre-qualification training, supervision and resources, 2010, Cipla’s product became and/or US FDA approval. which may not be available in many the first generic moxifloxacin to resource-limited settings where The basic Markush and compound be prequalified by WHO, and in DR-TB is prevalent. 2013 two more sources (Macleods patents which covered the and Sun Pharmaceuticals) were moxifloxacin molecule have started HIV co-infection prequalified. One additional source to expire around the world, and (Hetero) is SRA approved. Currently generic companies have worked No antiretroviral interaction seven manufacturers are under around the secondary patents on studies have been performed, but evaluation by WHO PQ. the crystal monohydrate form47 and based on the metabolism rate of moxifloxacin, levels of the drug may With additional quality-assured the process of preparing an oral 48 be reduced by the use of ritonavir sources entering the market, tablet formulation. As a result, and increased by atazanavir. Further access to moxifloxacin appears to generics are now available in the 49 research is needed to assess this. be relatively secure for the time US (launched in February 2014) , being. Prices, which in the past Canada and South Africa. Generic Protease inhibitors and efavirenz represented a barrier to access, versions have now been registered may prolong QT interval, so are continuously decreasing; since in South Africa and are supplied caution is advised in concomitant 2013, the lowest price on the for DR-TB treatment through the use with moxifloxacin, with market has decreased by 27%. national TB programme as part of electrocardiogram monitoring the government tender awarded recommended. Approved indication in 2011. Generic versions are also While moxifloxacin has been shown marketed in the Russian Federation. Oral absorption of fluoroquinolones to be effective against M. tuberculosis is reduced by buffered drugs, so and has been included in many Paediatrics doses should be separated from didanosine-buffered tablets. treatment guidelines for DR-TB, it The safety and efficacy of moxifloxacin has not yet received an approved in children has not been established. TB indication by any stringent Special caution While dosages are published in several regulatory authority. Moxifloxacin can affect cardiac 42,43 guidelines , there is an urgent need conduction (QT prolongation). QT for further research (pharmacokinetics, Patents prolongation can infrequently result pharmacodynamics, safety data) In India, the Markush and in a serious (rarely fatal) fast/irregular into the use of this drug in younger compound patent applications were heartbeat, known as torsades populations, in particular in children not eligible for product patents de point. This is an important aged under five years. Existing under the 1970 Patent Act, and consideration, as several new (such studies show substantially lower the crystal monohydrate form was as bedaquiline and delamanid) and serum concentrations in children rejected after a pre-grant opposition repurposed TB drugs (clofazimine) compared to adults at the currently was filed by Ranbaxy Laboratories. have a similar risk, and it is unclear recommended doses, probably due As a result, the drug has been in if this will be an additive effect. to faster elimination.50 generic production in India for This is an effect seen in this class several years and is registered by a As there is no paediatric formulation of drugs, but is most pronounced number of generic manufacturers available, paediatric doses are with moxifloxacin.

DR-TB Drugs Under the Microscope 21 LEVOFLOXACIN (Lfx) GROUP 3

GENERAL INFORMATION

• Therapeutic Class: Fluoroquinolone. to ofloxacin, based on availability and the indications of acute maxillary programme considerations. sinusitis, acute bacterial exacerbations • ATC Code: J01MA12.36 of chronic bronchitis, community- • Presentations available: 250mg, 500mg • Included in the WHO Guidelines and 750mg tablets; 25mg/ml oral solution. acquired pneumonia, uncomplicated as a Group 3 Fluoroquinolone.37 skin and skin structure infections,

LEVOFLOXACIN (L fx ) GROUP 3 • First approved by US FDA: • Included in the 19th edition of complicated urinary tract infections 20 December 1996. The paediatric the WHO Model List of Essential (UTI), and acute pyelonephritis. formulation (25mg/ml oral solution) was Medicines23 and in the 5th edition This was further expanded to approved on 21 October 2004.51 of the WHO Model List of Essential include uncomplicated UTI, chronic Medicines for Children.38 Levofloxacin • Approved indication in the US: bacterial prostatitis, and treatment of is considered a better alternative Levofloxacin was initially approved for inhalational anthrax (post-exposure).51

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

GDF pooled Apotex Cipla Hetero Labatec Macleods Microlabs procurement Quality WHO PQ WHO PQ WHO PQ WHO PQ GDF Quality SRA approved SRA approved status approved approved approved approved Assurance Policy 250mg 0.090* 0.061 0.059 1.538 0.043 0.057 0.033-0.055 tablet

500mg 0.130* 0.110 0.105 2.315 0.078 0.092 0.059-0.097 tablet

750mg 0.150* xx 0.240 xx 0.128 xx 0.100 tablet

* Inconterm CIF

22 Médecins Sans Frontières | March 2016 LEVOFLOXACIN (L fx ) GROUP 3

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

Number of quality sources of later generation fluoroquinolones, Currently, the majority of DR-TB Levofloxacin 250mg and 500mg including levofloxacin. However, programmes prepare paediatric oral formulations produced by levofloxacin does not have a TB doses by manipulating adult Cipla were prequalified by WHO indication approved by any stringent formulations to achieve target in December 2011, with Microlabs regulatory authority. doses. This requires a certain level of following in October 2012, Apotex training, supervision and resources, in June 2013 and Macleods in Patents which may not be available in many October 2014. Currently, an Patents on levofloxacin held by Daiichi resource-limited settings where DR- additional four manufacturers for Sankyo in the US and in several TB is prevalent. the 250mg product, and three European countries expired in 2010. manufacturers for 500mg, are under HIV co-infection evaluation by WHO Prequalification. Other patents in the US and in No antiretroviral interaction studies A significant number of generic several European countries claiming have been performed, but based on versions have been approved by levofloxacin expired in June 2011. the metabolism rate of levofloxacin, stringent regulatory authorities, no interactions are expected. since patents expired in the US Paediatrics However, further research is needed and in Europe in 2011. The US FDA has approved levofloxacin to assess this. for use in children aged over six The first 750mg formulation Protease inhibitors and efavirenz months, but only for acute infections. (produced by Apotex) was may prolong QT interval, so caution The safety of levofloxacin in children prequalified by WHO in June 2013, is advised in concomitant use with treated for more than 14 days has followed by Macleods, prequalified levofloxacin, with electrocardiogram not been studied; as this drug may be in October 2014. monitoring recommended. taken for up to two years, there is an urgent need for more safety data on Oral absorption of fluoroquinolones Evolution in price the use of levofloxacin for extended is reduced by buffered drugs, so The price of levofloxacin does not periods in children. doses should be separated from appear to be an issue, and it has didanosine-buffered tablets. continued to fall over recent years. While there are two manufacturers of the paediatric formulations Approved indication (25mg/ml oral solution) available The 2011 WHO programmatic in the US, these are not widely guidelines for DR-TB recommend use available elsewhere.

DR-TB Drugs Under the Microscope 23 ETHIONAMIDE (Eto) GROUP 4

GENERAL INFORMATION

• Therapeutic Class: Carbothionamides • Included in the 19th edition of the WHO • Approved indication in the group, derivative of isonicotinic acid. Model List of Essential Medicines23 and US: ethionamide is primarily in the 5th edition of the WHO Model indicated for the treatment of • ATC Code: J04AD03.36 List of Essential Medicines for Children.38 active tuberculosis in patients • Included in the WHO Guidelines with M. tuberculosis resistant

ETHIONAMIDE (E to ) GROUP 4 • Presentations available: 250mg and as a Group 4 oral bacteriostatic to isoniazid or rifampicin, or 125mg tablets. second-line agent.37 where the patient is intolerant • First approved by US FDA: 30 April 1965.52 to other drugs.52

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

GDF pooled Cipla Lupin Macleods Microlabs procurement Under evaluation WHO PQ WHO PQ WHO PQ by WHO PQ (ERP WHO PQ GDF Quality Quality status approved approved approved approved until approved Assurance Policy 02/07/2016 )

125mg tablet xx xx xx 0.112 xx xx

Manufacturer 250mg tablet 0.098 did not agree to 0.066 xx 0.082 0.062-0.080 publish prices

SPOTLIGHT ON ACCESS ISSUES

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

Number of quality sources Paediatrics HIV co-infection The supply and number of The safety and efficacy of While no antiretroviral interaction sources of ethionamide 250mg ethionamide in children has studies have been performed, is gradually improving, with not been established. pharmacokinetic profiles suggest four WHO-prequalified products that drug interactions with While dosages are published available. In addition, Macleods ethionamide are possible. in several guidelines, there has developed a 125mg paediatric is an urgent need for further There is the possibility of additive formulation which was approved research (pharmacokinetics, toxicities with antiretrovirals by the GDF/Global Fund Expert pharmacodynamics, safety data) which may cause hepatotoxicity, Review Panel (ERP) in July 2015. into the use of this drug in including efavirenz and nevirapine. Evolution in price younger populations, in With the potential for interactions with The price of ethionamide does particular in children aged some classes of antiretrovirals, there is not appear to be an issue. under five years. an urgent need for further studies.

24 Médecins Sans Frontières | March 2016 PROTHIONAMIDE (Pto) PROTHIONAMIDE (P to ) GROUP 4 GROUP 4

GENERAL INFORMATION

• Therapeutic Class: Carbothionamides Essential Medicines.23 Not included in • Approved indication in Germany: group, derivative of isonicotinic acid. the 5th edition of the WHO Model List Treatment of all forms and stages of Essential Medicines for Children.38 of pulmonary and extra-pulmonary 36 • ATC Code: J04AD01. tuberculosis as second-line drug in • Presentations available: 250mg tablet. • Included in the WHO Guidelines the case of proven multidrug as a Group 4 oral bacteriostatic • First approved by German Federal resistance of the pathogens against second-line agent.37 Institute for Drugs and Medical first-line drugs; treatment of diseases Devices (BfArM): First marketed in caused by so-called ubiquitous • Mentioned as an alternative to Germany in the 1970s but registered (atypical) mycobacteria; treatment ethionamide for tuberculosis in the in the framework of posterior of leprosy in the context of modified 19th edition of the WHO Model List of registration on 14 June 2005.53 therapy regimens.54

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

GDF pooled Fatol Lupin Microlabs Olainfarm procurement

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

Manufacturer did not Manufacturer did not 250mg tablet 0.120 0.100 0.130-0.178 agree to publish prices agree to publish prices

SPOTLIGHT ON ACCESS ISSUES

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

Number of quality sources Paediatrics HIV co-infection In February 2013, Microlabs was the The safety and effectiveness of While no antiretroviral interaction first manufacturer to secure WHO prothionamide in children has not studies have been performed, Prequalification for prothionamide, been established. The paediatric pharmacokinetic profiles suggest followed by Lupin in June 2014. formulation of ethionamide that drug interactions with There are now four quality-assured should be considered instead of prothionamide are possible. sources for the drug, given the two prothionamide. existing sources approved by stringent There is the possibility of additive While dosages are published in several regulatory authorities (Germany’s toxicities with antiretrovirals which guidelines, there is an urgent need Fatol and Latvia’s Olainfarm). may cause hepatotoxicity, including for further research (pharmacokinetics, efavirenz and nevirapine. An additional manufacturer has pharmacodynamics, safety data) submitted its dossier for WHO into the use of this drug in younger With the potential for interactions with prequalification. populations, in particular in children some classes of antiretrovirals, there is aged under five years. an urgent need for further studies.

Continued overleaf

DR-TB Drugs Under the Microscope 25 CYCLOSERINE (Cs) GROUP 4 ) GROUP 4

GENERAL INFORMATION

• Therapeutic Class: Analog Medicines23 and in the 5th edition • Approved indication in the US: of D-alanine. of the WHO Model List of Essential Cycloserine is indicated in the treatment Medicines for Children.38 of active pulmonary and extra-pulmonary • ATC Code: J04AB01.36 tuberculosis (including renal disease), • Presentations available: CYCLOSERINE (C s • Included in the WHO Guidelines when the causative organisms are 250mg capsule. as a Group 4 oral bacteriostatic susceptible to this drug and when second-line agent.37 • First approved by US FDA: treatment with the primary medications 29 June 1964.55 (streptomycin, isoniazid, rifampicin and • Included in the 19th edition of ethambutol) has proved inadequate.55 the WHO Model List of Essential

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

GDF pooled Cipla Dong A Macleods Microlabs Strides procurement

Under evaluation GDF Quality Under evaluation by WHO PQ (ERP Quality status WHO PQ approved WHO PQ approved WHO PQ approved Assurance of WHO PQ approved until Policy 24/07/2016)

Price was not Manufacturer 250mg available at time 0.216 0.390 did not agree to 0.600 0.187-0.330 capsule of data collection publish prices

26 Médecins Sans Frontières | March 2016 CYCLOSERINE (C s

SPOTLIGHT ON ACCESS ISSUES

Number of quality sources Active Pharmaceutical Paediatrics ) GROUP 4 Eli Lilly, the original licence holder Ingredient The British National Formulary of cycloserine, actively engaged Until 2006, the only quality-assured provides doses for children aged in technology transfer to three source for the active pharmaceutical 2 to 18 years, while the US generic manufacturers (Aspen, ingredient of cycloserine was Eli FDA states that the safety and Chao Center/Purdue GMP and Lilly. The company completed a effectiveness of cycloserine in SIA International) and ceased technology transfer for the API to children has not been established. Indian manufacturer Shasun in 2006. production in 2008. There is an urgent need for further Shasun API was subsequently US research (pharmacokinetics, There are currently four WHO- FDA approved in June 2008 and was pharmacodynamics, safety data) prequalified sources of cycloserine, WHO-prequalified in May 2013. including Dong A, Macleods, and into the use of this drug in younger There are currently three API populations, in particular in Biocom, the latter having secured manufacturers (Dong A, Shasun children aged under five years. approval in August 2013. In addition, and Macleods), and Enzychem of Cipla received WHO prequalification As there is no paediatric South Korea was expected to file in December 2015, however prices formulation available, paediatric API PQ in June 2015; this additional for this publication were collected in doses are obtained by manufacturer will make cycloserine manipulating adult formulations September 2015 and the price for API supply more sustainable. Cipla’s product is not available for to achieve target doses. This requires a certain level of training, this edition. In addition, Chao Evolution in price supervision and resources, which Center/Purdue have received In the last three years, with the may not be available in many approval from a stringent regulatory arrival of more quality-assured resource-limited settings where authority but are supplying the sources of API for cycloserine, DR-TB is prevalent. Northern American market. the finished product price has decreased from between US$0.39 Strides received joint GDF/ HIV co-infection and $0.78 per unit, to between Global Fund Expert Review Panel The metabolism of cycloserine $0.19 and $0.60 per unit. The temporary approval (until July is not completely understood, lowest unit price for a quality- 2016), making them eligible for and therefore interactions with assured source of cycloserine has Global Fund procurement. antiretrovirals are unpredictable. dropped by 52% in three years, Three other manufacturers have resulting in a considerable fall in There is a need for more research submitted dossiers for WHO the cost of treatment regimens into potential interactions between prequalification. containing this drug. antiretrovirals and cycloserine.

Continued overleaf

DR-TB Drugs Under the Microscope 27 TERIZIDONE (Trd) GROUP 4 rd ) GROUP 4 GENERAL INFORMATION

• Therapeutic Class: Analog of D-alanine. Model List of Essential Medicines for (BfArM): First marketed in Germany in Adults;23 not included in the 2013 the 1970s and is still in the process of • ATC Code: J04AK03.36 Model List of Essential Medicines for posterior registration. The filing date 54 • Included in the WHO Guidelines Children.38 for this process was 1 January 1978. TERIZIDONE (T as a Group 4 oral bacteriostatic • Approved indication in Germany: second-line agent.37 • Presentations available: 250mg capsule. Treatment of tuberculosis in • Mentioned as an alternative to • First approved by German Federal adults and adolescents aged 14 cycloserine in the 2015 WHO Institute for Drugs and Medical Devices years or older.54

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Fatol Macleods GDF pooled procurement

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

Manufacturer did not agree to 250mg capsule 0.850 1.588-1.666 publish prices

28 Médecins Sans Frontières | March 2016 TERIZIDONE (T

SPOTLIGHT ON ACCESS ISSUES rd ) GROUP 4 Terizidone is a combination of two molecules of cycloserine, and as such has a similar mode of action as cycloserine. There is complete cross-resistance to cycloserine and, in some countries, the drug is used instead of cycloserine.

Number of quality sources While dosages are published may not be available in many Germany’s Fatol is currently in several guidelines 42,43, there resource-limited settings where the sole quality-assured source is an urgent need for further DR-TB is prevalent. of terizidone. One additional research (pharmacokinetics, manufacturer (Macleods) has pharmacodynamics, safety data) HIV co-infection submitted dossiers for WHO into the use of this drug in younger As terizidone is a combination of prequalification. populations, in particular in two molecules of cycloserine and children aged under five years. Additional manufacturers exist, but the metabolism of cycloserine is not completely understood, interactions it is unknown whether they comply As there is no paediatric with antiretrovirals are unpredictable. with WHO quality standards. formulation available, paediatric doses are obtained by There is a need for more research Paediatrics manipulating adult formulations into potential interactions between The safety and effectiveness of to achieve target doses. This antiretrovirals and terizidone. terizidone in children has not requires a certain level of training, been established. supervision and resources, which

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

GENERAL INFORMATION

• Therapeutic Class: Salicylic acid anti-folate. • Presentations available: PAS: 4g • Approved indication in the US: sachet. PAS-sodium: 60% weight PAS is indicated for the treatment • ATC Code: for PAS: J04AA0136; for of tuberculosis in combination PAS-sodium: J04AA02.36 for weight granules 9.2g sachet and 100g jar; powder for solution 5.52g with other active agents. It is most commonly used in patients • Included in the WHO Guidelines – PAS: as sachet (equivalent to PAS 4g sachet). a Group 4 oral bacteriostatic second-line with multidrug-resistant TB or in agent; PAS-sodium: not included.37 • First approved by US FDA: situations when therapy with isoniazid PAS-sodium was first registered in a and rifampicin is not possible due • PAS is included in the 19th edition of the WHO to a combination of resistance Model List of Essential Medicines23 and in the tablet formulation on 8 March 1950. and/or intolerance.56 5th edition of the WHO Model List of Essential Currently, only PAS is available in Medicines for Children.38 PAS-sodium is the US, with the product registered not included in either document. on 30 June 1994.56

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

PAS Jacobus GDF pooled procurement

Quality status SRA approved GDF Quality Assurance Policy

4g sachet 1.500 1.333

PAS-SODIUM Macleods Olainfarm GDF pooled procurement

WHO PQ WHO PQ GDF Quality Quality status approved approved Assurance Policy sodium ) GROUP 4 SODIUM (PAS- and PARA-AMINOSALICYLATE ACID (PAS) PARA-AMINOSALICYLIC

60% w/w granules 1.690 xx 1.690 – 9.2g sachet

60% w/w granules 18.360 xx 18.360 – 100g jar

Powder for oral solution – xx 1.400 1.370 5.52g sachet

30 Médecins Sans Frontières | March 2016 PARA-AMINOSALICYLIC ACID (PAS) and PARA-AMINOSALICYLATE SODIUM (PAS- sodium ) GROUP 4

SPOTLIGHT ON ACCESS ISSUES

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

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

Number of quality sources of PAS-sodium has stagnated, As there is no paediatric formulation There is currently only one quality- while the second source price has available, paediatric doses are assured source of PAS (Jacobus), increased by 30% since 2013. obtained by measuring the adult and two quality-assured sources Prices of both PAS and PAS- granular formulations. Jacobus of PAS-sodium (Macleods and sodium remain a concern, and no supplies a graduated dosage Olainfarm), with no other sources additional quality-assured sources scoop for PAS, and Macleods offers in the pipeline. have been identified since 2011. measuring spoons for PAS-sodium, With three quality-assured sources both of which allow for a more Paediatrics of PAS and PAS-sodium now accurate paediatric dosage. These The safety and effectiveness of PAS available for procurement, supply spoons are product-specific and and PAS-sodium in children has not has improved, but is still considered cannot be interchanged. been established. vulnerable, particularly as the different formulations available are While dosages are published in several HIV co-infection not easily interchangeable. guidelines42,43, there is an urgent need No antiretroviral interaction studies for further research (pharmacokinetics, have been performed, but based Evolution in price pharmacodynamics, safety data) on the pharmacokinetic profile of The price of PAS has stagnated for into the use of this drug in younger PAS, drug interactions are unlikely. more than three years. The lowest populations, in particular in children Studies should be performed to price for a quality-assured source aged under five years. confirm this.

DR-TB Drugs Under the Microscope 31 CLOFAZIMINE (Cfz) GROUP 5

GENERAL INFORMATION

• Therapeutic Class: Phenazine Derivative. in the 5th edition of the WHO Model • Approved indication in US: List of Essential Medicines for Children Clofazimine is indicated in the • ATC Code: J04BA01.36 (as an anti-leprosy medicine),38 but treatment of lepromatous leprosy, • Included in the WHO Guidelines not yet included for TB indication. including dapsone-resistant

CLOFAZIMINE (C fz ) GROUP 5 CLOFAZIMINE as a Group 5 medicine (agents lepromatous leprosy and lepromatous 37 • Presentations available: 50mg with unclear efficacy). leprosy complicated by erythema and 100mg soft-gel capsules. 57 • Included in the 19th edition of the nodosum leprosum. WHO Model List of Essential Medicines • First approved by US FDA: (as an anti-leprosy medicine)23 and 15 December 1986.57

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Novartis GDF pooled procurement

Quality status SRA approved GDF Quality Assurance Policy

50mg soft-gel Manufacturer did not agree 0.547-0.713 capsule to publish prices

100mg soft-gel Manufacturer did not agree 1.095-1.267 capsule to publish prices

32 Médecins Sans Frontières | March 2016 CLOFAZIMINE (C fz ) GROUP 5

SPOTLIGHT ON ACCESS ISSUES

Clofazimine is a Group 5 medicine which is mainly used in patients with pre-XDR-TB and XDR-TB. With no official indication for DR-TB, and owing to its effectiveness in TB having not been clearly established, in 2014 Novartis filed an Investigational New Drug application with the US FDA linked to a clinical development programme for clofazimine for a potential DR-TB indication. The 2011 WHO programmatic guidelines37 recommend the use of clofazimine for patients with MDR or XDR-TB, when there are no other options available.

However, clofazimine is a key component of a shortened nine-month regimen, and recent systematic reviews suggest that clofazimine could be considered as an additional therapeutic option in the treatment of DR-TB.58

Novartis does not make this drug available for DR-TB treatment on the basis of a lack of efficacy and safety data, and owing to concerns over liability for off-label use. Because the company donates clofazimine to WHO as part of a multi-drug co-blistered therapy for leprosy59, Novartis did not submit a price for this publication.

As TB programmes’ demand for this drug has increased, WHO has been in discussion with Novartis since 200860 to address the liability for off-label use and patient safety of clofazimine when used to treat TB, and for the drug to become available for MDR and XDR-TB treatment.

Eight years on, the difficulties in accessing clofazimine for DR-TB treatment remain acute61, with no plan for technology transfer for the finished product formulation to another manufacturer having been announced. Novartis needs to ensure a secure, affordable supply of clofazimine for use in DR-TB treatment, or provide the necessary details for a technology transfer to allow another manufacturer to take over the supply of quality-assured clofazimine. The evaluation of a DR-TB indication for clofazimine will take several years. In the meantime, as recommended by WHO, clofazimine is needed for patients with MDR or XDR-TB that have not been cured with other options.

Number of quality sources Evolution in price A 50mg soft-gel capsule is currently Clofazimine produced by Sandoz Price is not currently a barrier for available, but this formulation India for Novartis is currently the patients to access clofazimine, makes it impossible to fraction the sole quality-assured source of the but rather Novartis’s restrictive dose for children. drug. Although there are additional approach to the supply of this drug, manufacturers in India and Europe, which it reserves exclusively for HIV co-infection there has been very little effort to leprosy treatment. Clofazimine may have a significant identify a second potential quality- drug-drug interaction with some The GDF catalogue lists clofazimine assured source in order to ensure antiretrovirals. No studies have been at 100mg and 50mg strengths. access to clofazimine for DR-TB. performed, but clofazimine is a weak The product can be procured for inhibitor of the CYP3A4 metabolism In order to send a clear message non-leprosy use on a named-patient pathway and may increase levels of to manufacturers that clofazimine basis only. With this caveat, it can be protease inhibitors and etravirine. is needed, the drug was included procured at a price of US$1.10 per in the WHO Prequalification 13th 100mg capsule and $0.55- $0.71 per Expression of Interest in August 50mg capsule through Pharmaworld, Special caution 2015. Clofazimine is also included a supplier in Switzerland.63,64 Clofazimine can affect cardiac in the joint GDF/Global Fund conduction (QT prolongation). Invitation to Manufacturers to Paediatrics QT prolongation can infrequently result in a serious (rarely fatal) submit an Expression of Interest for The safety and effectiveness of fast/irregular heartbeat, known the evaluation of products by the clofazimine in children has not as torsades de point. This is an Expert Review Panel.62 been established. important consideration as several As demand for clofazimine is While dosages are published other drugs, such as moxifloxacin, expected to grow in light of in several guidelines, there delamanid and bedaquiline have a the increased use of shortened is an urgent need for further similar risk and it is unclear if this regimens, there is a need for research (pharmacokinetics, will be an additive effect. alternative quality-assured sources pharmacodynamics, safety data) of the drug other than the existing into the use of this drug in younger Novartis product, which is not populations, in particular in children easily available. aged under five years.

DR-TB Drugs Under the Microscope 33 LINEZOLID (Lzd) GROUP 5

GENERAL INFORMATION

• Therapeutic Class: of the WHO Model List of Essential • Approved indication in US: Linezolid is Oxazolidinone antibiotic. Medicines23 and in the 5th edition indicated for treatment of susceptible of the WHO Model List of Essential strains of designated microorganisms • ATC Code: J01XX08.36 LINEZOLID (L zd ) GROUP 5 Medicines for Children with a for nosocomial pneumonia; and tuberculosis indication.38 • Included in the WHO Guidelines complicated and uncomplicated skin as a Group 5 medicine (agents • Presentations available: 600mg tablet; and skin structure infections. It is with unclear efficacy).37 100mg/5ml powder for suspension. not indicated for the treatment of • Linezolid has been included for Gram-negative infections and • First approved by US FDA: 18 April 2000.57 the first time in the 19th edition community-acquired pneumonia.65

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Hetero Macleods Pfizer GDF pooled procurement

Under evaluation GDF Quality Quality status SRA approved SRA approved by WHO PQ Assurance policy Manufacturer did not agree 600mg tablet 5.800 5.500 5.350-5.480 to publish prices 100mg/ml powder Manufacturer did not agree xx xx xx for suspension to publish prices

SPOTLIGHT ON ACCESS ISSUES

With capreomycin and PAS, linezolid is one of the three medicines which weigh heavily in the overall cost of a DR-TB regimen. Although linezolid has no official indication for DR-TB treatment, the 2011 WHO programmatic guidelines recommend the use of linezolid as a Group 5 drug37 for patients with MDR or XDR-TB, when there are no other options available. In April 2012, a systematic review outlined the efficacy of linezolid in DR-TB treatment.66 Data has also been presented at international conferences, and small case series reports have been published.67 The literature review has allowed the WHO Expert Committee to add linezolid to the WHO EML with a DR-TB indication. Linezolid has a relatively high number of adverse side effects, including myelosuppression, anaemia, and irreversible peripheral and optical neuropathies. Nonetheless, linezolid plays a pivotal role in the treatment of patients with XDR- TB.68 The use of linezolid is expected to grow with the increased use of new drugs bedaquiline and delamanid, due to the importance of not adding a single (new) drug to a failing regimen, and due to linezolid’s lack of a QT effect.

Number of quality sources other generic companies can enter Nevertheless, due to Teva’s ‘First Currently two manufacturers – the market with their own products to File’ status giving them market Pfizer and Hetero – are approved – and subsequently launched their exclusivity on linezolid for six by a stringent regulatory authority. generic linezolid on the US market at months, other generic companies the end of June 2015, with no plans In addition, Macleods and one will be able to market their own to supply other markets. A further further source are under WHO product only from January 2016; five manufacturers (Mylan, Glenmark, PQ evaluation. Mylan has since launched their Amneal, Alkem and Gate Pharma) generic linezolid.69 Teva had a ‘First To File’ status for have tentative approval from the US linezolid with the US FDA – which FDA. The primary patent on linezolid Apotex Canada is also another provides 180 days of generic drug expired at the end of 2014 in most source of quality-assured linezolid exclusivity on the market before countries, including in the USA. supplying only the Canadian

34 Médecins Sans Frontières | March 2016 LINEZOLID (L zd ) GROUP 5

market. The availability of additional Patents settled when Alkem and Glenmark quality-assured sources for DR-TB The basic patent claiming linezolid committed to not infringe the patients is required to address the was filed by Upjohn Company* patented process in the production needs of DR-TB programmes for in the US in 1993 and expired in of linezolid. Currently Hetero affordable sources of this product. 201470 in the US and China. In Drugs therefore holds considerable South Africa, the key patents on control over the most efficient Linezolid is included in the 13th linezolid71 also expired in 2014. process of API production.80 WHO Prequalification Expression of Upjohn Company also filed patents As of November 2015, the Interest (since August 2015) with in the US on a crystalline form Medicines Patent Pool (MPP) has two dosages, 600mg coated tablet II which will expire in the US by a mandate to negotiate voluntary and 150mg dispersible tablet. 2021.72 The crystalline form patent licences for TB drugs. There is has been rejected in Brazil, has In case of severe anaemia and no indication yet whether Pfizer lapsed in South Africa, and has severe peripheral neuropathy, or other companies that own ceased in China, but it remains patients should be switched from a secondary patents will provide valid in India until 2021.73 600mg to a 300mg dose; there is broad, public health-friendly a need for 600mg scored tablets or There is also a tablet formulation voluntary licences to the MPP that 300mg strength tablets. patent filed in the US in 2001.74 take into account all remaining This tablet formulation patent has secondary patents for linezolid Evolution in price been granted in India and China75, which may block some generic Although the primary patent has and will remain valid until 2021. producers – especially those in expired in the US and most other However, the same patent on the China and India – in producing and countries, the cost of the drug is tablet formulation has lapsed in entering into a particular market. extremely high. Patients failing South Africa due to non payment conventional DR-TB treatment but who of fees76, has lapsed and been Paediatrics could have a chance to survive through withdrawn from the European Pharmacokinetic studies have been the use of linezolid are often denied Patent Office77, and has lapsed in completed in children from birth, this option due to the prohibitively Brazil due to non payment of fees.78 and dosages are approved by the US FDA exclusively for infections expensive cost of the drug. In India, the basic compound patent with gram-positive bacteria could not be filed in 1993 since In South Africa, for example, the resistant to other antibiotics. price of Pfizer-produced linezolid in India’s patent law did not allow for the private sector is ZAR655 (US$47) pharmaceutical product patenting A paediatric formulation exists as a per tablet. With the treatment at the time. However, as mentioned solution for suspension, produced duration using linezolid lasting above, the patent applications on by Pfizer. The reconstituted on average four to six months, the crystalline form II and the tablet product can be stored at room this takes the cost per patient of formulation, which have been temperature. Although linezolid linezolid alone to around $10,000 rejected, lapsed, withdrawn or ceased 150mg dispersible tablet has been to $15,000 – to which the cost of in other countries, have been granted introduced in the Expression of other medicines in the regimen in India and will only expire in Interest of the WHO PQ, no dossier needs to be added. Considering 2021.79 However, none of these block has been submitted yet. generic competition. Several Indian the current commitment by the There is a need for further safety generic companies produce the API South African Ministry of Health to and efficacy data on the use of start 3,000 patients on bedaquiline and have been marketing generic linezolid for extended periods in before the end of 2016, and the versions of linezolid for several years. children with DR-TB. need of linezolid as a companion More recently, a patent on a drug to bedaquiline, the high cost of process which is more economical HIV co-infection linezolid will remain a limiting factor for the preparation of linezolid No antiretroviral interaction for scale up. has led to a legal dispute among studies have been performed but The availability of more quality- generic companies. Symed Labs – interactions are unlikely. There assured generic sources of linezolid a subsidiary of Hetero Drugs – has may, however, be an increased and the increase in order volumes enforced its API process-related risk of myelosuppression and have changed matters somewhat. patents (IN213062 and IN213063) mitochondrial toxicities with Although the price has decreased against Glenmark, Alkem and long-term use in combination with by 22% since 2013, the price still other companies, and successfully certain antiretrovirals (zidovudine, remains high, with the current obtained injunctions against them. stavudine, didanosine). Further lowest price at $5.35 per tablet. This patent dispute was finally studies are required to confirm this.

* In 1995, Upjohn merged with PharmaciaAB, to form Pharmacia & Upjohn. After subsequent restructuring, today the remainder of Upjohn is owned by Pfizer.

DR-TB Drugs Under the Microscope 35 BEDAQUILINE (Bdq) NEW DRUG/GROUP 5

GENERAL INFORMATION

• Therapeutic Class: diarylquinoline MDR-TB in June 201383; bedaquiline • First conditionally approved by (first-in-class) with bactericidal was allocated to Group 5 drugs. US FDA: 28 December 2012.84 and sterilising activity against • Bedaquiline has been included • Approved indication in US: Treatment Mycobacterium tuberculosis or for the first time in the 19th of multidrug-resistant pulmonary other mycobacterial species.81 edition of the WHO Model List tuberculosis in adults. Bedaquiline is • ATC Code: J04AK05.82 of Essential Medicines.23 indicated for treatment of pulmonary multidrug-resistant tuberculosis as • WHO issued interim guidelines on • Presentations available: part of combination therapy only the use of bedaquiline to treat 100mg tablet. when an effective treatment regimen cannot otherwise be provided.85 BEDAQUILINE (B dq ) NEW DRUG/GROUP 5 PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Janssen GDF pooled procurement

Quality status SRA approved* GDF Quality Assurance policy

Tiered pricing based on disease burden and 100mg tablet affordability. Please refer to both GDF and/or Free of charge (donation) USAID donation program.

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

SPOTLIGHT ON ACCESS ISSUES

Bedaquiline received conditional approval in the standard treatment group. When greater numbers of patients are by the US FDA in late December 2012 Although many of these deaths are reached worldwide in the future, Janssen based on Phase II clinical trial data. attributed to TB itself, the difference is may look into engaging with other global Janssen Pharmaceuticals are required to significant and a source of concern, and partners for production and/or marketing. submit additional clinical data for the needs careful future monitoring as the Bedaquiline has received approvals drug to receive full FDA approval.86 use of bedaquiline increases. Assessing in 9 out of the 27 high MDR-TB these concerns should form part of The first compound in the diarylquinoline burden countries – where 60% of phase III trials. class, bedaquiline’s novel mechanism of total patients from the high burden action inhibits mycobacterial adenosine WHO issued interim guidelines on the countries live – Russia, India, South 5’-triphosphate (ATP) synthase. The use of bedaquiline to treat MDR-TB Africa, Philippines, Peru, South Korea, drug is intended as part of combination in June 2013.83 The scale up of Turkmenistan, and Armenia, and has therapy for DR-TB, and it inhibits both programmatic use of bedaquiline has ongoing submissions in 9 of 27 high actively replicating and non-replicating been slow but is increasing, with just over MDR-TB burden countries (covering wild-type and resistant M. tuberculosis. 2,300 patients on bedaquiline as part of a further 20% of total patients from programmatic use as of February 2016.15 high burden countries). Bedaquiline In placebo-controlled studies of MDR has recently been registered by and XDR-TB patients (including At this time there is no evidence on the Indian Central Drugs Standard those co-infected with HIV), 79% the safety and efficacy of combining Control Organisation for use in the of patients given bedaquiline had bedaquiline with delamanid, and treatment of multidrug-resistant TB negative TB cultures after 24 weeks. currently there is no recommendation under the strict supervision of the Culture conversion happened 33% regarding their combination. Drug- Revised National Tuberculosis Control faster in patients taking bedaquiline drug interaction studies are due to Program. Sale or supply of bedaquiline as compared to the standard WHO- commence in early 2016 to look at the in the private sector is not allowed. recommended MDR-TB regimen.87,83 cardiac safety of combining these two The file to register bedaquiline has been drugs with QT prolongation potential.88 There are concerns around safety rejected in Kyrgyzstan due to a lack of however. During drug trials, 10 out of Number of quality sources phase III clinical studies. In addition, 79 patients in the bedaquiline group Janssen is currently responsible for all Janssen entered into a licensing died, compared to 2 out of 81 patients global manufacturing of bedaquiline. agreement with Pharmstandard to

36 Médecins Sans Frontières | March 2016 BEDAQUILINE (B dq ) NEW DRUG/GROUP 5

register and commercialise landscape report of its patent status in of compound patents. This problem can bedaquiline in the Commonwealth major developing countries.92 partially be addressed by applying strict of Independent States as well as in patentability criteria and by proactively The base compound patent on Georgia, Turkmenistan and Ukraine. bedaquiline has been granted in challenging secondary patents. In India By the end of 2015 Janssen announced India, China and South Africa, which and in other countries where such it was phasing out its compassionate will expire between 2023-2025.93 strategies can be employed, pre-grant use programmes, which had been the The patent application on the base oppositions of patent applications by major access channel of bedaquiline compound remains pending in Brazil.94 third parties on secondary patents until its donation came into effect. for bedaquiline will therefore be an The basic patent has also been Prices important strategy to avoid patent term granted in several countries including Janssen officially announced a donation extensions beyond the expiry of the Armenia, Azerbaijan, Kazakhstan, programme for bedaquiline on 11 basic patent in 2023. Russia, Tajikistan, Ukraine and a December 201489, where over the next number of African Intellectual Property In addition, some governments – and four years, they will donate 30,000 Organisation (ARIPO) and Organisation particularly India, where the product treatment courses of bedaquiline. From Africaine de la Propriété Intellectuelle patent blocks the manufacture of 1 April 2015, bedaquiline ordered (OAPI) countries.94 generics even for export to countries through the Global Drug Facility is free where there is no applicable patent – if procured for countries eligible for In India, the patent office has granted will have to decide whether to employ the Janssen donation (eligible countries the compound patent on bedaquiline compulsory licensing to enable the are Global Fund-eligible countries for – IN236811 – to Janssen which will expire production, use and export of more TB grants), with South Africa being in 2023. Generic manufacturers are not excluded from the donation. keen to develop the drug unless they affordable generic versions. are provided a licence to market and Janssen communicated for the As of November 2015, the Medicines supply developing countries. Janssen has purposes of this report that it will be Patent Pool (MPP) has been given filed several other types of evergreening implementing a three-tiered pricing a mandate to negotiate voluntary patent applications for bedaquiline that, 99 ‘framework’, in an attempt ‘to balance licences for TB drugs. There is no if granted, would further extend Janssen’s a country’s ability to pay with the indication yet whether Janssen will monopoly and restrict the timely entry of burden of disease’ for countries that are negotiate a voluntary licence with affordable generic versions in India and not eligible for Global Fund grants.90 the MPP that will include a broad many developing countries. The patent Countries will be classified into three geographic scope that includes all on the use of bedaquiline in treating DR- groups, which initial communication low- and middle-income countries. TB (6315/DELNP/2006) has been granted with the company suggests will be (IN264718) and this patent expires only Paediatrics labelled ‘high-income’, ‘upper middle- in May 2025.95 This patent has also been The safety and effectiveness of income’, and ‘least-developed/resource- granted in South Africa, but remains bedaquiline in children has not limited’. For a six-month treatment pending in China and Brazil.94 been established. course, a country in the high-income bracket would pay US$30,000, a The Indian application on the salt form There is an urgent need for further country in the upper middle-income (1220/MUMNP/2009) was opposed research (pharmacokinetics, bracket would pay $3,000, and a in March 2013 by the Network of pharmacodynamics, safety data) into the country in the least-developed/resource- Maharashtra People Living with HIV use of this drug in younger populations, 96 limited bracket would pay $900. Janssen (NMP+), and the decision is awaited. in particular in children aged under five points to the fact that its proposed This patent remains pending in China years. Paediatric studies are planned as pricing for the middle and lower pricing and Brazil, but has been granted in part of the paediatric development plan 94 tiers is aligned with a WHO-sponsored South Africa. required for the company to complete cost effectiveness assessment of 100,101 Another patent application covering the the regulatory approval process. bedaquiline.91 process of preparation of bedaquiline, There is no paediatric formulation including its API, is pending, and if Janssen have indicated that countries currently available. will be classified in the ‘framework’ granted will expire in 2026.97 This patent both according to World Bank gross has also been granted in South Africa and HIV co-infection national income per capita definitions China, but remains pending in Brazil.94 Early research shows that efavirenz and according to disease burden as interacts with bedaquiline by reducing It is also important to note that per the WHO’s MDR- and XDR-TB its blood concentration, while bedaquiline is included in patents for 2010 Global Report on Surveillance lopinavir/ritonavir slightly increases the tuberculosis combination therapies. and Response. However, the company These patents, such as WO2010026526, concentration of the drug. was unwilling to divulge placement can potentially block the development of of individual countries in the three More detailed studies are required. new treatment regimens.98 This patent respective groups until regulatory is pending in several countries and if Special caution efforts had concluded (and, where granted it would not lapse before 2029. Bedaquiline can affect cardiac applicable, ‘following completion conduction (QT prolongation). QT of reimbursement processes’). It Given the patent barriers on bedaquiline prolongation can infrequently result remains to be seen what pricing will both as a standalone treatment and in a serious (rarely fatal) fast/irregular be offered to countries like China as a part of combination therapies, a heartbeat, known as torsades de point. which is simultaneously a high-burden proactive strategy will be needed to This is an important consideration TB country and in the upper middle- mitigate access challenges. as several other drugs (such as income bracket. Secondary and follow-on patents moxifloxacin and delamanid) and Patents are a typical problem in the area of repurposed TB drugs (clofazimine) have Bedaquiline is a newly approved drug pharmaceuticals and such patents often a similar risk and it is unclear if this will and UNITAID has published a patent extend monopolies even after the expiry be an additive effect.

DR-TB Drugs Under the Microscope 37 DELAMANID (Dlm) NEW DRUG/GROUP 5

GENERAL INFORMATION

• Therapeutic Class: nitroimidazole (Nitro- • Delamanid was included for the first • Approved indication in EMA: dihydro-imidazo-oxazole derivative). time in the 19th edition of the WHO “as part of an appropriate Model List of Essential Medicines.23 combination regimen for pulmonary • ATC Code: J04AK06.82 multidrug-resistant tuberculosis in • Presentations available: 50mg film • WHO issued interim guidelines on adult patients when an effective coated tablets. the use of delamanid to treat MDR- treatment regimen cannot otherwise TB in October 2014. Delamanid was • Approved in April 2014 by the be composed for reasons of allocated to Group 5 drugs.102 European Medicines Agency (EMA).32 resistance or tolerability.”32 DELAMANID (D lm ) NEW DRUG/GROUP 5

PRICE (IN US$) AND QUALITY INFORMATION Price of the lowest unit (i.e. the price of one tablet, capsule or vial)

Otsuka GDF pooled procurement

Quality status SRA approved* GDF Quality Assurance policy

50mg film Manufacturer has not made pricing strategy public 2.530 coated tablet for non Global Fund-eligible countries

* Delamanid received EMA conditional approval on the basis of phase IIb clinical trial data.

SPOTLIGHT ON ACCESS ISSUES

Delamanid received approval from of favourable outcomes (cure or In February 2016, Otsuka and the European Medicines Agency treatment completed) (75.5% the GDF announced a price of $1,700 (EMA) and Japan’s Pharmaceuticals versus 55%) and lower mortality per treatment course, available Medical Devices Agency (PMDA) (1% versus 8.3%). to Global Fund-eligible countries in 2014. Delamanid, previously through the GDF.31 However, with The Phase III trial to assess efficacy OPC-67863, is a drug of the delamanid currently registered in just against MDR-TB using six months dihydro-nitroimidazole class and Japan, South Korea and the European is thought to primarily inhibit of delamanid added to a WHO- Union, programmatic access in the synthesis of methoxy-mycolic and recommended Optimal Background medium term will remain extremely keto-mycolic acid, components of Regimen has recently completed difficult, while in the short term, the mycobacterial cell wall. recruitment and results are most countries will have to issue expected late 2017/early 2018. import waivers. Clinical trial data come from three related Phase IIb studies WHO issued interim guidelines At this time there is no evidence on the same cohort of MDR-TB on the use of delamanid to treat on the safety and efficacy of patients (Trial 204, Trial 208 and MDR-TB in November 2014. The combining delamanid with Observational Study 116). These scale up of the use of delamanid has bedaquiline, and there is no studies showed promising results been slow, with just 180 patients on recommendation regarding their amongst patients who received delamanid outside of clinical trials combination. Drug-drug interaction 6-8 months of treatment with as of February 2016. The majority studies are due to commence in delamanid, compared to those who of patients who have accessed early 2016 to look at the cardiac received 0-2 months of delamanid, delamanid have done so through safety of combining these two drugs with significantly higher proportion compassionate use programmes. with QT prolongation potential.103

38 Médecins Sans Frontières | March 2016 DELAMANID (D lm ) NEW DRUG/GROUP 5

Prices The working statement (Form 27) There is no indication yet whether The GDF price for Global Fund-eligible related to the patents on the drug, Otsuka will negotiate a voluntary countries is $1,700 per treatment as submitted to the Indian patent licence with the MPP that will course.31 Given that delamanid is just office, reveals a startling fact - that include a broad geographic scope one drug combined with multiple the patented invention is not being that includes all low- and middle- other drugs needed to form a DR-TB worked in India. The working income countries. regimen, this price is prohibitively statement also shows that neither Paediatrics expensive for most high-burden is it being imported from any The safety and effectiveness of countries. The manufacturer has not other country, nor there are any delamanid in children has not disclosed the pricing strategy for non applicable licences or sub-licences been established. Global Fund-eligible countries. on the invention. Paediatric studies are currently Number of quality sources The patent on the base compound underway. Bioequivalence studies Delamanid has received approval of delamanid has also been granted have been completed. Patient only from the EMA, Japan and in China, South Africa and the US, cohorts have commenced enrolment South Korea. Registration has been and will expire between 2023-2025.94 with data submitted for 6 to 15 submitted in China and Hong Kong. The patent application remains years old age group, commencing 94 Patents pending in Brazil. In addition, there enrolment for the 3 to 5 years old The originator company Otsuka is one patent on the composition cohort and 0 to 3 years old groups. has applied multiple patents of delamanid and its derivative 104 There is a paediatric formulation upon delamanid. forms , and another patent on the combination of delamanid and other under development. India - a key producer of TB drugs - 105 compounds , have been granted in HIV co-infection has granted the compound patent India, China and South Africa, and Early research shows delamanid on delamanid (IN250365) to Otsuka 60 remain pending in Brazil. These does not have a significant effect Pharmaceutical Ltd, which is set to 94 patents will remain valid until 2026. on concentrations of tenofovir, expire in 2023. By granting the salt lopinavir–ritonavir, or efavirenz. form patent (9790/DELNP/2009) A number of other secondary Lopinavir plus ritonavir however, of the drug (an obvious form), the patents on delamanid may also was associated with a 20% increase patent office has already extended add to the obstacles in introducing in delamanid exposure and a 30% the monopoly an additional three generic products into the market. increase in delamanid’s metabolite years, from 2023 to 2026. Another In particular, two patents covering DM-6705.110 application (1255/KOLNP/2008) on the process of producing delamanid its use in combination with other intermediates have been granted More detailed studies are required. drugs has been also granted. in India and China, and will remain Special caution valid until 2023-2025.106,107 A Further, Otsuka, which holds Delamanid can affect cardiac separate patent on the process of multiple Indian patents (DEL conduction (QT prolongation). preparation of delamanid has also compound IN250365, DEL salt form QT prolongation can infrequently been granted in India and China, IN253642 and DEL combination result in a serious (rarely fatal) and will expire in 2025.108 In China, IN268015) for this drug, has also fast/irregular heartbeat, known an additional patent on delamanid not exerted itself to work the patent as torsades de point. This is an intermediate has also been granted in India by filing for registration, important consideration as several and will expire in 2031.109 doing necessary local trials or other drugs (such as moxifloxacin making the drug available to the As of November 2015, the Medicines and bedaquiline) and repurposed national TB programme, even Patent Pool (MPP) has been given TB drugs (clofazimine) have a though over three years have lapsed with a mandate to negotiate similar risk and it is unclear if this since the grant of the patents. voluntary licences for TB drugs. will be an additive effect.

DR-TB Drugs Under the Microscope 39 ANNEX 1: SUMMARY TABLE OF PRICES PROVIDED BY PHARMACEUTICAL COMPANIES

The price corresponds to the price of one unit (tablet, capsule, etc.). Please refer to Annex 2 for the conditions of eligibility set by individual companies, and for the incoterms associated with these prices.

GDF pooled Drug Companies procurement

AMIKACIN GDF Cadila Cipla Pharmatex Vianex

500mg/2ml solution 0.678-0.805 0.980 1.600 0.678 2.500 for injection

KANAMYCIN Macleods Meiji Panpharma

Manufacturer did not agree 1g powder for injection 1.000-1.721 1.000 xx to publish prices

1g/4ml solution for Manufacturer did not 2.560 xx xx injection agree to publish prices

CAPREOMYCIN Akorn Aspen Hisun Macleods Vianex

Manufacturer did not agree 1g powder for injection 3.800-4.700 8.000 8.100 4.150 6.000 to publish prices

MOXIFLOXACIN Cipla Hetero Macleods Microlabs Sunpharma

Manufacturer did not 400mg tablet 0.437-0.540 0.600 0.660 0.580 0.510 agree to publish prices

LEVOFLOXACIN Apotex* Cipla Hetero Labatec Macleods Microlabs

250mg tablet 0.033-0.055 0.090 0.061 0.059 1.538 0.043 0.057

500mg tablet 0.059-0.097 0.130 0.110 0.105 2.315 0.078 0.092

750mg tablet 0.100 0.150 xx 0.240 xx 0.128 xx

ETHIONAMIDE Macleods Cipla Lupin Macleods Microlabs

125mg tablet xx 0.112 xx xx xx xx

Manufacturer did not agree 250mg tablet 0.062-0.080 xx 0.098 0.066 0.082 to publish prices

PROTHIONAMIDE Fatol Lupin Microlabs Olainfarm

Manufacturer did not agree to Manufacturer did not 250mg tablet 0.130-0.178 0.120 0.100 publish prices agree to publish prices

CYCLOSERINE Cipla Dong-A Macleods Microlabs Strides

Price was not available at time Manufacturer did not 250mg cap 0.187-0.330 0.216 0.390 0.600 of data collection agree to publish prices

TERIZIDONE Fatol Macleods

Manufacturer did not agree to 250mg capsule 1.588-1.666 0.850 publish prices

PAS Jacobus

4g sachet 1.333 1.500

PAS-SODIUM Macleods Olainfarm ANNEX 1: SUMMARY TABLE OF PRICES PROVIDED BY PHARMACEUTICAL COMPANIES TABLE ANNEX 1: SUMMARY 60% w/w granules – 1.690 1.690 xx 9.2g sachet

60% w/w granules – 18.360 18.360 xx 100g jar

Powder for oral solution – 1.370 xx 1.400 5.52g sachet

CLOFAZIMINE Novartis

Manufacturer did not agree to 50mg soft-gel capsule 0.547-0.713 publish prices

Manufacturer did not agree to 100mg soft-gel capsule 1.095-1.267 publish prices

LINEZOLID Hetero Macleods Pfizer

Manufacturer has not made 600mg tablet 5.350-5.480 5.800 5.500 pricing strategy public

100mg/ml powder Manufacturer has not made xx xx xx for suspension pricing strategy public

BEDAQUILINE Janssen

Tiered pricing based on disease 0.00 burden and affordability. Please 100mg tablet (donation) refer to both GDF and/or USAID donation program

DELAMANID Otsuka

Manufacturer has not made 50mg film coated tab 2.530 pricing strategy public for non Global Fund-eligible countries

* Incoterm CIF

40 Médecins Sans Frontières | March 2016 ANNEX 2: CONDITIONS OF OFFER, AS QUOTED BY COMPANIES ANNEX 2: CONDITIONS OF OFFER, AS QUOTED BY COMPANIES

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

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

AKORN Price is eligible outside US and No restriction Min. purchase: one batch Ex-works Canada only

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

ASPEN South Africa only No restriction Ex-works

CADILA All countries except European No restriction Price is valid until Ex-works countries & USA November 2016

CIPLA Generic accessible countries Public sector Ex-works

DONG-A Ex-works

FATOL No restriction No restriction Ex-works

HETERO No restriction No restriction Ex-works

JACOBUS No restriction No restriction Ex-works

JANSSEN All countries In low- and middle-income As of 1st April 2015, USAID Delivery of goods is countries, bedaquiline is made and Janssen have jointly done in a majority available through the Global Drug announced a four-year of cases via the Facility. Alternatively, for selected bedaquiline donation Global Drug Facility. middle- and high-income countries program. For further Please refer directly bedaquiline is also supplied details on eligibility please to the GDF for full through the local Janssen affiliate refer to http://www.stoptb. information. directly to the MoH/NTP (or org/gdf/drugsupply/ designated purchasing entities). bedaquiline.asp

LABATEC

LUPIN All countries where GDF, MSF, All institutional buyers, Ex-works UNDP, PAHO or Damien are including GDF, MSF, PAHO, supplying TB medicines to MoH UNDP and Damien. and/or specific projects.

MACLEODS Prices are subject to volumes and Prices are subject to volumes. Ex-works registrations. Macleods will not ship Macleods has no restrictions in to countries where products are selling products to any customer. under patent. Macleods will not ship to countries where products are not registered, without a registration waiver.

MICROLABS No restriction No restriction Ex-works

OLAINFARM No restriction No restriction Ex-works

OTSUKA No price communicated No restriction Ex-works

PANPHARMA

PHARMATEX No restriction No restriction Ex-works

SUNPHARMA No restrictions as long as goods are No restriction Ex-works imported against an import permit or a valid registration in that country.

VIANEX No restriction except USA No restriction Ex-works

For more information on incoterms used to describe delivery of goods, please refer to the Glossary.

DR-TB Drugs Under the Microscope 41 ANNEX 3: COMPANY CONTACTS

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

Akorn Hetero Microlabs Lana Vostrova Prashant Sisodia N.K.Kothari Associate Director, Global Business Development Vice President, International Marketing President, International Operations 1925 West Field Court, Suite 300, Hetero Labs Ltd, Hetero Corporate, 7-2-A2, Microlabs Ltd, No.11 Bank Street, Lake Forest, Illinois 60045 USA Industrial Estates, Sanath Nagar, Kilpauk, Chennai 600010, India Tel: +1 631 789 8228 (ext. 4185) Hyderabad-500 013, Telangana, India Tel: +91 44 26450789, 26471205 E-mail: [email protected] Tel: +91 40 23704923/24/25 E-mail: [email protected], [email protected] E-mail: [email protected] Apotex Patti Black Jacobus Olainfarm Manager, International Tenders Laura Jacobus Mrs. Elena Vasilevskaya 150 Signet Drive, Toronto, Senior Manager, Business Development Division ANNEX 3: COMPANY CONTACTS ANNEX 3: COMPANY Ontario Canada M9L 1T9 Vice President Jacobus Pharmaceutical Co. Inc., 5 Rupnicu Street, Olaine LV-2114, Latvia Tel: +1 416 401 7345 Tel: +371 67013745 37 Cleveland Lane, Princeton, E-mail: [email protected] E-mail: [email protected], New Jersey 08540 USA [email protected] Aspen Tel: +1 609 921 7447 (Ext. 208) Stavros Nicolaou E-mail: [email protected] Otsuka Senior Executive, Strategic Trade Development Building 7, Healthcare Park, Woodlands Janssen Marc Desito Communications Director Drive, Woodmead, Sandton, 2196 South Africa Ross Underwood 7 Rue du Mont-Blanc, 1201 Geneva, Tel: +2 711 239 6798 Global Access Commercial Leader E-mail: [email protected] Switzerland Janssen Pharmaceuticals Inc, Tel: +41 22 5607960 1000 U.S. Route 202 South, Raritan, E-mail: [email protected] Cadila New Jersey 08869 USA Supreet Sharma Tel: +1 908 722 5393 PanPharma Manager, International Business E-mail: [email protected] Cadila Pharmaceuticals Ltd, Sarkhej Dholka Road, Gildas Blonsard Bhat, Ahmedabad - 382210, Gujarat, India Sales Manager Labatec Tel: +91 27 18225001 ZI du Clairay 35133 Luitré, France E-mail: [email protected] Faisal Darwazeh Tel: +33 299979212 General Manager E-mail: [email protected] Cipla 31 Rue du Cardinal Jounet, Mr. Sharadd Jain, Mr. Rahul Lande 1217 Meyrin, Switzerland Pharmatex Global Institutional Business Tel: +41 5937825 Antonio Sergio Tripodi Cipla Ltd, 289, Belasis Road, E-mail: [email protected] CEO Mumbai Central, Mumbai-08, India Pharmatex Italia Srl, Via Appiani, Tel: +91 22 2302 5387, 5686 Lupin 22-20121 Milan, Italy E-mail: [email protected] Srikant Kulkarni/Mukul Jerath Tel: +39 02 29000410 [email protected] Senior Vice President-Exports/ E-mail: [email protected] General Manager-Global Institutional Business Dong-A Lupin Limited, Laxmi Towers, B Wing, Sunpharma Patch Lee 4th Floor, Bandra Kurla Complex, Ravi Mehta Regional Manager Bandra (East), Mumbai, India 400086 Head of Global ARV Business 64, Cheonho-daero, Dongdaemun-gu, Tel: +91 22 66402242 Sun Pharmaceutical Industries Ltd, 201 B/1, Seoul, South Korea Western Express Highway, Georegaon [E], E-mail: [email protected] Tel: +82 2 920 8683 Mumbai 400063, India [email protected] E-mail: [email protected] Tel: +91 22 43244324 E-mail: [email protected] Macleods Fatol Ulrike Wandt Vijay Agarwal Vianex International Business Business Development Director Mrs. Lemonia Xenitos RIEMSER Pharma GmbH, Site Fatol Macleods Pharmaceuticals Lts, Export Director Arzneimittel, Robert-Koch-Strasse, 304 Atlanta Arcade, Andheri Kurla Road, Tatoiou Street, 18th km National Road 66578 Schiffweiler, Germany Andheri East, Mumbai, 400099 India Athens-Lamia, 146 71 Athens, Greece Tel: +49 30 33 84 27 411 Tel: +91 22 61132900 Tel: +30 210 800 9634 E-mail: [email protected] E-mail: [email protected] E-mail: [email protected]

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Continued overleaf

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ABBREVIATIONS

ANDA – Abbreviated New Drug GDF – Global Drug Facility PAS – Para-aminosalicylic acid Application GFATM – Global Fund to Fight AIDS, PIH – Partners In Health API – Active pharmaceutical ingredient Tuberculosis and Malaria PQ – Prequalification API PQ – Active Pharmaceutical GLC – Green Light Committee R&D – Research and development Ingredient-Prequalification HIV – Human immunodeficiency virus SRA – Stringent regulatory authority CEWG – Consultative Expert IDR – Interactive Research TB – Tuberculosis Working Group & Development TDR-TB – Totally drug-resistant CIS – Commonwealth of IP – Intellectual property tuberculosis Independent States LIC – Low-income countries TRIPS – (Agreement on) Trade-Related DR-TB – Drug-resistant tuberculosis Aspects of Intellectual Property Rights MDR-TB – Multidrug-resistant DS-TB – Drug-sensitive tuberculosis tuberculosis USAID – US Agency for EMA – European Medicines Agency International Development MCC - Medicines Control Council EML – Essential Medicines List (South Africa) US FDA – US Food and Drug Administration EoI – WHO Prequalification MIC – Middle-income countries Expression of Interest w/w – weight for weight MRC – Medical Research Council (UK) ERP – Expert Review Panel WHO – World Health Organization MSF – Médecins Sans Frontières WHO PQ – World Health Organization EU – European Union NMRA – National Medicine Prequalification Programme FDC – Fixed-dose combination Regulatory Authority XDR-TB – Extensively drug-resistant GLI – Global Laboratory Initiative NGO – Non-governmental organisation tuberculosis

46 Médecins Sans Frontières | March 2016 GLOSSARY GLOSSARY

Abbreviated New Drug adverse effects of other treatments) Expert Review Panel (ERP) Application (ANDA) for health interventions (e.g., drugs, An independent technical body An Abbreviated New Drug Application diagnostics, devices, therapy protocols). composed of external technical experts, (ANDA) contains data that, when hosted by the WHO Department of Compassionate Use submitted to the US FDA, provides for Essential Medicines and Pharmaceutical The terms “compassionate use,” the review and ultimate approval of a Policies. Their purpose is to review the “expanded access” or “special access” generic drug product. Generic drug potential risks and benefits associated applications are called “abbreviated” programmes have essentially the same with the use of antiretroviral, anti-TB and because they are generally not meaning. They refer to programmes antimalarial products which are not yet required to include preclinical that are intended to provide potentially WHO-prequalified or authorised by a (animal) and clinical (human) data to lifesaving experimental treatments stringent regulatory authority. The ERP establish safety and efficacy. Instead, to patients suffering from a disease makes recommendations to the Global a generic applicant must scientifically for which no satisfactory authorised Fund and the Global Drug Facility on demonstrate that its product is therapy exists and/or who cannot enter whether procurement of such products bioequivalent (i.e. performs in the a clinical trial. It refers to programmes can be authorised. The recommendation same manner as the innovator drug). that make medicinal products available is valid for a period of no more than 12 Once approved, an applicant may either on a named-patient basis or to months or until the product is either manufacture and market the generic cohorts of patients. Compassionate WHO-prequalified or SRA-authorised. drug product to provide a safe, use needs to be framed within national (http://www.theglobalfund.org/en/ effective, low-cost alternative in the US. legislation that establishes under procurement/quality/pharmaceutical/). what conditions the drug is made Bangladesh trial/regimen available. Refer to Annex 5 (Use of Extensively drug-resistant TB A non-randomised observational study experimental drugs outside of clinical see XDR-TB in Bangladesh which looked at a nine- trials “compassionate use”) of the Extra-pulmonary TB month combination of existing TB WHO Guidelines for the programmatic Form of TB where M. tuberculosis drugs for the treatment of MDR-TB. The management of drug-resistant infects parts of the body other than study regimen included ethambutol, tuberculosis: Emergency update 2008. the lungs. This occurs most commonly pyrazinamide, gatifloxacin and in the lymph nodes, bones, central clofazimine throughout, supplemented Culture nervous system, cardiovascular and by kanamycin, prothionamide and high- Bacterial culture is a laboratory method gastrointestinal systems. dose isoniazid in the first four months. to multiply bacteria in order to assess their presence or not in a patient’s First-line drugs Active pharmaceutical ingredient (API) sample. This is done by letting the The drugs used as the first resort to Any substance or mixture of substances bacteria grow in predetermined culture treat a disease. In the case of TB, the intended to be used in the manufacture media under controlled laboratory following four drugs are usually chosen: of a pharmaceutical dosage form and conditions, outside the natural isoniazid (H), rifampicin (R), ethambutol that, when so used, becomes an active environment where they usually grow (E), pyrazinamide (Z). These drugs are ingredient of that pharmaceutical highly effective in drug-susceptible TB dosage form. (e.g. for TB, the human body). and patients usually tolerate them well. CIF: Cost, Insurance and Freight Drug resistance Streptomycin (S) injectable is used in (named port of destination) When a drug used to treat tuberculosis first-line treatment of TB meningitis. A commercial term (incoterm 2010), is in fact ineffective against a strain of Global Drug Facility (GDF) meaning that the seller must pay M. tuberculosis, the bacteria is said to A mechanism hosted by UNOPS to the costs and freight to bring the be resistant to the drug (as opposed to expand access to, and availability goods to the port of destination. drug-susceptible or drug-sensitive). of, quality-assured anti-TB drugs Risk is transferred to the buyer once Drug-susceptible/drug-sensitive TB and diagnostics through pooled the goods are loaded on the vessel. Bacteria are said to be sensitive to a procurement. Products procured comply Insurance for the goods is included drug when the drugs are effective in with the GDF’s Quality Assurance and paid by the seller; only maritime killing or stopping the multiplication of policy, which deems eligible for GDF transports are covered. bacteria in the body and can therefore procurement all products that are CIS: Commonwealth of clear the infection. The strains of TB included on the WHO List of Prequalified Independent States which are sensitive to all first-line drugs Medicinal Products, that are approved The Commonwealth of Independent are called drug-susceptible. by a stringent regulatory authority, or States is a regional organisation formed Ex-works that are temporarily approved by the during the breakup of the Soviet Union, A commercial term (incoterm 2010) Expert Review Panel. whose participating countries are some meaning that the seller delivers when Global Fund former Soviet Republics. the goods are placed at the disposal The Global Fund to Fight AIDS, Clinical trials of the buyer at the seller’s premises Tuberculosis and Malaria is an Sets of tests in medical research and or another named place (i.e. works, international financing institution that drug development that generate safety factory, warehouse etc.), not cleared invests in 150 countries to support large- and efficacy data (including information for export and not loaded on any scale prevention, treatment and care about adverse drug reactions and collecting vehicle. programs against the three diseases.

Continued overleaf

DR-TB Drugs Under the Microscope 47 Glossary continued

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

48 Médecins Sans Frontières | March 2016 ACKNOWLEDGEMENTS:

Médecins Sans Frontières wishes to thank manufacturers and the Global Drug Facility for sharing price information for this publication.

Front cover photo: © Helmut Wachter

Back cover photo: © Helmut Wachter

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

DISCLAIMER: DR-TB Drugs Under the Microscope - The Sources and Prices of Medicines for Drug-Resistant Tuberculosis is a pricing guide and cannot be regarded as a company price list nor as a clinical guideline. It is crucial that any purchaser verify prices and availability as well as quality status directly with the supplier before procurement. Médecins Sans Frontières (MSF) has made every effort to ensure the accuracy of prices and other information presented in this report, but MSF makes no representations or warranties, either expressed or implied, as to their accuracy, completeness or fitness for a particular purpose. Inclusion of a product in this document does not indicate MSF purchases or uses the product. Information in this guide is indicative only and not exhaustive, and should be verified with relevant offices when used for purposes other than providing general information. Clinical decisions should not be made based on this document.

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