DR-TB Drugs Under the Microscope

THE MSF CAMPAIGN FOR ACCESS TOESSENTIAL MEDICINESIn 1999, in the wake of Médecins Sans Frontières (MSF) beingawarded the Nobel Peace Prize, MSF launched the Campaign forAccess to Essential Medicines. Its sole purpose has been to pushfor access to, and the development of life-saving and life-prolonging medicines, diagnostics and vaccines for patients inMSF programmes and beyond.

THE INTERNATIONAL UNION AGAINSTTUBERCULOSIS AND LUNG DISEASEThe mission of the International Union Against Tuberculosis andLung Disease (The Union) is to bring innovation, expertise,solutions and support to address health challenges in low- andmiddle-income populations. With nearly 10,000 members andsubscribers from 152 countries, The Union has its headquarters inParis and offices serving the Africa, Asia Pacific, Europe, LatinAmerica, Middle East, North America and South-East Asia regions.Its scientific departments focus on tuberculosis and HIV, lunghealth and non-communicable diseases, tobacco control andresearch.

March 2011

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TABLE OF CONTENTS

14 Introduction

16 The problems that plague DR-TB medicines17 Limited number of quality sources 19 Limited affordability10 The neglect of children, and people living with HIV/AIDS12 Conclusions: Breaking the vicious circle

14 Drug Profiles

Group Two: Injectables14 Kanamycin16 Amikacin18 Capreomycin

Group Three: Fluoroquinolones20 Moxifloxacin22 Levofloxacin24 Ofloxacin

Group Four: Oral bacteriostatic second-line agents26 Ethionamide28 Prothionamide30 Cycloserine32 Terizidone34 PAS

Group Five: Agents with unclear efficacy36 Clofazimine38 Linezolid

Annexes40 Methodology41 Glossary and Abbreviations43 References45 Company contacts47 Disclaimer

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Introduction

Tuberculosis (TB) is a curable diseasethat continues to kill nearly 1.4 millionpeople1 across the globe each year,and is the main cause of death inpeople living with HIV/AIDS2. Of the9.4 million new tuberculosis cases eachyear, 440,000 are forms of the diseasethat are multi-drug-resistant3, meaningthey can not be treated with the twoprimary antibiotics used to treat TB.Over the last decade, roughly fivemillion people developed drug-resistant TB, but less than 1% hadaccess to appropriate treatment, and1.5 million died4.

That such an appallingly lowproportion of patients should accessappropriate treatment is due to anumber of factors. Treating DR-TB iscomplicated from a programmatic

perspective: treatment is individualised,tailored according to which drugs apatient is resistant to. It is long andtaxing, requiring people to take acourse of antibiotics for up to twoyears and endure often intolerable sideeffects. Partly as a result of thecomplexities of treatment,programmes must devote considerableresources to adherence counselling, themanagement of side effects andpsychosocial care, all of which placelarge demands on human resources. Insome countries, the lack of political willto appropriately address DR-TB is amajor barrier.

Another factor that hampers scale-upof treatment - and the focus of thisreport - is the limited availability andhigh cost of quality-assured second-line

medicines. For many DR-TB medicines,the sustainability of drug supply isconstantly under threat and thereforeextremely vulnerable to disruption. Forsome medicines, there is only onequality-assured source, while for othersthere may be several but they all relyon a single source of the activepharmaceutical ingredient required tomake the drug.

Some of the DR-TB drugs come atextremely high prices, with the resultthat one patient's treatment can costalmost $9,000 - nearly 475 times morethan a $19 treatment course for drug-sensitive TB. Alarmingly, in recent yearsprices have actually been increasing assome manufacturers put an end tosubsidies that have kept prices lower.

DR, MDR, XDR, PDR: the many faces of resistant TBDrug-resistant tuberculosis (DR-TB) is used to describe strains of TB that show resistance to one or more first-line drugs.Multidrug-resistant tuberculosis (MDR-TB) is defined by TB that is resistant to at least isoniazid and rifampicin, the twomost powerful anti-TB drugs.

Extensively drug-resistant tuberculosis (XDR-TB) is caused by strains of MDR-TB that are also resistant to second-linedrugs, including at least one from the class of fluoroquinolones, and at least one of three injectable second-line drugs(capreomycin, kanamycin and amikacin).

All forms of resistance to more than one of the first-line antibiotics, and which are neither MDR-TB nor XDR-TB, aredefined as polydrug-resistant TB (PDR-TB).

MSF AND TB

In 2010, MSF treated close to 30,000 peoplefor tuberculosis, of which 3,300 werechildren under the age of 15. MSF - oftenworking alongside national health authorities- treats patients for TB in 29 countries in awide variety of settings, ranging from urbanslums to rural areas, prisons or refugeecamps.

In recent years, MSF has worked to increasethe numbers of people it treats with drug-resistant tuberculosis from 11 patients in2001 to around 1,000 people across 15countries in 2010.

THE UNION AND TBThe International Union Against Tuberculosis and Lung Disease(The Union) has been the leading international TB control andprevention agency since 1920. Each year The Union works inmore than 70 countries, providing technical assistance at therequest of national tuberculosis control programmes; conductingoperational research and clinical trials; organising conferencesand courses; and publishing both a peer-reviewed journal and arange of technical guides. In addition, The Union regularlymonitors MDR-TB project sites and provides technical assistanceon all aspects of MDR-TB management in Africa, Asia, LatinAmerica and the Middle East. Its clinical trial of a shortenedstandardised MDR-TB treatment regimen will begin enrollingpatients in 2011 and has the potential to revolutionise themanagement of MDR-TB.

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DR-TB can be cured, but treatmentrequires people to take a course of upto six different antibiotics – as many as20 pills per day for up to two years,plus, for the first six months, a dailypainful injection. Patients often endureintolerable side effects. These caninclude nausea, severe vomiting,depression, aggressive behaviour,hallucinations, vertigo, hearing loss,diarrhoea and lethargy. Patientsmay need to take additionalmedication to mitigate these sideeffects. Treatment needs to betailored to the precise drugs thatwill be effective for a patient,depending on their drug-resistanceprofile. People's lives are interruptedby DR-TB treatment, and many findadhering to it too arduous to bear.Happiness Dlamini from Swazilandshares what life is like on DR-TBtreatment.

Happiness Dlamini lives with hereleven year-old son and four-yearold daughter in the village ofEmhlabeni - four hours drive fromMbabane, the capital ofSwaziland. Before getting sick, sheworked as a housekeeper. She isliving with HIV and is also infectedwith multidrug-resistanttuberculosis, which is all toocommon in the small southernAfrican country. One third of thosenewly diagnosed with TB inSwaziland have DR-TB12.

“I had been coughing for a longtime, so after discussion with myfamily, we felt I should go gettested for TB,” she says. “I wasvery scared when they told me Ihad MDR-TB. To me, it meant theend of my life, because everyonein my community that I knew hadMDR-TB had died.”

Happiness learned that if she wasable to stick to her treatment, shehad a good chance at surviving

MDR-TB. She started treatmentthrough MSF's community careMDR-TB programme in ShiselweniRegion, after she was diagnosed inDecember 2010. When she startedtreatment, she had to take 18 and ahalf tablets every day, in addition toreceiving a painful injection from ahealth worker who comes to herhome. Now, over three months laterher daily routine still consists of aninjection and 15 and a half pills.

The side-effects the medicines causeare harsh - she can barely list all ofthem - and have made her feelmentally unstable and physically ill.

“It was like I was losing my mind - Ihad hallucinations and found myselfbanging against things at night,”she says. “I have sore feet and mylegs cramp up. I have diarrhoea andI often vomit after taking the pills, soI have to take them again if it was

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

Photo © Krisanne Johnson

within 30 minutes to make sure I'mnot defaulting on my treatment.”

Every day, Happiness struggles notonly with the burdens of treatment,but with the stress of not being ableto provide for her family. Andkeeping her distance from herchildren to make sure they don'tget infected is affecting herrelationship with her four-year-olddaughter in particular - littleNokwenza has now become closerto her grandmother.

Happiness has responded well totreatment so far and has beendetermined to stay the course. Butshe does not find it easy to beoptimistic.

“I have to be honest that when itcomes to my future, I am veryunsure,” Happiness says. “I reallydon't know what will happen.”

Happiness Dlamini lies with her daughter Nokwenza outside her home inSwaziland. She keeps her distance so she does not spread MDR-TB to her child.

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This report provides an overview ofavailable DR-TB medicines, providingrelevant information for each product,including its sources, quality status andprice, that can aid treatment providers,treatment programmes and nationalprocurement centres in makingprocurement decisions. Transparencyof price and quality information is oneproblem that this document also aimsto help overcome. In providing thisoverview, a number of importantproblems that hamper access tomedicines are brought to light.

The medicines examined in this reportare those DR-TB drugs classified ingroups 2-5 of the World HealthOrganization's 2008 Guidelines for theProgrammatic Management of Drug-resistant Tuberculosis. Certain problemsare more relevant to some drug classesthan others.

GROUPING

Group 1 - First-line oral agents

Group 2 - Injectable agents

Group 3 - Fluoroquinolones

Group 4 - Oral bacteriostatic second-line agents

Group 5 - Agents with unclearefficacy

DRUGS

isoniazid*, rifampicin*,ethambutol*, pyrazinamide*,rifabutin*

kanamycin, amikacin, capreomycin,streptomycin*

moxifloxacin, levofloxacin,ofloxacin

ethionamide, prothionamide,cycloserine, terizidone, p-aminosalicylic acid (PAS)

clofazimine, linezolid,amoxicillin/clavulanate*,thioacetazone*,imipenem/cilastatin*, high-doseisoniazid*, clarithromycin*

The problems that plague DR-TB medicines

* this report does not include first-line oral agents, first-line injectable agents, or certain group 5 agents

In response to a growing need forDR-TB treatment - and to preventfurther drug resistance fromdeveloping through improper useof DR-TB drugs - the World HealthOrganization, together with MSF,and other partners, created the'Green Light Committee' Initiative(GLC) in 20009. The core functionof the Green Light Committee hasbeen to provide technical review ofproposed DR-TB treatmentprojects, and 'green-light' them ifthey meet certain criteria.Approved projects then get accessto quality-assured drugs at reducedprices - since 2002, these havebeen procured through the WHO-hosted Global Drug Facility.

From 2000 to end 2010, a cumulative total of 105,140 patients were approved for treatmentthrough the GLC - although lessthan half of these (under 30,000patients) had actually been startedon treatment by the end of 200972.

Until now, programmes without GLCapproval are not allowed to turn tothe Global Drug Facility to accessWHO quality-assured medicines.

Not surprisingly, nearly one decadeon, only 13% of the estimated DR-TB drug market is channelledthrough the Global Drug Facility. In2010, only 12,000 patients wereenrolled in GLC-approved treatment

programmes, compared to anestimated 440,000 new cases and150,000 deaths3.

Many programmes continue to useDR-TB drugs from outside the GLCprocess, where drug quality may beuncertain, and drug prices may besubstantially higher7. This isespecially concerning in countrieswith the highest disease burden.

The GLC Initiative has beenundergoing a reform process sinceearly 2010 and an intended keychange is to let all programmespurchase quality-assured medicinesthrough the GDF13.

How countries procure DR-TB drugs

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Global DR-TB drug market

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

The market has been growing by approximately 5% per year, with India and China taking the largest share, at 63% and17%, respectively17.

Relatively few products for thetreatment of drug-resistant tuberculosisare included on the WHO List ofPrequalified Medicinal Products orapproved by a stringent drugregulatory authority such as the USFood and Drugs Administration. Suchquality approval is a requirement bydonors financing MDR programmessuch as the Global Fund to Fight AIDS,TB and Malaria.

To date, of the DR-TB medicinescovered in this report, only sixproducts (for five different drugs) havebeen prequalified by WHO and onlyfour sources (for two differentmedicines) are recommended forpurchase in 2011 by the Expert ReviewPanel14, a joint mechanism of theGlobal Fund to Fight AIDS, TB, andMalaria and the GDF that givestemporary purchase permission fordrugs still under evaluation.

Few quality-assured sources exist.For many DR-TB drugs, such ascapreomycin, prothionamide,terizidone, PAS and clofazimine, onlyone quality-assured source exists. Forothers, including ethionamide*,moxifloxacin and PAS-Sodium, thereare only two quality-assured sources.Although there has been some recentprogress - with a decrease in thenumber of products that had only onesupplier, down from 11 in 2008 to fourin 20115 - for all of these medicines,supply is extremely vulnerable todisruption.

1. Limited number of quality sources

The example of kanamycin illustratesthe risks associated with relying on fewsources for a given medicine. In thepast, several manufacturers hadkanamycin registered for use in the US,although all but one subsequentlyceased production, because of fallingdemand in wealthy countries. Today,only three quality-assured sources areidentified. Of those, the first was forcedto suspend production because of therelocation of its supplier of activepharmaceutical ingredient in 2009.The second also experienced a supplyproblem in 2010 and ceasedproduction for a period of time, leavingprogrammes dependent on a thirdmanufacturer with limited capacity, somuch so that its production is solelydedicated to GDF procurement,leaving other DR-TB treatmentprogrammes with no quality-assuredsource.

For a number of DR-TB medicines,multiple producers in Russia, India,China and other countries are knownto manufacture DR-TB drugs, butwhether they could comply with WHOor stringent regulatory authoritystandards is unknown. Part of theproblem of too few quality-assuredsources for international supply couldbe resolved by encouragingmanufacturers to improve theircompliance with internationallyrecognised quality standards andsubmit product dossiers for qualityassessment through the WHOPrequalification Programme orstringent regulatory authorities.

One welcome step is that the GlobalDrug Facility now has a clear policy,sending a signal to manufacturers toinvest in quality, by requiring productsto be either quality assured by theWorld Health Organization'sprequalification programme, orapproved by the Expert Review Panel.The Panel provides time-limitedapproval for products that have fewerthan three sources approved by eitherthe WHO Prequalification or a stringentregulatory authority. With theimplementation of the GDF quality-assurance policy, price is no longer themain determinant for purchasingdecisions.

Sources of active pharmaceuticalingredients are limited. Thedifficulties faced in trying to increasethe number of quality-assured sourcesfor some DR-TB drugs are to a largeextent due to those associated with theproduction of the activepharmaceutical ingredient (API). Forseveral drugs, such as capreomycin andkanamycin, only one quality-assuredAPI source has been identified. In thecase of capreomycin, all quality-assuredfinished products identified in thisdocument are reliant on a single sourceof API, again making the entire supplyof capreomycin extremely vulnerableto disruption. A recent study for theGDF noted that the supply of API wasvulnerable for amikacin, kanamycin,prothionamide and clofazimine11.

Part of the problem is due to thecomplexity of production. For

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

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example, producing the API for theinjectables capreomycin and kanamycinrequires a fermentation process that ismore complex than the syntheticprocess. The complexity is furtherincreased as the API should be sterile.

Some medicines that are activeagainst DR-TB are not reaching theDR-TB market. Developed for thetreatment of infectious diseases, somemedicines do not have an approvedindication for use in DR-TB, even thoughthey have shown efficacy in in-vitrostudies and have been used for manypatients and recommended intreatment guidelines. This is particularlythe case for the latest group ofantibiotics used in DR-TB treatment, thefluoroquinolones (such as moxifloxacin, levofloxacin andofloxacin).

Although a number of quality-assuredmanufacturers exist for such medicines -in the case of levofloxacin, for example,there are 13 producers that havesecured tentative approval in the US, formoxifloxacin there are two and forofloxacin three - none of them haveapplied to participate in the GDFprocurement tender. As such, theperspective of higher earnings bytargeting more profitable diseases thanDR-TB acts as a barrier to increasing thenumber of quality-assured sources ofDR-TB medicines.

Getting medicines into countries: Lead times and regulatory constraints

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

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

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

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

Photo © Bruno de C

ock

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2. Limited affordability

First-line TB treatment costs $19 perpatient for a six-month treatmentcourse32. Yet the cost of DR-TBtreatment is considerably moreexpensive, and this acts as a barrier totreatment scale up. For both drug-sensitive and drug-resistant TB, to theprice of the medicines must be addedsignificant costs in terms of biologicalmonitoring, human resources formedical and psychosocial care, andtreatment to counter side effects.

The price of DR-TB treatment variesconsiderably, as treatment must beindividualised according to a patient'sdrug resistance profile. Drugs procuredthrough the GLC/GDF cost between$4,400 and almost $9,000 per patientfor a standard 18-24 month treatmentcourse. For drugs purchased outside ofthe GLC/GDF, prices may be evenhigher.

These prices are a reflection ofinsufficient market competition amongmultiple producers, both at the level ofAPI production, as well as at finishedproduct level. They are also aconsequence of limited demand forDR-TB drugs, as with low volumes,manufacturers cannot hope to achieveeconomies of scale necessary to bringprices down. This is one area where anew diagnostic test, by diagnosingpatients more effectively and more

quickly with DR-TB, will increasedemand for more second-line anti-tuberculosis medicines.

The price of four medicines inparticular weigh heavily in theoverall cost of a DR-TB regimen.Overall costs of the DR-TB regimen areparticularly driven by capreomycin,moxifloxacin, PAS and cycloserine.

For most DR-TB drugs, patents arenot typically a factor in causing highprices because the medicines weredeveloped so long ago that patents onmost have long run out.

However, moxifloxacin is one notableexception. Until now, Bayer'smonopoly has kept prices high. Butnow that there is one WHOPrequalified generic moxifloxacinsource available, the situation willchange, and as the number of genericsources increases, the price should fall.Although patents claimingmoxifloxacin as a compound shouldhave expired in most countries,subsequent patents could possiblystand in the way of generic productionand/or distribution in countries wheresuch patents have been granted andremain valid.

The threat of rising prices still exists foroff-patent DR-TB drugs if producing

countries introduce additionalmonopoly protection such as dataexclusivity provisions, as for examplecurrently demanded by the EuropeanUnion as a part of the EU-India FreeTrade Agreement negotiations.

Some DR-TB drug prices haveincreased considerably between 2001and 2011, including for the medicinesprocured through the GDF for GLC-approved treatment programmes. Theprices of amikacin, kanamycin,cycloserine and capreomycin have allincreased substantially in recent years(see table below).

For kanamycin, the hike in price ispartly due to GDF turning to Meiji aftersupply problems affected theproduction of more affordable versionsmade by APPPharma and PanPharma.For capreomycin and cycloserine, therise in price can be explained by thefact that Eli Lilly has ceased production,and put an end to the subsidised pricesit was offering the GLC. Since 2003,the US company has been activelyengaged in technology transfer togeneric manufacturers, and those whonow produce charge substantiallyhigher prices. In fact, the price ofcapreomycin is expected to continuerising, and double in the near future -from $4 to $8 per unit - as Eli Lilly'sexisting stock at the GDF eventually

Prices available for GLC - approved programmes, in US$

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

Amikacin 500mg 0.11 1.20 +991%

Kanamycin 1g 0.36 2.58 +617%

Cycloserine 250mg 0.14 0.59 +321%

Capreomycin 1gr 1.02 4.00 +292%

Ethionamide 250mg 0.10 0.09 Stable

Prothionamide 250mg 0.10 0.10 Stable

PAS 4g sachet 1.51 1.57 Stable

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3. The neglect of children and people living with HIV/AIDS

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

Prices directly frommanufacturers - the overwhelmingmajority of patients who receive DR-TBtreatment are not funnelled throughthe GLC process. They may receivetreatment through nationalprogrammes or NGOs or othertreatment providers, or moreconcerning is on the private market.No analysis of the private market wasundertaken and is outside the scope ofthis report.

Until today, there has been very littleresearch to even determine the bestuse of existing drugs used for MDR-TB.In fact, today's treatment for DR-TB islargely based on experience and expertopinion, not randomised clinical trials,with a large number of 'grey areas'where expert opinions may beconflicting4.

Children are particularly neglected.At least 10-15% of total TB cases eachyear occur in children and a similarpercentage can be assumed amongnew DR-TB cases in children48. Yet onlytwo medicines featured in this report(amikacin and levofloxacin) have beendeveloped as paediatric formulations,and these are not widely available. Thismeans that treatment providers whoattempt to treat children must do soby manipulating adult formulations,such as breaking or crushing tablets toapproximate the required dose. Thiscarries a major risk or over- or under-dosing a child.

In addition, safety and efficacy data inchildren have not been established forthe majority of the medicines used inDR-TB treatment. Only three medicinesin this report have been licensed foruse in children. One of those that islicensed for paediatric use, levofloxacin,has however not been approved

beyond 14 days of treatment, when achild with drug-resistant tuberculosiswould need to take the medicine forclose to two years. For cycloserine,different guidelines give differentrecommendations so there is no clarityregarding the safety and efficacy of theuse of this drug in children.

Even when a drug is registered for usein children and a paediatric formulationdoes exist - for amikacin, for example -it is not included in the GDF productcatalogue, meaning that GLC-approved programmes cannotpurchase it through the GDF.

The interactions of DR-TB drugswith AIDS medicines are alsolargely unknown. There is preciouslittle information on how DR-TBdrugs interact with antiretroviralmedicines used to treat HIV/AIDS70 -this has not been a priority fordevelopers of HIV drugs as co-infection with TB is today uncommonin wealthy countries. This isparticularly problematic given that TBis the biggest killer of people livingwith HIV today2.

For many DR-TB medicines the crucialresearch is lacking. For kanamycin,amikacin and capreomycin, forexample, the potential for renal

toxicity when used with tenofovir(the backbone of the WHO-recommended first-line antiretroviralregimen) is unstudied. The medicinesof the fluoroquinolone class -moxifloxacin, levofloxacin andofloxacin - are thought to interactwith crucial protease inhibitors likeritonavir and atazanavir (both part ofsecond-line AIDS regimens). Druginteractions are also predictedbetween ethionamide andprothionamide and ARVs such asnevirapine and efavirenz. There isprecious little knowledge aboutpossible interactions for othermedicines, such as terizidone, PASand cycloserine.

The adaptability of some DR-TBmedicines for use in resource-poorsettings is also a concern. ManyDR-TB drugs are poorly adapted tothe constraints of health systems inhigh-burden settings. PAS requiresrefrigeration, which is an addedlogistical burden for programmes,particularly in sub-Saharan Africa. Theuse of injectable products likekanamycin and amikacin also imposesburdens both on the programme, asqualified staff will be required foradministration of the product, and onthe patient, who must undergo sixmonths of painful injections.

Photo © D

ieter Telemans

MDR-TB patients in Cambodia.

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The medicines used in DR-TBtreatment cause often intolerableside effects, which can includenausea, severe vomiting, depression,aggressive behaviour, hallucinations,vertigo, hearing loss and diarrhoea.With such a litany of complaintsassociated with drug-resistanttuberculosis treatment, many look tothe research and development(R&D) pipelines for a new regimento answer these problems.

R&D into TB drugs and diagnosticswere neglected for decades becausethe disease primarily affectsdeveloping countries and thereforedid not represent a lucrative marketfor the pharmaceutical industry. Thisapplies as much to drug-susceptibleas drug-resistant TB. In the case ofsecond-line TB medicines, however,the problem is amplified, as thedrugs used are of limitedeffectiveness, with success rates ofthe current treatment at around 80%at best.

After having been at a virtualstandstill for about 40 years, the TBdrug pipeline has seen encouragingprogress in recent years68, withrenewed R&D activities by the GlobalAlliance for TB Drug Development(the product developmentpartnership established in 2000 tofoster development of new TB drugs)and a few pharmaceuticalcompanies. However, compared toother disease R&D pipelines, TB'sremains fairly limited, and no newdrug has yet reached the market.

The objective of the TB Alliance, theleading product developmentpartnership in TB drug R&D, is todeliver a new regimen able to treatboth drug-sensitive and drug-resistant TB, shorter than currentfirst-line treatment and compatiblewith HIV treatment69. Currently thereare ten new or repurposed

compounds in the clinical developmentstage and the intention is that some ofthem will be part of a future singletreatment regimen active against bothdrug-sensitive and all forms of drug-resistant TB18.

It is questionable whether this objectivecan be achieved within reasonabletimelines. In addition, the most urgentpriority is to improve treatment ofMDR-TB, given length, toxicity andlimited effectiveness of currenttreatment.

Among the new drugs, Tibotec'sTMC20719 and Otsuka's OPC6768320

are in most the advanced stages, andhave recently completed Phase IIbclinical trials in MDR-TB patients. TMC207 is expected to get acceleratedapproval for use in DR-TB treatment asearly as 2012. However, further studieswill be needed to determine if theaddition of the new drug will allowsome of the older drugs to beremoved from the regimen and howmuch the treatment regimen can beshortened.

To ensure a range of effectivetreatment options in the long-term, alarge number of new drug candidateswith novel mechanisms of action need

to be available to allow for theselection of optimum regimens andmeet the goal of a single therapyeffective against both drug-sensitiveand drug-resistant TB. Thus drugdiscovery efforts need to be scaledup in order to have a healthypipeline able to deliver an optimaltreatment regimen.

In the immediate term, it is crucialto make today's DR-TB treatment astolerable as possible for patients.This entails conducting studies onhow to alleviate the worst sideeffects caused by existing drugs, byfor example looking at ways tospace the intake of drugs, optimisedoses, develop alternative, moreuser-friendly formulations (for theinjectables) and study their use inchildren and people living with HIV.

Part of these efforts involveexploring new combinations ofexisting medicines to reduce theduration of treatment21. A shorterregimen has already been used inBangladesh, the results of whichhave been recently published. Basedon this experience, The Union willconduct a clinical trial of thisshortened regimen and will beginenrolling patients in 2011.

R&D for TB: A long story of neglect

Photo © Krisanne Johnson

MDR-TB patient in Swaziland awaits painful daily injection

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Conclusions: Breaking the vicious circle

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

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

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

A number of targeted interventions are also needed to stimulate the MDR-TB drug market. The framework of the GreenLight Committee Initiative and the work of the Global Drug Facility may have made an important contribution but havenot yet been able to overcome supply problems and decrease prices. The GLC Initiative and the GDF have beenundergoing a reform process since early 2010 - what is needed is for GDF to take a clear break from its previous short-termapproach and limited focus on risk minimising strategies. The GDF can and should play a stronger market shaping role,guided and supported by users and donors.

The Global Drug Facility:

■ Should publish prices of medicines procured on its website in order to improve transparency.

■ Should no longer restrict sale of quality-assured medicines to GLC-approved programmes. All treatment programmes should be able to buy quality-assured medicines, as currently envisioned as part of the GLC reform;

■ Should further develop and pursue the activities outlined as a part of its 'Roadmap for MDR-TB Scale Up', which lists a number of market interventions to attract new suppliers. This roadmap includes:

■ giving manufacturers long-term contracts to ensure increased production volumes;

■ a strategic revolving fund to provide manufacturers a financial guarantee while countries await fund disbursement;

■ providing manufacturers with reliable demand forecasting per country, both in the short and in the longer term;

■ the expansion of the existing rotating stockpile to decrease the time it takes for countries to receive medicines.

■ a transparent market share allocation mechanism to manufacturers to provide incentives to manufacturers to participate in GDF procurement.

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Manufacturers and drug developers:

■ Should agree to provide information on prices and pricing conditions in order to improve the transparency on the price of DR-TB medicines

■ Should broadly register their products in endemic countries

■ Should invest in production and WHO prequalification of existing DR-TB drugs, and develop paediatric formulations adapted to resource limited settings, anticipating an international treatment scale up;

■ Drug developers currently investing in the development of new TB drugs should trial their compounds in DR-TB patient populations. Efforts should be undertaken to make new drugs available as quickly as possible via compassionate use and expanded access programmes.

■ Drug developers should study the safety and efficacy of existing and new medicines in paediatric formulations and for possible drug interactions with antiretrovirals.

Countries affected by TB:

■ Should ensure that first-line treatment is continuously available for TB patients to prevent generating new MDR-TB cases;

■ Should invest in the scale up of DR-TB treatment including investment in increased diagnostic and programmatic capacity to enrol progressively more patients on treatment. Innovative models for community-based treatment that allow to reach more patients and better are showing good results and should be supported;

■ Should commit to purchase only quality-assured medicines. This will benefit patients and act against further resistance development but will also help to create increased economies of scale for quality-assured products;

■ High-level support is needed in many high-burden countries to ensure fast track registration of DR-TB medicines or easier mechanisms for importation;

■ Good in-country drug management systems are needed to ensure continued drug supply at programme level and input into reliable international drug forecasting.

Donors:

■ Have an important role to play to guide and support financially the market interventions outlined in the GDF's Roadmap, as these are needed to improve international DR-TB drug supply and reduce prices;

■ Donors' support will be critical to ensure international treatment scale-up, although many DR-TB high-burden countries have contributed and need to continue contributing significant resources to MDR-TB programmes. It has beenestimated that $16.2 billion areneeded between 2010-2015 tosupport treatment in the 27 high-burden countries; and

■ Donors should support research to define a better and shorter DR-TB treatment regimen with the inclusion of newer drugs.

Photo © Ivan Sigal

MDR-TB patient receives care throughMSF in Uzbekistan

14

KANAMYCIN (Km)

• Therapeutic Class:Aminoglycoside antibiotic

• ATC Code: J01GB0422

• Included in the WHO Guidelines as Group 2 injectable agent23

• Included in the 16th edition of the WHO Model List of Essential Medicines24 and in the 2nd edition of the WHO Model List of Essential Medicines for Children25

• Presentations available: solution for injection: 1g/4ml, 500mg/2ml, 1g/3ml. As powder for injection: 1g

• First approved by U.S. Food and Drug Administration (FDA): The date of the original New Drug Application (NDA) is notpublically available on the US FDAwebsite. The first Abbreviated NewDrug Application (ANDA) wasapproved on 13 February 1973.The only registered product in theUS today was approved on 17November 2002

• Approved indication in the US:Kanamycin is indicated in the short-term treatment of serious infections caused by susceptible strains of microorganisms44

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

Manufacturer

Quality status

1g powder forinjection

1g/4ml solutionfor injection

1g/3ml solutionfor injection

Meiji

Approved by SRA

xx

No priceinformation given

xx

Panpharma

Approved by SRA

0.84*

xx

xx

APP Pharma

Approved by SRA

xx

xx

Not currently inproduction

GDF pooledprocurement

price

GDF QualityAssurance Policy


2.58(Meiji)

xx

General Information

Macleods

Under evaluation


xx

xx

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

15

There is no clinical difference betweenkanamycin and amikacin. They havesimilar side effect profiles and showcross reactivity and therefore almostidentical resistance23. The choice of aNational TB Programme or treatmentprovider will also therefore depend onother factors including price,availability and adaptability of theformulation.

Number of quality sourcesIn the past, kanamycin formulationsfrom several different manufacturerswere registered in the US. Today,however, only three kanamycinproducts approved by a stringentregulatory authority were identified inthis report. No sources of kanamycinare approved through WHOPrequalification, although onemanufacturer (Macleods) hassubmitted a dossier to WHOPrequalification and has been acceptedfor evaluation.

Despite this, the supply of kanamycinremains vulnerable to disruption.Today, only one company (APPPharma) has an active registration inthe US - but they have not had anyproduction since February 2009 due tothe relocation of the APImanufacturer26. In the EU, there is onlyone approved manufacturer(Panpharma) but in 2010 they had aproblem with the API resulting in aninterruption in supply. As this was theonly quality-assured source available toGDF at the time, this resulted in asignificant problem for GLC-approvedprogrammes and other treatmentproviders. The problem has beenrectified but capacity issues remain.

In reaction to the potential shortage ofquality-assured kanamycin, GDFidentified an alternative source inJapan (Meiji). While this helped toensure continual supply whilePanpharma was not in production,Meiji has limited production capacity

Spotlight on access issues

and the price is considerably morethan the Panpharma product. Thesupply is also reserved for GDF leavingother treatment providers with noalternative quality-assured sources.

This is a good example of thevulnerability of supply with limitedsources. Additional manufacturers mayexist in China, India, the former SovietUnion, and other countries, butwhether they comply with WHOquality standards is unknown.

Active PharmaceuticalIngredientIncreasing the number of quality-assured sources for the finishedproduct is to a large extent tributary ofthe difficulties associated with theproduction of the activepharmaceutical ingredient (API).

Kanamycin API is manufactured by aprocess of fermentation. This is aspecialised process, and there are notmany manufacturers globally whohave the capacity to produce quality-assured API produced through thefermentation process - the complexityis further increased as the API shouldbe sterile. In today's regulatoryenvironment, the quality assurance ofthe API is critical in the approvalprocess of the finished productthrough WHO Prequalification or astringent regulatory authority.

Evolution in priceIn 2001, Green Light Committee-approved programmes were able toaccess kanamycin for US$ 0.36 pervial27. Since then the price has slowlyincreased and today the mostaffordable price available through theGDF, for a fully liquid ampoule, ismore than seven times the priceoffered to the GLC in 2001. Thereason for this is not clear, but partiallythis is related to the unavailability ofthe Panpharma product in 2010, andthe identification of Meiji as a quality-

assured alternative. The Panpharmaprice offered to this report is still morethan double the 2001 price, but dueto capacity issues this source is notassured.

AdaptabilityKanamycin, like the otheraminoglycosides and capreomycincannot be administered orally. Thisimposes burdens both on theprogramme, as qualified staff will berequired for administration of theproduct, and on the patient, whomust undergo six months of painfulinjections.

Kanamycin is available in both apowder and a fully liquid formulation;the latter is more adaptable toresource-limited settings asreconstitution of the powder is notrequired.

PaediatricsThe safety and effectiveness in childrenhas not been established. While thereare dosages published in severalguidelines, there is an urgent need forfurther research (pharmacokinetics,pharmacodynamics, safety data), intothe use of this drug in the youngerpopulations, in particular childrenaged under five, so that dosages canbe clarified and child adaptedformulations developed to be able todeliver these dosages to children.

HIV co-infectionThere have been no studiesperformed, but based onpharmacokinetic profiles, the potentialfor drug interactions are low. There ishowever potential for additivetoxicities in particular withantiretrovirals which may cause renaltoxicity like tenofovir28. Further studiesare required to confirm this.

GROUP 2

16

AMIKACIN (Am)

• Therapeutic Class: Aminoglycoside antibiotic


• Included in the WHO Guidelines as a Group 2 injectable agent23


• Presentations available: solution for injection: 500mg/2ml; 100mg/2ml. As powder for injection: 100mg, 500mg & 1g

• First approved by U.S. Food and Drug Administration (FDA): The date of the original New Drug Application (NDA) is notpublically available on the US FDAwebsite. The first Abbreviated NewDrug Application (ANDA) wasapproved on 22 January 198145

• Approved indication in the US:Amikacin is indicated in the short-term treatment of serious infectionsdue to susceptible strains of Gram-negative bacteria, includingbacterial septicemia (includingneoatal sepsis), serious infections ofthe respiratory tract, bones andjoints, central nervous system(including meningitis) and skin andsoft tissue; intra-abdominalinfections (including peritonitis);burns and postoperative infections(including postvascular surgery)46


Manufacturer

Quality status

500mg/2mlsolution forinjection

Medochemie

Approved by SRA

1.06*

Cipla

Approved by WHOPQ


Help SA

Approved by SRA

1.54*


price


1.20*(Medochemie)

General Information


17

There is no clinical differencebetween kanamycin and amikacin.They have similar side effect profilesand show cross reactivity andtherefore almost identical resistance23.The choice of a National TBProgramme or treatment provider willtherefore depend on other factorsincluding price, availability andadaptability of the formulation.

Number of quality sourcesSeveral companies have amikacinapproved by stringent regulatoryauthorities. In addition, in January2011, the first generic amikacin fromCipla was prequalified by WHO. Afurther Indian manufacturer (MicroLabs) is expected to submit a dossierto WHO Prequalification during thecourse of 2011.

There are multiple sources of quality-assured amikacin, possibly becauseother approved indications of useexist for the drug. The supply ofamikacin is therefore secure.


Evolution in priceIn 2001, Green Light Committee-approved programmes were able toaccess amikacin for US$ 0.11 per vialor ampoule27. Since then, the pricehas slowly increased and today themost affordable price availablethrough the GDF is $1.20 per vial orampoule. This is an increase of closeto 1000% since 2001, the reasons forwhich are unclear.

Nevertheless this remains considerablymore affordable than prices paid inrich countries - the British NationalFormulary lists a price of $16.49 pervial29,30.

AdaptabilityAmikacin, like the otheraminoglycosides and capreomycincannot be administered orally. Thisimposes burdens both on theprogramme, as qualified staff will berequired for administration of theproduct, and on the patient, whomust undergo six months of painfulinjections.

Amikacin is available in both a powderand a fully liquid formulation; thelatter is more adaptable to resource-limited settings as reconstitution ofthe powder is not required.

PaediatricsAmikacin is licensed for use inneonates, infants and children31.There is a smaller dosage(100mg/2ml) available which allowsfor more accurate dosing inchildren.

No prices were offered for thisproduct for this report. In addition,the GDF does not include thisformulation in its product catalogue,meaning that GLC-approvedprogrammes cannot order thisproduct for children through theGDF32.

HIV co-infectionThere have been no studiesperformed, but based onpharmacokinetic profiles, thepotential for drug interactions arelow. There is however potential foradditive toxicities in particular withantiretrovirals which may causerenal toxicity like tenofovir28. Furtherstudies are required to confirm this.

GROUP 2

18

CAPREOMYCIN (Cm)

• Therapeutic Class: polypeptide antibiotic


• Included in the WHO Guidelines as a Group 2 injectable agent23


• Presentations available: 1g powder for injection

• First approved by U.S. Food and Drug Administration (FDA): 2 June 197133

• Approved indication in the US:Capreomycin is to be used concomitantly with otherappropriate anti-tuberculosisagents, is indicated in pulmonaryinfections caused by capreomycin-susceptible strains of M. tuberculosiswhen the primary agents(isoniazid, rifampicin, ethambutol,aminosalicylic acid, andstreptomycin) have been ineffectiveor cannot be used because oftoxicity or the presence of resistanttubercle bacilli33


Manufacturer

Quality status

1g powder forinjection

Akorn

Approved by SRA

8.00

Macleods

Under evaluation



price


4.00*(Eli Lilly)

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

General Information

19

Number of quality sourcesEli Lilly filed the initial application tothe US FDA in 1971. Since 2003, thecompany has been actively engaged intechnology transfer to three genericmanufacturers (Aspen, Hisun and SIAInternational) and today has ceasedproduction of capreomycin in the US.None of these manufacturers has yetreceived regulatory approval by a SRAor WHO PQ.

Today, there are no sources ofcapreomycin approved through WHOPQ. In the US, Eli Lilly's license was soldto Akorn, which today is the onlyquality-assured source available to GDF.An additional manufacturer (Macleods)has submitted a dossier to WHOPrequalification and has been acceptedfor evaluation, and Aspen is expectedto submit during the course of 2011.

The supply of quality-assuredcapreomycin therefore remainsvulnerable to disruption. Additionalmanufacturers may exist in China,India, the former Soviet Union, andother countries, but whether theycomply with WHO quality standards isunknown.

Active PharmaceuticalIngredientIncreasing the number of quality-assured sources for the finishedproduct is to a large extent tributary ofthe difficulties associated with theproduction of the activepharmaceutical ingredient (API).

Capreomycin API is manufactured by aprocess of fermentation. This is aspecialised process, and there are notmany manufacturers globally who havethe capacity to produce quality-assuredAPI produced through thefermentation process - the complexityis further increased as the API shouldbe sterile. In today's regulatory


environment, the quality assurance ofthe API is critical in the approvalprocess of the finished productthrough WHO Prequalification or astringent regulatory authority.

Eli Lilly transferred the technology forcapreomycin API to only onemanufacturer - the Chinese genericproducer Hisun in 2003. Although thishas been a success, with the Hisun APIbeing approved by the US FDA in June2006, all manufacturers of quality-assured capreomycin are reliant on thisone source.

Although other API manufacturersexist, none of them has yet beenapproved by a stringent regulatoryauthority or by the WHOPrequalification Programme.

Evolution in priceIn 2001, Green Light Committee-approved programmes were able toaccess capreomycin for US$ 1.02 pervial27. Since this time, the price hasincreased, with prices reported in theGlobal Fund Price and QualityReporting (PQR) Tool between 2007and today ranging between $3.21 and$3.64 per vial.64

For a number of years, Eli Lillysubsidised the price of thecapreomycin for programmesapproved by the Green LightCommittee. Since transferring thetechnology to other manufacturers,however, the price of capreomycin hasincreased by almost 300%. Now thatEli Lilly has ceased production for thismarket, the price will not be subsidisedanymore and we will see a furtherincrease in prices.

The price currently quoted by GDF forthis report corresponds to the Eli Lillysubsidised price as stock is stillavailable. We can therefore expect to

see a further price increase in thefuture as GDF turns to Akorn forsupplies. If the price Akorn charges forGDF remains the same as the one themanufacturer provided for thisdocument ($8), the impact on theoverall cost of a drug-resistanttuberculosis treatment containingcapreomycin will be an increase ofaround $720.

Nevertheless the Akorn price remainsconsiderably more affordable thanprices paid in rich countries - the BritishNational Formulary lists a price of$40.95 per vial29,30.

AdaptabilityCapreomycin, like DR-TB medicinesfrom the aminoglycosides class, cannotbe administered orally. This imposesburdens both on the programme, asqualified staff will be required foradministration of the product, and onthe patient, who must undergo sixmonths of painful injections.

PaediatricsThe safety and effectiveness in childrenhas not been established. While thereare dosages published in severalguidelines, there is an urgent need forfurther research (pharmacokinetics,pharmacodynamics, safety data), intothe use of this drug in the youngerpopulations, in particular children agedunder five, so that dosages can beclarified and child adaptedformulations developed to be able todeliver these dosages to children.

HIV co-infectionThere have been no studies performed,but based on pharmacokinetic profiles,the potential for drug interactions arelow. There is however potential foradditive toxicities in particular withantiretrovirals which may cause renaltoxicity like tenofovir28. Further studiesare required to confirm this.

GROUP 2

20

MOXIFLOXACIN (Mfx)

• Therapeutic Class: Fluoroquinolone

• ATC Code: J01MA1422

• Included in the WHO Guidelines as a Group 3 Fluoroquinolones23

• Not included in the 16th edition of the WHO Model List of EssentialMedicines24 nor in the 2nd editionof the WHO Model List of EssentialMedicines for Children25

• Presentations available: 400mg tablet

• First approved by U.S. Food and Drug Administration (FDA): 12 October 199971

• Approved indication in the US:Moxifloxacin was initially approved for the indications of bacterialsinusitis and community acquiredpneumonia. This was furtherexpanded to include acutebacterial exacerbation of chronicbronchitis, uncomplicated andcomplicated skin and skin structureinfection and complicated intra-abdominal infections35


Manufacturer

Quality status

400mg tablet

Macleods

Under evaluation


Cipla

Approved by WHOPQ


Bayer

Approved by SRA



price


1.70(Cipla)

General Information

21

Number of quality sourcesFor many years, Bayer was the onlyquality-assured source of moxifloxacinavailable. In November 2010, the firstmoxifloxacin was prequalified by WHO(Cipla) and a second manufacturer(Macleods) has submitted a dossierthat has been accepted for evaluation.The supply of moxifloxacin willtherefore be relatively secure in thenear future (although price remains abarrier).

In addition, we can expect to seefurther sources of quality-assuredmoxifloxacin, because other approvedindications of use exist for the drug.Indeed, there are two genericmanufacturers (Dr Reddy's and Teva)that have US FDA tentative approval,waiting to enter the US market whenthe patent expires.

Additional manufacturers may exist inChina, India, the former Soviet Unionand other countries, but whether theycomply with WHO quality standards isunknown.

Evolution in priceWith the entry of a quality-assuredgeneric into the market the price hasreduced considerably. Prior to this theonly option available was Bayer andprices for this product reported in theGlobal Fund Price and QualityReporting (PQR) Tool between 2009and today range between US$ 3.97and $5.03 per tablet.64

This shows that some developingcountries are therefore paying priceshigher than those paid in rich countries- the British National Formulary lists aprice of $4.03 per tablet29,30. With moregeneric manufacturers expected toenter the market, we could expect tosee this price continue to fall.


Approved IndicationWhile moxifloxacin has been shown tobe effective against MycobacteriumTuberculosis (Mtb)36 and has beenincluded in many guidelines for use inDR-TB, it does not have an indicationapproved by any stringent regulatoryauthority. When moxifloxacin is used asa part of a DR-TB treatment regimen, itis therefore essentially being used “offlabel” for this indication. This mayincrease complexities for manufacturerstrying to register their products for theindication of TB in some countries.

In August 2005, Bayer and TB Alliancesigned an agreement to conduct aglobal clinical developmentprogramme, aiming to registermoxifloxacin for a first-line TBindication. Three Phase II trials havebeen completed, and a Phase III trial isongoing.

Other actors, including The Union, arecurrently involved in clinical trialslooking at the use of moxifloxacin in aregimen to shorten the treatment ofMDR-TB21.

PatentsAlthough patents covering themoxifloxacin molecule have nowexpired in most countries, subsequentpatents claiming a crystal monohydrateform of moxifloxacin appear to standin the way of generic production. Suchpatents, due to run until 2016, havebeen granted in several countriesincluding China, Russia, South Africaand Ukraine.

In India, where this patent waswithdrawn by Bayer, additional patentson other pharmaceutical forms havebeen granted but do not appear to beblocking generic manufacture.

PaediatricsThe safety and effectiveness in childrenhas not been established. While there

are dosages published in severalguidelines, there is an urgent need forfurther research (pharmacokinetics,pharmacodynamics, safety data), intothe use of this drug in the youngerpopulations, in particular children agedunder five, so that dosages can beclarified and child adapted formulationsdeveloped to be able to deliver thesedosages to children. As there is nopaediatric formulation available today,paediatric doses are obtained bymanipulating adult formulations toachieve target doses. Today the onlyquality-assured adult source availablethrough the GDF does not have a breakline to allow for accurate fractioning ofthe dose.

One alternative is to use anextemporaneously preparedmoxifloxacin oral suspension, thesubject of a stability study published in200938. This suspension allows for amore accurate way to measure andadminister a dose to a child. However,preparing this formulation requires acertain level of training, supervision andresources, which may not be availablein many settings where DR-TB isprevalent. This solution is far from idealand there is therefore a need for acommercially available paediatricformulation.

HIV co-infectionNo interaction studies have beenperformed, but based on theknowledge of the metabolism ofmoxifloxacin, levels of the drug may bereduced by ritonavir and increased byatazanavir. Further research is neededto assess this.

Protease inhibitors and efavirenz mayprolong QT interval so concomitant usewith moxifloxacin should be cautious,with electrocardiogram monitoring.Oral absorption of fluoroquinolones arereduced by buffered drugs, so dosesshould be separated from didanosine-buffered tablets28.

GROUP 3

22

LEVOFLOXACIN (Lfx)


• ATC Code: J01MA1222


• Included in the 16th edition of the WHO Model List of Essential Medicines24 and in 2nd edition ofthe WHO Model List of EssentialMedicines for Children25.Levofloxacin is considered a betteralternative to ofloxacin based onavailability and programmeconsiderations

• Presentations available: 250mg, 500mg and 750mg tablets, 25mg/ml oral solution

• First approved by U.S. Food and Drug Administration (FDA): 20 December 1996. The paediatric formulation (25mg/ml oral solution) was approved on 21 October 200440

• Approved indication in the US:Levofloxacin was initially approved for the indications of acute maxillary sinusitis, acute bacterialexacerbations of chronic bronchitis,community-acquired pneumonia,uncomplicated skin and skinstructure infections, complicatedurinary tract infections (UTI), andacute pyelonephritis. This wasfurther expanded to includeuncomplicated UTI, chronicbacterial prostatitis, and treatmentof inhalational anthrax (post-exposure)40

General Information


Manufacturer

Quality status

250mg tablet

500mg tablet

Cipla

Under evaluation



Macleods

Under evaluation




price


0.05(Macleods)

0.08(Macleods)

23

Number of quality sourcesTwo manufacturers have dossierssubmitted and accepted for evaluationby WHO Prequalification. These Cipla(250mg) and Macleods (250mg and500mg) sources have already beenassessed by the Expert Review Panel forthe GDF and the Global Fund and arecurrently listed as purchasable in 2011with Global Fund money.

An additional manufacturer (MicroLabs) is expected to submit to WHOPrequalification during the course of2011. The supply of levofloxacin istherefore relatively secure.

In addition, there are multiple sources ofquality-assured levofloxacin, becauseother approved indications of use existfor the drug. Indeed, a further 13manufacturers have obtained US FDAtentative approval for levofloxacin,waiting to enter the US market whenthe patent expires in the US in June2011. However, none of theseproducers have applied for WHOPrequalification, nor have made theirproducts available to GDF.

Evolution in priceThe prices reported in the Global FundPrice and Quality Reporting (PQR) toolbetween 2007 and today has remainedat US$ 0.05 per 250mg tablet, and hasvaried between $0.05 and $0.10 per500mg tablet34.

This remains considerably moreaffordable than prices paid in richcountries - the British NationalFormulary lists a price of $2.36 per250mg tablet and $4.21 per 500mgtablet29,30. The price of levofloxacin doesnot appear to be an issue.

Approved IndicationWhile levofloxacin has been shown tobe effective against MycobacteriumTuberculosis (Mtb)36 and has beenincluded in many guidelines for use in


DR-TB, it does not have an indicationapproved by any stringent regulatoryauthority. When levofloxacin is used as apart of a DR-TB treatment regimen, it istherefore essentially being used “offlicense” for this indication. This maycreate problems for manufacturerstrying to register their products for theindication of TB in some countries.

PatentsPatents claiming levofloxacin wereoriginally filed in 198165 and 198666 byDaiichi Seiyaku, now a subsidiary ofDaiichi Sankyo, and licensed to Janssen.Although 20-year patents expired in2001 and 2006 respectively, patentprotection has been extended until June2011 in several European countries andthe US.

As the patent will expire soon,manufacturers are already registeringtheir product in the US and the EU.Those manufacturers should becontacted by GDF to see if they could beinterested, once the patent has expired,in also supplying GLC-approvedprogrammes.

PaediatricsLevofloxacin has been approved in theUS for children aged over six months,but only for use in children for acuteinfections. The safety in paediatricpatients treated for more than 14 dayshas not been studied. Because childrenwith DR-TB may be treated with thisdrug up for up to two years, there istherefore a need for more safety data onthe use of levofloxacin for extendedperiods of time in children.

Children metabolise levofloxacin fasterthan adults and smaller children need toreceive doses twice a day rather thandaily as recommended for adults. Thiscan be difficult to implementprogrammatically if strict directlyobserved therapy is followed. The US-approved product information suggests

twice a day dosing for children betweensix months and 17 years. Otherpublications suggest twice a day dosingfor under five years, while the WHOguidelines suggest a once a day dosing.This can be confusing to National TBProgrammes and dangerous for children.There is a need for a further clarificationand a consensus on the dosing of smallchildren.

While there is paediatric formulation(25mg/ml oral solution) available in theUS, this is not widely available elsewhere.There has been a study publishedlooking at the stability of anextemporaneously prepared levofloxacinoral suspension39. This suspension allowsfor a more accurate way to measure andadminister a dose to a child. However,preparing this formulation requires acertain level of training, supervision andresources, which may not be available inmany settings where DR-TB is prevalent.

The reality today is adult formulationsare manipulated in order to achievetarget doses. Today the only quality-assured source available through GDFdoes not have a break line to allow foraccurate fractioning of the dose. Both ofthese solutions are far from ideal andthere is therefore a need for thepaediatric formulation to be made morewidely available.

HIV co-infectionNo interaction studies have beenperformed, but based on the knowledgeof the metabolism of levofloxacin, nointeractions are predicted. Furtherresearch is needed to assess this.Protease inhibitors and efavirenz mayprolong QT interval so concomitant usewith levofloxacin should be cautious,with electrocardiogram monitoring.Oral absorption of fluoroquinolones isreduced by buffered drugs, so dosesshould be separated from didanosine-buffered tablets28.

GROUP 3

24

OFLOXACIN (Ofx)


• ATC Code: JJ01MA0122


• Included in the 16th edition of the WHO Model List of EssentialMedicines24 nor in the 2nd editionof the WHO Model List of EssentialMedicines for Children25

• Presentations available: 200mg, 300mg, 400mg tablet

• First approved by U.S. Food and Drug Administration (FDA): 28 December 199071

• Approved indication in the US:Ofloxacin is approved for the indications of acute bacterialexacerbations of chronic bronchitis,acute uncomplicated uretheral andcervical gonorrhea, non-gonococcal urethritis and cervicitis,acute pelvic inflammatory diseaseand uncomplicated skin and skinstructure infections41


Manufacturer

Quality status

200mg tablet

400mg tablet

Cipla

Under evaluation



Macleods

Under evaluation




price


0.06(Macleods)

0.06(Macleods)

General Information

25


Approved IndicationWhile ofloxacin has been shown to beeffective against MycobacteriumTuberculosis (Mtb)36 and has beenincluded in many guidelines for use inDR-TB, it does not have this indicationapproved by any stringent regulatoryauthority. When ofloxacin is used as apart of a DR-TB treatment regimen, itis therefore essentially being used “offlicense” for this indication. This maycreate problems for manufacturerstrying to register their products forthe indication of TB in some countries.

PaediatricsThe safety and effectiveness inchildren has not been established.While there are dosages published inseveral guidelines, there is an urgentneed for further research(pharmacokinetics,pharmacodynamics, safety data), intothe use of this drug in the youngerpopulations, in particular childrenaged under five, so that dosages canbe clarified and child adaptedformulations developed to be able todeliver these dosages to children.

As there is no paediatric formulationavailable today, children's doses areobtained by manipulating adultformulations to achieve target doses.Today the only quality-assured sourceavailable through GDF does not havea break line to allow for accuratefractioning of the dose.

HIV co-infectionNo interaction studies have beenperformed, and based on themetabolism of ofloxacin, interactionsare not predicted. However onesource suggests there may be apotential interaction with atazanavirand lopinavir. There is an urgent needfor further research to clarify theseinconsistencies regarding druginteractions to guide clinicians ondrug dosing51.

Protease inhibitors and efavirenz mayprolong QT interval so concomitantuse with ofloxacin should be cautious,with electrocardiogram monitoring.

Oral absorption of fluoroquinolonesare reduced by buffered drugs, sodoses should be separated fromdidanosine-buffered tablets28.

Number of quality sourcesToday there is no ofloxacin approvedby WHO PQ, but three manufacturers(including Cipla and Macleods) havedossiers submitted and accepted forevaluation, and an additionalmanufacturer (Micro Labs) is expectedto submit during the course of 2011.The supply of ofloxacin will thereforebe relatively secure in the near future.

In addition, there are multiple sourcesof quality-assured ofloxacin, becauseother approved indications of useexist for the drug. As the patent forofloxacin has now expired, there arethree generic manufacturers (Ranbaxy,Teva, and Dr. Reddy's) that haveproducts available on the US marketand several others on the EU market,but none of them have made theirproducts available to GDF.

Evolution in priceIn 2001, Green Light Committee-approved programmes were able toaccess ofloxacin for US$ 0.33 pertablet27. Since then, the price hasdecreased dramatically with pricesreported in the Global Fund Price andQuality Reporting (PQR) Tool between2007 and today ranging between$0.03 and $0.06 per 200mg tabletand between $0.05 and $0.07 per400mg tablet64. These prices remainconsiderably more affordable thanprices paid in rich countries - theBritish National Formulary lists a priceof $1.09 per 200mg tablet and $0.89per 400mg tablet29,30.

The price of ofloxacin does not appearto be an issue.

GROUP 3

26

ETHIONAMIDE (Eto)

• Therapeutic Class:carbothionamides group, derivative of isonicotinic acid23

• ATC Code: J04AD0322

• Included in the WHO Guidelines as a Group 4 oral bacteriostatic second-line agent23

• Included in the 16th edition ofthe WHO Model List of EssentialMedicines24 and in 2nd edition ofthe WHO Model List of EssentialMedicines for Children25


• First approved by U.S. Food and Drug Administration (FDA): 30 April 196571

• Approved indication in the US:ethionamide is primarily indicated for the treatment of activetuberculosis in patients with M. tuberculosis resistant to isoniazidor rifampicin, or when there isintolerance on the part of thepatient to other drugs42


Manufacturer

Quality status

250mg tablet

Lupin

Under evaluation

0.09

Cipla

Under evaluation


Macleods

Approved by WHOPQ


Pfizer

Approved by SRA

3.50


price


0.09(Macleods)

General Information

27

Prothionamide is the propyl analog ofethionamide. There is complete crossresistance between ethionamide andprothionamide and the two are usedinterchangeably43.

Number of quality sourcesToday only two ethionamide productsare quality-assured; one is prequalifiedby WHO (Macleods) and Pfizer hasthe marketing license for ethionamidein the US and Canada. Such a limitednumber of quality-approved sourcesmeans this product is relativelyvulnerable to supply disruption.

The situation is likely to improve as afurther two manufacturers (Lupin,Cipla) have submitted dossiers toWHO Prequalification and have beenaccepted for evaluation. The Ciplaproduct has already been assessed bythe Expert Review Panel for the GDFand the Global Fund and is currentlylisted as purchasable in 2011 withGlobal Fund money. An additionalmanufacturer (Micro Labs) is expectedto submit during the course of 2011.



Evolution in priceThe current price available directlythrough manufacturers or through theGDF shows little evolution over thepast ten years. In 2001, Green LightCommittee-approved programmeswere able to access ethionamide forUS$0.10 per tablet - the price today isidentical27. The price of ethionamidedoes not appear to be an issue.

Pfizer has the marketing license forethionamide in the US and Canadaand does not currently have a pricingstructure for other markets.


As there are no paediatricformulations commercially availabletoday, dosages for children areobtained by manipulation of adultformulations. The one quality-assuredsource available today is a film-coatedtablet that is not breakable, whichmeans that fractioning the tablet isnot accurate.

HIV co-infectionThere have been no studiesperformed, but based onpharmacokinetic profiles, druginteractions are predicted. There arepotentially interactions with someclasses of antiretrovirals and there isan urgent need for further studies toconfirm this. There is also potential foradditive toxicities in particular withantiretrovirals which may causehepatotoxicity including efavirenz andnevirapine28.

GROUP 4

28

PROTHIONAMIDE (Pto)

• Therapeutic Class:carbothionamides group, derivative of isonicotinic acid23

• ATC Code: J04AD0122




• First approved by German Federal Institute for Drugs and Medical Devices (BfArM):First marketed in Germany in the 1970s but registered in theframework of posterior registrationprocess in Germany on 14 June200550

• Approved indication in Germany: Treatment of all formsand stages of pulmonary andextra-pulmonary tuberculosis assecond-line drug in the case ofproven multidrug-resistance of thepathogens against first-line drugs;treatment of diseases caused by so-called ubiquitous (atypical)mycobacteria; treatment of leprosyin the context of modified therapyregimens52

General Information


Manufacturer

Quality status

250mg tablet

Lupin

Under evaluation

0.08

Fatol

Approved by SRA

0.14*


price


0.14*(Fatol)


29

Prothionamide is the propyl analog ofethionamide. There is complete crossresistance between ethionamide andprothionamide and the two are usedinterchangeably43.

Number of quality sourcesToday there is only oneprothionamide product approved bya stringent regulatory authority (Fatolproduct in Germany) and none isprequalified by WHO. Such a limitednumber of quality-approved sourcesmeans this product is relativelyvulnerable to supply disruption.

The situation is likely to improve as afurther manufacturer (Lupin) hassubmitted a dossier to WHOPrequalification and has beenaccepted for evaluation, and anadditional producer (Micro Labs) isexpected to submit during the courseof 2011.



Evolution in priceThe current price available directlythrough manufacturers or through theGDF shows little evolution over thepast ten years. In 2001, Green LightCommittee-approved programmeswere able to access prothionamide forUS$0.10 per tablet - the price today isalmost identical27. The price ofprothionamide does not appear to bean issue.


As there are no paediatricformulations commercially availabletoday, dosages for children areobtained by manipulation of adultformulations. The only quality-assuredsource available today does have abreak line, which facilitates breakingthe tablet in half. Howeverprothionamide has a very unpleasanttaste and breaking the tablet is notideal. There is a need for a paediatricformulation to be made available.

HIV co-infectionThere have been no studiesperformed, but based onpharmacokinetic profiles, druginteractions are predicted. There arepotentially interactions with someclasses of antiretrovirals and there isan urgent need for further studies toconfirm this. There is also potential foradditive toxicities in particular withantiretrovirals which may causehepatotoxicity including efavirenz andnevirapine28.

GROUP 4

30

CYCLOSERINE (Cs)

• Therapeutic Class:analog of D-alanine23

• ATC Code: J04AB0122


• Included in the 16th edition ofthe WHO Model List of EssentialMedicines24 and in 2nd edition ofthe WHO Model List of EssentialMedicines for Children25

• Presentations available: 250mg capsule

• First approved by U.S. Food and Drug Administration (FDA): 29 June 196471

• Approved indication in the US:Cycloserine is indicated in the treatment of active pulmonary andextra-pulmonary tuberculosis(including renal disease) when thecausative organisms are susceptibleto this drug and when treatmentwith the primary medications(streptomycin, isoniazid, rifampicinand ethambutol) has provedinadequate53


Manufacturer

Quality status

250mg capsule

Lupin

Under evaluation

0.60

Aspen

Approved by WHOPQ

0.78

Macleods

Approved by WHOPQ


Purdue GMP

Approved by SRA



price


0.59 and 0.78(Macleods and

Aspen)

General Information

31

Number of quality sourcesEli Lilly filed the initial application tothe US FDA in 1964. Since 2003, thecompany has been actively engagedin technology transfer to threegeneric manufacturers (Aspen, PurdueGMP and SIA International) and in2008 ceased production ofcycloserine. Two of thesemanufacturers (Aspen & PurdueGMP) now produce quality-assuredcycloserine.

In additional, another manufacturer(Macleods) has cycloserine approvedby WHO Prequalification and threeother manufacturers (including Lupinand Cipla) have submitted dossiers toWHO Prequalification and have beenaccepted for evaluation.

The supply of quality-assuredcycloserine is therefore relativelysecure.

Active PharmaceuticalIngredientUntil 2006, the only quality-assuredsource for the active pharmaceuticalingredient was Eli Lilly.

Eli Lilly started the technology transferfor the API to Shasun, India, in 2003 aprocess that was concluded in 2006.This was a success with the ShasunAPI being approved by the US FDA inJune 2008.


Evolution in priceIn 2001, Green Light Committee-approved programmes were able toaccess cycloserine for US$ 0.14 percapsule27. Since this time the price hasslowly increased, with prices reportedin the Global Fund Price and QualityReporting (PQR) Tool between 2007and today ranging between $0.48and $0.68 per capsule34.

For a number of years, Eli Lillysubsidised the price of the cycloserinefor programmes approved by theGreen Light Committee. Sincetransferring the technology to othermanufacturers, however, the price ofcycloserine has increased by morethan 300% to $0.59 per capsule.

This remains considerably moreaffordable than prices paid in richcountries - the British NationalFormulary lists a price of $5.43 percapsule29,30.

PaediatricsThe British National Formularyprovides doses for children aged 2 to18 while the US FDA states that thesafety and effectiveness in childrenhas not been established. This is aclear example of different guidelinesproviding different recommendations.There is an urgent need for furtherresearch (pharmacokinetics,pharmacodynamics, safety data), intothe use of this drug in the youngerpopulations, in particular childrenaged under five, so that dosages canbe clarified and child adaptedformulations developed to be able todeliver these dosages to children.

As there are no paediatricformulations commercially availabletoday, dosages for children areobtained by manipulation of adultformulations. All of the quality-assuredsources available today are capsules,which means that it is not possible toaccurately fraction the capsule.

HIV co-infectionThe metabolism of cycloserine is notcompletely understood, and henceinteractions are unpredictable28. Thereis a need for more research into theinteractions between antiretroviralsand cycloserine.

GROUP 4

32

TERIZIDONE (Trd)

• Therapeutic Class:analog of D-alanine23

• ATC Code: J04AK0322

• Included in the WHO Guidelines as a Group 4 oral bacteriostatic second-line agent 23

• Not included in the 16th edition of the WHO Model List of EssentialMedicines24 nor in 2nd edition ofthe WHO Model List of EssentialMedicines for Children25

• Presentations available: 250mg capsule

• First approved by German Federal Institute for Drugs and Medical Devices (BfArM):First marketed in Germany in the 1970s and is still in the process ofthe posterior registration process inGermany. The filing date for thisprocess was 1 January 197850

• Approved indication in Germany: Treatment oftuberculosis in adults and juvenilesaged 14 or older54

General Information


Manufacturer

Quality status

250mg capsule

Fatol

Approved by SRA

1.68*


price


1.65*(Fatol)


33

Terizidone is a combination of twomolecules of cycloserine, and as suchhas a similar mode of action ascycloserine. There is complete crossresistance to cycloserine54. It is beingused in some countries instead ofcycloserine, and assumed to be asefficacious; however, there are nodirect studies comparing the twodrugs, and terizidone is therefore notyet recommended by WHO23.

Number of quality sourcesToday there is only one quality-assured source of terizidone available.There are no manufacturers withdossiers submitted to WHO PQ, andno manufacturers likely to submitdossiers in 2011. The supply ofquality-assured terizidone thereforeremains extremely vulnerable todisruption.

Additional manufacturers may exist inChina, India and the former SovietUnion and other countries, butwhether they comply with WHOquality standards is unknown.


Evolution in priceNo price for terizidone was reportedin the Global Fund Price and QualityReporting (PQR) Tool.


As there are no paediatricformulations commercially availabletoday, dosages for children areobtained by manipulation of adultformulations. The only quality-assuredsource available today is a capsule,which cannot be accuratelyfractioned.

HIV co-infectionAs terizidone is a combination of acouple of molecules of cycloserineand the metabolism of cycloserine isnot completely understood,interactions are unpredictable28. Thereis a need for more research into theinteractions between antiretroviralsand terizidone.

GROUP 4

34

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

• Therapeutic Class: salicylic acid -anti folate23

• ATC Code: for PAS: J04AA01For PAS-Sodium: J04AA0222

• Included in the WHO Guidelines PAS: as a Group 4 oral bacteriostatic second-line agent. PAS-sodium: not included23

• PAS included in the 16th edition of the WHO Model List of EssentialMedicines24 and in the 2nd editionof the WHO Model List of EssentialMedicines for Children25. PAS-Sodium is not included in eitherdocument.

• Presentations available: PAS: 4g sachet. PAS-Sodium: 60% weight for weight granules 9.2gsachet and 100g jar; powder forsolution 5.52g sachet (equivalentto PAS 4g sachet)

• First approved by U.S. Food and Drug Administration (FDA): PAS-Sodium was first registered in a tablet formulation inthe US on 8 March 1950. There areno manufacturers of PAS-Sodiumon the market in the US today. Theonly product on the market todayin the US is PAS and this wasregistered on 30 June 199455

• Approved indication in the US:PAS is indicated for the treatment of tuberculosis in combination withother active agents. It is mostcommonly used in patients withmultidrug-resistant TB or insituations when therapy withisoniazid and rifampicin is notpossible due to a combination ofresistance and/or intolerance55


Manufacturer

Quality status

PAS 4g sachet

PAS-Sodium - 60%w/w granules -9.2g sachet

PAS-Sodium - 60%w/w granules -100g jar

PAS-Sodium -powder forsolution- 5.52gsachet

Jacobus

Approved by SRA

1.57

xx

xx

xx

Olainfarm

Approved by SRA

xx

xx

xx


General Information

Macleods

Approved by WHOPQ

xx



xx


price


1.57(Jacobus)


24.00(2.21)*

(Macleods)

1.50(Olainfarm)

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

35

Para-aminosalicylate sodium (PAS -Sodium) is the sodium salt of para-aminosalicylic acid (PAS). 1.38g ofPAS-Sodium is approximatelyequivalent to 1g of PAS56. None of thequality-assured sources of either PASor PAS-Sodium come in the sameformulation as each other, whichmeans depending on the product,different doses of granules andpowders are required to deliver thesame quantity of PAS. This can be canbe particularly confusing if multipleformulations exist in one treatmentprogramme.

Number of quality sourcesToday there is only one quality-assured source of PAS (Jacobus), andtwo quality-assured sources of PAS-sodium (Macleods and Olainfarm),with no products in the pipeline. Thismeans the supply of quality-assuredproduct is vulnerable.

The PAS-Sodium formulation fromMacleods was approved by WHO PQin 2009, but the unexpectedly largedemand for this product led tocapacity problems, resulting in longlead times for orders. This should berectified in 2011.


Evolution in priceIn 2001, Green Light Committee-approved programmes were able toaccess PAS for US$1.51 per 4gsachet27. Since this time the price hasslowly increased, with prices for thisproduct reported in the Global FundPrice and Quality Reporting (PQR)Tool between 2007 and todayranging from $1.88 and $2.00 per 4gsachet.


Heat-stable PAS-Sodium is availabletoday range in price between $1.5and $2.21 for an equivalent dose ofPAS.

While the price of PAS and PAS-Sodium has remained relatively stablein recent years, the medicine accountsfor between 25 and 50% of the totalcost of a patient's treatment overallcost, depending on which medicinesand which products are used. Areduction in the price of PAS and PAS-Sodium would therefore have a largeimpact on the overall cost oftreatment.

AdaptabilityThe PAS marketed by Jacobus, mustbe stored at temperatures below15°C. This is problematic for manysettings where DR-TB is prevalent, asmaintaining a functional cold chainrequires a certain level of investmentboth in infrastructure and humanresources.

The product information states “thepackets may be stored at roomtemperature for short periods oftime”. This should be clarified to givetreatment providers guidance on theexact length of time the product maybe stored above 15°C beforedispensing to patients, without risk ofdegradation. The availability of a PASproduct that can be kept at roomtemperature for a determined periodof time will have positive implications,especially where programmes aremoving to a decentralised approachand may not have access to coldchain.

The PAS-Sodium products do notrequire any special storage conditions.


As there are no paediatricformulations commercially availabletoday, dosages for children areobtained by manipulation of adultformulations. As all the availableformulations are either granules orpowders, measuring the exact dosefor a child is difficult and requirescalibrated scales to be available at thepoint of dispensing. The PAS-Sodiumproduct from Macleods that issupplied in the 100g jar is howeversupplied with a graduated measuringcup to allow for some estimations ofdose, but this is still not accurateenough.

An additional complexity is thatdosages are not given for PAS-Sodium, and that doses have to becalculated based on the content ofPAS in PAS-Sodium. This has thepotential to increase the risk ofprescribing and dispensing errors.

There is therefore a need for acommercially available paediatricformulation.

HIV co-infectionThere have been no studiesperformed, but based on thepharmacokinetic profile of the PAS,drug interactions are unlikely. Studiesshould be performed to confirm this28.

GROUP 4

36

CLOFAZIMINE (Cfz)

• Therapeutic Class:Phenazine Derivative23

• ATC Code: J04BA0122

• Included in the WHO Guidelines as a Group 5medicine; agents with unclearefficacy23

• Included in the 16th edition of the WHO Model List of EssentialMedicines (as an anti-leprosymedicine)24 and in the 2nd editionof the WHO Model List of EssentialMedicines for Children (as an anti-leprosy medicine)25

• Presentations available: 50mg and 100mg soft-gel capsules

• First approved by U.S. Food and Drug Administration (FDA): 15 December 198657

• Approved indication in US:Clofazimine is indicated in thetreatment of lepromatous leprosy,including dapsone-resistantlepromatous leprosy andlepromatous leprosy complicatedby erythema nodosum leprosum57

General Information


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

37

Clofazimine was first synthesised in1954 as an anti-TB compound. Thedrug was thought to be ineffectiveagainst TB but in 1959 effectivenessagainst leprosy was demonstrated.After clinical trials the product waslaunched in 1969 and marketed byNovartis for use in leprosy.

Even though clofazimine has noofficial indications for the treatment ofDR-TB, clinical data on use in TB hasbeen published and the drug isrecommended by WHO.

Number of quality sourcesToday there is only one sourceapproved by a stringent regulatoryauthority. This product is produced bySandoz for Novartis. Additionalmanufacturers may exist in China,India, the former Soviet Union andother countries, but whether theycomply with WHO quality standards isunknown.

Clofazimine was not included in the10th Invitation to Manufacturers tosubmit an Expression of Interest (EoI)for product evaluation by WHOPrequalification (August 2010 -revised February 2011). Because ofthis, there are no manufacturers withdossiers currently under evaluation.The drug was however included inthe joint GDF/Global Fund Invitationto manufacturers to submit anExpression of Interest for productevaluation issued by the ExpertReview Panel in January 2011.

With no market for this product inwealthy countries, there is no reasonfor a manufacturer to seekauthorisation through a stringentregulatory authority. It is thereforeimperative that WHO Prequalificationincludes clofazimine in the next EoI,to send a clear message tomanufacturers that the product isneeded.


Even if demand is low, there is a needto have an alternative source to theNovartis product which is not easilyavailable and/or too expensive.

Evolution in priceIn late 1999, Novartis signed aMemorandum of Understanding(MoU) with the WHO leprosyprogramme for a donation ofclofazimine and rifampicin47. InNovember 2005, this donation wasextended until the end of 2010.

For patients who require this drug, itcan be purchased through certainprivate pharmacies, but the cost isquite high, at US$ 0.86 for the 50mgcapsule and $1.43 for the 100mgcapsule in Switzerland, for example58.

PaediatricsThe safety and effectiveness inchildren has not been established, butseveral case reports of children treatedwith clofazimine have been publishedin the literature. While there aredosages published in severalguidelines, there is an urgent need forfurther research (pharmacokinetics,pharmacodynamics, safety data), intothe use of this drug in the youngerpopulations, in particular childrenaged under five, so that dosages canbe clarified and child adaptedformulations developed to be able todeliver these dosages to children.

Today there is a 50mg soft-gel capsuleavailable, but this formulation makesit impossible to fraction the dose, andclinicians are put in a difficult positionto either over-dose the child andincrease the risk of side effects orunder-dose and increase the risk ofamplification of the child's resistanceprofile. This is far from ideal.

HIV co-infectionThere have been no studiesperformed, but clofazimine is a weakinhibitor of CYP3A4, and so proteaseinhibitor and etravirine concentrationsmay be increased.

Further studies are required to confirmthis28.

GROUP 5

38

LINEZOLID (Lzd)

• Therapeutic Class:Oxazolidinone antibiotic

• ATC Code: J01XX0822

• Included in the WHO Guidelines as a Group 5medicine; agents with unclearefficacy23


• Presentations available: 600mg tablet, 100mg/5ml powder for suspension

• First approved by U.S. Food and Drug Administration (FDA): 18 April 200059

• Approved indication in US:Linezolid is indicated for treatmentof susceptible strains of designatedmicroorganisms for the followingconditions, nosocomialpneumonia, complicated anduncomplicated skin and skinstructure infections. It is notindicated for the treatment ofGram-negative infections andcommunity acquired pneumonia60

General Information


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

39

Even though linezolid has beenclassified by WHO as an agent withunclear efficacy, it has been shown tohave in-vitro activity againstMycobacterium Tuberculosis. Data hasbeen presented at internationalconferences and small case seriesreports have been published on itsuse in treatment of DR-TB67. Linezolidis associated with a relatively highnumber of adverse effects, includingmyelosuppression, anaemia andperipheral and optical neuropathies.Linezolid does however play animportant role in patients with XDR-TB. Pfizer and Astra Zeneca arecurrently investigating othermedicines in the oxazolidinone groupin the hope of developing a moreefficacious and safer molecule thanlinezolid.

Number of quality sourcesToday only one manufacturer, Pfizer,is approved by a stringent regulatoryauthority. A further fourmanufacturers (Teva, Mylan,Glenmark and Gate Pharma) havetentative approval from the US FDA,waiting to enter the US market whenthe patent expires.


Linezolid was not included in the 10thInvitation to Manufacturers to submitan Expression of Interest (EoI) forproduct evaluation by WHOPrequalification (August 2010 -revised February 2011). Because ofthis, there are no manufacturers withdossiers currently under evaluation.The drug was however included in


the joint GDF/Global Fund Invitationto manufacturers to submit anExpression of Interest for productevaluation issued by the ExpertReview Panel in January 2011.

As linezolid has a market in wealthycountries, manufacturers with SRAapproval should be approached tomake their products available for theDR-TB market. It is imperative thatWHO Prequalification includeslinezolid in the next EoI to send aclear message to manufacturers thatthis product is also needed for the TBmarket.

Evolution in priceThere was no price supplied forlinezolid from GDF and no entriesreported in the Global Fund Price andQuality Reporting (PQR) tool.

An indicative price is given in theBritish National Formulary - US$72.37 for the 600mg tablet and$361.82 for a 150ml bottle of thepaediatric suspension.

The arrival of alternative source will becritical to ensure price reductions.

PatentsThe basic patent claiming linezolidwas first filed in 1993 by UpjohnCompany in the US and is due toexpire in May 201561. Similar patentswere also granted in China, thePhilippines and South Africa.

Upjohn Company also filed patentsclaiming crystal forms62 and to a tabletformulation63 of linezolid in 2001 inmany developing countries includingArgentina, Brazil, China, Colombia,India, EAPO countries, Mexico,Ukraine and South Africa.

PaediatricsPharmacokinetic studies have beencompleted in children from birth,and dosages are approved by the USFDA. Safety data is based on trials,where patients took linezolid for 28days. As children with DR-TB may betreated with this drug for up to twoyears, there is a need for more safetydata on the use of linezolid forextended periods of time.

Today there is a paediatricformulation available. It is supplied asa powder for suspension and sorequires reconstitution at the point ofdispensing. This requires trained staffto accurately measure the requiredwater needed to suspend the powderand access to clean, safe water. Thereconstituted product can be storedat room temperature.

HIV co-infectionThere have been no studiesperformed, but interactions areunlikely. There may be increase risk ofmyelosuppression and mitochondrialtoxicities with long-term use incombination with certainantiretrovirals (zidovudine, stavudine,didanosine).28 Further studies arerequired to confirm this.

GROUP 5

40

This report looks at the sources andprices of anti-tuberculosis medicinesclassified in World HealthOrganization Groups 2 (injectableagents), 3 (fluoroquinolones), 4 (oralbacteriostatic second-line agents) and5 (agents with unclear efficacy)1.Questionnaires were sent only tocompanies that had at least one anti-tuberculosis product listed on theWHO List of Prequalified MedicinalProducts or quality-approved by astringent regulatory authorityaccording to MSF or The Union’sknowledge. The data were collectedup to March 2011.

Price information: Prices are listedwhere manufacturers agreed to shareinformation. A number ofmanufacturers, including Cipla,Macleods, Bayer, Meiji, and Olainfarmdid not have prices available or didnot agree to publish prices, and noresponses were received from Eli Lilly,Mylan, Chao Centre and APP Pharma.Prices paid for by the Global DrugFacility pooled procurementmechanism are also listed, althoughthese prices are reserved for projectsthat have received approval from theGreen Light Committee.

Prices are given in US$, rounded upto the nearest second decimal point,and correspond to the lowest unitprice (i.e. the price of one tablet,capsule or vial). When prices thatvaried according to packaging (e.g.blisters or bottle) were received froma manufacturer for the sameformulation, the lowest price wasselected. Prices received in currenciesother than US$ were converted on 7 March 2011 using the currencyconverter site www.oanda.com. Priceslisted are 'ex-works'.

The prices listed in this publicationare the ones provided by themanufacturers. The prices paid by thepurchaser might be higher because ofadd-ons (such as import taxes anddistribution mark-ups), or may belower after negotiations. Thedocument should not be viewed as amanufacturer's price list, andprocurement agents are advised tocontact manufacturers directly toconfirm prices.

Quality information: Products thatare either listed on the WHO List ofPrequalified Medicinal Products orapproved by a stringent regulatoryauthority are listed in the price tablesas 'approved'. Products that areundergoing review by either theWHO Prequalification or by astringent regulatory authority arelisted in the price tables as 'underevaluation'. Submissions to WHOPrequalification are confidential andall companies mentioned that havethe dossier accepted for review havegiven permission to do so. Productsthat have not yet been submitted toWHO Prequalification or to astringent regulatory authority havenot been included in the table.

Products procured by the GlobalDrug Facility comply with the GDF'sQuality Assurance policy. This deemseligible for GDF procurement allproducts that are included on theWHO List of Prequalified MedicinalProducts, that are approved by astringent regulatory authority, or thatare approved by the Expert ReviewPanel (ERP) also used by the GlobalFund. The GDF quality assurancepolicy can be found at:http://www.stoptb.org/gdf/drugsupply/quality_sourcing_process.asp

As the information on the WHO Listof Prequalified Medicinal Products isupdated regularly, the list should beconsulted for up-to-date informationregarding quality:http://apps.who.int/prequal/

Methodology

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

41

Abbreviated New DrugApplication (ANDA)An Abbreviated New DrugApplication (ANDA) contains datathat, when submitted to FDA's Centerfor Drug Evaluation and Research,Office of Generic Drugs, provides forthe review and ultimate approval of ageneric drug product. Generic drugapplications are called "abbreviated"because they are generally notrequired to include preclinical(animal) and clinical (human) data toestablish safety and effectiveness.Instead, a generic applicant mustscientifically demonstrate that itsproduct is bioequivalent (i.e.performs in the same manner as theinnovator drug). Once approved, anapplicant may manufacture andmarket the generic drug product toprovide a safe, effective, low costalternative to the American public1.

Active pharmaceuticalingredient (API)Any substance or mixture ofsubstances intended to be used in themanufacture of a pharmaceuticaldosage form and that, when so used,becomes an active ingredient of thatpharmaceutical dosage form2.

CultureBacterial culture is a laboratorymethod to multiply bacteria in orderto assess their presence or not in apatient's sample. This is done byletting the bacteria grow inpredetermined culture media undercontrolled laboratory conditions,outside the natural environmentwhere they usually grow (e.g. for TB,the human body).

Drug resistanceWhen a drug used to treattuberculosis is in fact ineffectiveagainst a strain of M. tuberculosis, thebacteria is said to be resistant to thedrug (as opposed to drug-susceptibleor drug-sensitive).

Drug-susceptible/drug-sensitive TBBacteria are said to be sensitive to adrug when the drugs are effective inkilling or stopping the multiplicationof bacteria in the body and cantherefore clear the infection. Thestrains of TB which are sensitive to allfirst-line drugs are called drug-susceptible.

Ex worksA commercial term (incoterm)meaning that the seller delivers whenthe goods are placed at the disposalof the buyer at the seller's premises oranother named place (i.e. works,factory, warehouse etc.), not clearedfor export and not loaded on anycollecting vehicle.

Expert Review Panel (ERP)An independent technical bodycomposed of external technicalexperts, hosted by the WHODepartment of Essential Medicinesand Pharmaceutical Policies. Theirpurpose is to review the potentialquality risk of using antiretroviral,anti-TB and antimalarial productswhich are not yet WHO prequalifiedor authorised by a stringentregulatory authority, and to giveadvice to the Global Fund and theGlobal Drug Facility whetherprocurement of such products can beauthorised.

Extensively drug-resistant TB see XDR-TB

Extra-pulmonary TBForm of TB where M. tuberculosisinfect parts of the body other thanthe lungs. This is most commonly thelymph nodes, bones, central nervoussystem, cardiovascular andgastrointestinal systems.

First-line drugsThe drugs used as the first resort totreat a disease. In the case of TB, thefollowing five drugs are usuallychosen: isoniazid (H), rifampicin (R),

ethambutol (E), pyrazinamide (Z) andstreptomycin (S). These drugs arehighly effective in drug-susceptible TBand patients usually tolerate themwell.

Global Drug Facility (GDF)A mechanism hosted by WHO toexpand access to, and availability of,quality-assured anti-TB drugs anddiagnostics through pooledprocurement. Products procuredcomply with the GDF's QualityAssurance policy. This deems eligiblefor GDF procurement all productsthat are included on the WHO List ofPrequalified Medicinal Products, thatare approved by a stringentregulatory authority, or that areapproved by the Expert Review Panelalso used by the Global Fund

Global FundThe Global Fund to Fight AIDS,Tuberculosis and Malaria is aninternational financing institution thatinvests the world's money to savelives. To date, it has committed US$21.7 billion in 150 countries tosupport large-scale prevention,treatment and care programs againstthe three diseases3.

Green Light Committee (GLC)The GLC Initiative helps countriesgain access to quality-assured second-line anti-TB drugs so they can providetreatment for people with multidrug-resistant tuberculosis in line with theWHO guidelines, the latest scientificevidence and country experiences.The Initiative consists of a secretariat,the Green Light Committee (anexpert review and WHO advisorybody) and the Global Drug Facility(the drug procurement arm of theInitiative).

MicroscopyMicroscopy is currently the mostcommonly used technique todiagnose TB. Two to three sputum

Glossary and abbreviations

1 http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm#N)2 QAS terminology database: http://www.who.int/medicines/services/expertcommittees/pharmprep/TermListcategory.pdf3 WHO

42

samples are taken from the patientand the sample will be stained andlater read under the microscope. If TBbacilli are present, they occur in theform of small red rods, while the restof the sample is blue.

Multidrug-resistant TB (MDR-TB)Patients infected with strains of TBthat are resistant to (at least) the twomost powerful first-line antibioticsused to treat TB, namely rifampicinand isoniazid, are said to havemultidrug-resistant TB, or MDR-TB

MycobacteriaTypes of bacteria, of the genusMycobacterium, that cause diseasessuch as TB and leprosy.

M. TuberculosisA pathogenic bacterial species of thegenus Mycobacterium and thecausative agent of most cases of TB.First discovered in 1882 by RobertKoch.

New Drug Application (NDA)When the sponsor of a new drugbelieves that enough evidence on thedrug's safety and effectiveness hasbeen obtained to meet FDA'srequirements for marketing approval,the sponsor submits to FDA a newdrug application (NDA). Theapplication must contain data fromspecific technical viewpoints forreview, including chemistry,pharmacology, medical,biopharmaceutics, and statistics. Ifthe NDA is approved, the productmay be marketed in the UnitedStates. For internal tracking purposes,all NDA's are assigned an NDAnumber4.

Pharmacokinetic (PK) The way the body affects the drugwith time.

Pharmacodynamic (PD) The effects of the drug on the body.

Point-of-Care testing (POC)Testing at the point-of-care meansthat diagnosis is carried out as closeas possible to the site of patient care.The driving notion behind point-of-care testing is having a test asconvenient to the patient as possibleand giving immediate results that canlead to prompt initiation oftreatment.

Pulmonary TBForm of TB where M. tuberculosisbacteria are infecting the lungs.

QT IntervalIn cardiology, the QT interval is ameasure of the time between thestart of the Q wave and the end ofthe T wave in the heart's electricalcycle. This represents the totalduration of electrical activity of theventricles. A prolonged QT interval isa biomarker of life-threateningventricular tachyarrhythmias -including torsdes de pointes.

Second-line drugsSecond-line drugs are used when thefirst-line drugs are no longer effectiveto cure a patient. In the case oftuberculosis, they are less effectiveand have many more side-effectsthan first-line drugs. This report looksat the sources and prices of second-line anti-tuberculosis medicinesclassified in World HealthOrganization Groups 2 (injectableagents), 3 (fluoroquinolones), 4 (oralbacteriostatic second-line agents) and5 (agents with unclear efficacy)

Stringent regulatory authority(SRA)Is a regulatory authority which ‘is (a)a member of the InternationalConference of Harmonization (ICH);or (b) an ICH Observer, being theEuropean Free Trade Association(EFTA) as represented by Swiss Medic,Health Canada and World HealthOrganization (WHO); or (c) aregulatory authority associated withan ICH member through a legally

4 http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm#N5 http://www.theglobalfund.org/documents/psm/List_of_Countries_SRA.pdf6 QAS terminology database: http://www.who.int/medicines/services/expertcommittees/pharmprep/TermListcategory.pdf7 WHO

binding mutual recognitionagreement including Australia,Norway, Iceland and Liechtenstein.(as may be updated from time totime)5.

TB AllianceThe TB Alliance is a not-for-profit,product development partnershipaccelerating the discovery anddevelopment of new TB drugs thatwill shorten treatment, be effectiveagainst susceptible and resistantstrains, be compatible withantiretroviral therapies for those HIV-TB patients currently on suchtherapies, and improve treatment oflatent infection. The TB Alliance iscommitted to ensuring that approvednew drug regimens are affordable,widely adopted and available to thosewho need them.

Tentative FDA approval Is awarded by the US Food and DrugAdministration (FDA) to a drugproduct that has met all requiredquality, safety and efficacy standards,but is not eligible for marketing in theUS because of existing patentprotection. Tentative approval doesmake the product eligible forpurchase outside the US under thePEPFAR programme6.

WHO Prequalification (PQ)The Prequalification Programme, setup in 2001, is a service provided bythe World Health Organization(WHO) to facilitate access tomedicines that meet unifiedstandards of quality, safety andefficacy for HIV/AIDS, malaria andtuberculosis7.

XDR-TBPatients, who have MDR-TB and alsoshow resistance to second-line drugs,including at least one from the classknown as fluoroquinolones and oneof the injectable drugs, are describedas suffering from extensively drug-resistant TB or XDR-TB.

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1. Blanc L, Falzon D, Fitzpatrick C, Floyd K,Garcia I, Gilpin C, et al. Global tuberculosiscontrol: WHO report 2010. [Online].Geneva: World Health Organisation; 2010.[cited 2011 March 14]. Available from:http://whqlibdoc.who.int/publications/2010/9789241564069_eng.pdf

2. WHO. Tuberculosis. (Fact Sheet no.104). [Online]. Geneva: World HealthOrganisation; 2010, November. [cited2011, March 14]. Available from:http://www.who.int/mediacentre/factsheets/fs104/en/

3. Falzon D, Glaziou P, Jaramillo E, MirzayevF, Nathanson E, Sismanidis C, et al.Multidrug and extensively drug resistant TB(M/XDR-TB): 2010 global report onsurveillance and response. [Online].Geneva: World Health Organisation; 2010.[cited 2011 March 14]. Available from:http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf

4. Salmaan Keshavjee, M.D., Ph.D., andPaul E. Farmer, M.D., Ph.D. Picking Up thePace - Scale-Up of MDR TuberculosisTreatment Programs. [Online]. NewEngland Journal of Medicine 2010 Nov 4;363:1781-1784. [cited 2011, March 14].Available from:http://www.nejm.org/doi/full/10.1056/NEJMp1010023

5. Stop TB Partnership. Road Map forMDR-TB scale up: The Global Drug Facility.[Online]. Stop TB Partnership, 2010, Nov.[cited 2011, March 14]. Available:http://www.stoptb.org/assets/documents/resources/publications/plan_strategy/GDF%20ROADMAP%20FOR%20MDR%20TB%202010%20Final.pdf

6. WHO. The Green Light CommitteeInitiative - frequently asked questions: Whatare the lead times for ordering second-lineanti-TB drugs? [Online]. Geneva: WorldHealth Organisation, . [cited 2011, March14]. Available: http://www.who.int/tb/challenges/mdr/greenlightcommittee/faq8_lead_times/en/index.html

7. TB Alliance. Pathway to Patients:charting the dynamics of the global TBdrug market - Compendium of findings.[Online]. TB Alliance, 2007, May. [cited2011, March 14]. Available:http://www.tballiance.org/downloads/publications/Pathway_to_Patients_Compendium_FINAL.pdf

8. WHO. The Green Light CommitteeInitiative - frequently asked questions: Howis the quality of second-line anti-TB drugsassured? [Online]. Geneva: World HealthOrganisation, . [cited 2011, March 14].Available: http://www.who.int/tb/challenges/mdr/greenlightcommittee/faq9_quality_assurance/en/index.html

9. Salmaan Keshavjee, MD, Ph.D. Role ofthe Green Light Committee Initiative inMDR-TB Treatment Scale-up. [Online].Proceedings of WHO presentation, 2009,April 3, Beijing. Geneva: World HealthOrganisation [cited 2011, March 14].Available: http://www.who.int/tb_beijingmeeting/media/press_pack/presentations/day3_presentation4.pdf

10. World Lung Foundation. Tuberculosis:Global impact in The Acute RespiratoryInfections Atlas, first edition. [Online]. 2010.World Lung Foundation. [cited 2011,March 15]. Available: http://www.ariatlas.org/tb_beijingmeeting/media/press_pack/presentations/day3_presentation4.pdf

11. Dalberg. Analysis of the 2nd line TBdrugs market and the feasibility ofadvanced purchase commitments. 2010November.

12. Sanchez-Padilla E, Dlamini T, TeferaZ.D, Ascorra A, Ruesch-Gerdes S, Calain P,et al. National survey on the prevalence ofanti-tuberculosis drug resistance in theKingdom of Swaziland. Epicentre, Paris,France; National Tuberculosis ControlProgram, Manzini, Swaziland; MSF-Switzerland, Genève, Switzerland; NationalReference Center for Mycobacteria, Borstel,Germany. 2009.

13. Khan A. Stop TB Partnership: DraftConsensus Paper on New Framework forSupporting MDR-TB Scale Up. Email toTido von Schoen-Angerer 2011, February 9[cited 2011, March 21].

14. The Global Fund to Fight AIDS,Tuberculosis and Malaria. Lists of ARVs, TBand Malaria products. [Online]. 2011 [cited2011, March 14]. Available athttp://www.theglobalfund.org/en/procurement/list/?lang=en

15. Stop TB Partnership. Procurement andSupply. [Online] 2011 [cited 2011, March14] Available at: http://www.stoptb.org/gdf/drugsupply/default.asp

16. UNITAID. MDR-TB Scale-up andAcceleration of Access.[Online] 2010. [cited2011, March 14] Available at:http://www.unitaid.eu/en/mdr-tb-scale-up.html

17. Cambridge Economics Policy Associates(CEPA) LLP. Market Dynamics Studyproduced for the Global Fund to FightAIDS, Tuberculosis and Malaria, Phase IReport. 2011 January 14.

18. Zhenkun M PhD, Lienhardt C PhD,McIlleron H PhD, Prof Nunn AJ MSc, ProfWang X MD. Global tuberculosis drugdevelopment pipeline: the need and thereality. [Online] The Lancet, 2010 June 12,Vol 375 (9731): 2100 - 2109. [PublishedOnline: 2010 May 19] Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60395-9/abstract

19. David McNeely and Andreas Diaconpersonal communication, IUATLDConference, Berlin November 2010.Available at http://uwclh.conference2web.com/content/187

20. Christian Lienhardt personalcommunication, IUATLD Conference, BerlinNovember 2010. Available at http://uwclh.conference2web.com/content/391

21. Aït-Khaled N, Alarcón E, Armengol R, etal. Management of Tuberculosis: A Guide tothe Essentials of Good Clinical Practice,sixth edition. [Online] The InternationalUnion Against Tuberculosis and LungDisease. 2010, March. [cited 2011, March14]. Available at: http://www.theunion.org/component/option,com_guide/Itemid,79/

22. WHO/Norwegian Institute for PublicHealth. ATC/DDD Index 2011. [Online]2010, December 12 [cited 2011, March14]. World Health OrganisationCollaborating Centre for Drug StatisticsMethodology. Available at:http://www.whocc.no/atc_ddd_index/

23. WHO. Guidelines for the programmaticmanagement of drug-resistant tuberculosis:Emergency Update 2008. [Online] 2008.[cited 2011, March 14]. World HealthOrganisation. Available at:http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf

24. WHO. WHO Model List of EssentialMedicines, 16th edition (updated).[Online]. 2010, March. [cited 2011, March14] World Health Organisation. Available at:

References

44

http://www.who.int/medicines/publications/essentialmedicines/Updated_sixteenth_adult_list_en.pdf

25. WHO. WHO Model List of EssentialMedicines for Children, 2nd edition(updated). [Online] 2010, March [cited2011, March 11] World HealthOrganisation. Available at:http://www.who.int/medicines/publications/essentialmedicines/Updated_second_children_list_en.pdf

26. Harmon, F. Public letter on delayedsupplies of kanamycin. [Online] 2009,February 25 [cited 2011, March 3]. APPPharmaceuticals. Available at:http://www.apppharma.com/images/stories/appfiles/Kanamycin_Ltr_2_24_09_ltrhd.pdf

27. Gupta R, Kim J.Y, Espinal M.A, CaudronJ-M, Pecoul, Farmer P.E, et al. Respondingto Market Failures in Tuberculosis Control.[Online] Science, 2001, August 10: 1049-1051. Published online 2001, July 19 [cited2011, March 10] Available at:http://www.sciencemag.org/content/293/5532/1049.summary?sid=296cc982-def8-4a77-b4ec-a7c4cc474993

28. Coyne K.M, Pozniak A.L, Lamorde M,Boffito M. Pharmacology of second-lineantituberculosis drugs and potential forinteractions with antiretroviral agents.[Online] AIDS. 2009, February 20, Vol 23(4): 437-446 [cited 2011, March 16]Available at: http://journals.lww.com/aidsonline/fulltext/2009/02200/pharmacology_of_second_line_antituberculosis_drugs.1.aspx

29. British National Formulary. BritishNational Formulary 60. PharmaceuticalPress. 2010, September 2010

30. Oanda.com GBP converted to USD[Online] [cited 2011, March 7] Available atwww.oanda.com

31. Costello, I. British National Formularyfor Children 2006, Cdr edition.Pharmaceutical Press. 2007, April 30

32. Stop TB Partnership. GDF productcatalogue. [Online] 2011 [cited 2011,March 10] Available at: http://www.stoptb.org/gdf/drugsupply/drugs_available.asp

33. US FDA. Approved product label:USFDA Capastat. [Online] United StatesFood and Drug Administration. 2008,January 14. [cited 2011, March 15].Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails

34. WHO. Global Price ReportingMechanism. [Online] World HealthOrganisation. [cited 2011, March 10]Available at: http://apps.who.int/hiv/amds/price/hdd/index.aspx

35. US FDA. Highlights of prescribinginformation: Avelox. [Online] United StatesFood and Drug Administration. 2011,January. [cited 2011, March 9] Available at:http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021085s047,021277s041lbl.pdf

36. Rodríguez JC, Ruiz M, Climent A, RoyoG. In vitro activity of four fluoroquinolonesagainst Mycobacterium tuberculosis.[Online] Int J Antimicrob Agents. 2001,March 17 (3):229-31. [cited 2011, March11] Available at: http://www.ncbi.nlm.nih.gov/pubmed/11282270

37. TB Alliance. TB Alliance Portfolio:Moxifloxacin. [Online] 2011, March. [cited2011, March 15] Available at:http://www.tballiance.org/new/portfolio/html-portfolio-item.php?id=17

38. Hutchinson D.J, Johnson C.E, Klein K.C.Stability of extemporaneously preparedmoxifloxacin oral suspensions. [Online]American Journal of Health-SystemPharmacy. 2009, April 1, Vol. 66 (7): 665-667. [cited 2011, March 10] Available at:http://www.ajhp.org/content/66/7/665.abstract

39. VandenBussche H.L, Johnson C.E,Fontana E.M, Meram J.M. Stability oflevofloxacin in an extemporaneouslycompounded oral liquid. [Online] AmericanJournal of Health-System Pharmacy. 1999,Vol 56 (22) 2316-2318. [cited 2011, March15] Available at: http://www.ajhp.org/content/56/22/2316.abstract?sid=f1807999-6f27-4f55-a74e-10700869f728

40. US FDA. Levofloxacin drud details.[Online] United States Food andDrug Administration.[cited 2011, March 7]Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

41. US FDA. Floxin Tablets (oxfloxacintablets). [Online] United States Foodand Drug Administration. 2008,September. [cited 2011, March 7] Availableat: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019735s059lbl.pdf

42. US FDA. Trecator (ethiomanide tablets,USP). [Online] United States Food andDrug Administration. 2005, December(revised) [cited 2011, March 10] Availableat: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/013026s024lbl.pdf

43. Wang F, Langley R, Gulten G, DoverLG, Besra GS, Jacobs WR Jr, et al.Mechanism of thioamide drug actionagainst tuberculosis and leprosy. [Online] JExp Med. 2007, January 22, Vol 204 (1):73-8. Published online 2007, January 16[cited 2011, March 8] Available at:http://www.ncbi.nlm.nih.gov/pubmed/17227913

44. Drugs.com. Kantrex official FDAinformation, side effects and uses. [Online]2006, March [cited 2011, March 7]Available at: http://www.drugs.com/pro/kantrex.html

45. US FDA. Amikacin overview. [Online].[cited 2011, January 4] Available athttp://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=AMIKACIN%20SULFATE

46. Drugs.com. Amikacin official FDAinformation, side effects and uses. [Online]2007, December. [cited 2011, March 15]Available at http://www.drugs.com/pro/amikacin.html

47. Green Light Committee Initiative.Annual Report 2008. [Online] World HealthOrganisation/Stop TB Partnership. 2009[cited 2011, March 21]. Available athttp://whqlibdoc.who.int/hq/2009/WHO_HTM_TB_2009.421_eng.pdf

48. TDR. Childhood tuberculosis:addressing a forgotten crisis. [Online]UNICEF/UNDP/World Bank/WHO. 2011,January 11 [cited 2011, March 16] Availableat: http://apps.who.int/tdr/svc/news-events/news/paediatric-tb

49. Médecins Sans Frontières. Scaling-UpDiagnosis Treatment of Drug-ResistantTuberculosis in Khayelitsha: An Integrated,Community-based Approach. [Online]March 2011 [cited 2011, March 21]Available at http://www.msf.org.za

50. Axel A, Dr. Personal Communicationwith Karen Day. [E-mail]. 2011, March 11

51. HIV Drug Interactions. Drug Interactioncharts - interactions with anti-HIV and otherdrugs. [Online] The University of Liverpool.2010 [cited 2011, March 18] Available at:http://www.hiv-druginteractions.org/Interactions.aspx

52. Axel A, Dr. Petha: Summary of ProductCharacteristics, Revision Dec 2008 (EnglishTranslation supplied by Fatol). Personalcommunication with Karen Day. [E-mail]2011, March 9.

45

53. The Chao Center. Seromycin;Cycloserine capsules USP. [Online] 2005,April 28 (revised) [cited 2011, March 18]Available at: http://www.thechaocenter.com/seromycin/product_insert.pdf

54. Axel A, Dr. Terizidon: Summary ofProduct Characteristics, Revision Dec 2009(English Translation supplied by Fatol).Personal communication with Karen Day.[E-mail] 2011, March 11.

55. US FDA. Paser drug details. [Online]United States Food and DrugAdministration. [cited 2011, March 18]Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails

56. Sweetman, S.C. Martindale CompleteDrug Reference Guide, 33rd Edition.Pharmaceutical Press, 2002. pp148-3

57. US FDA. Lamprene drug details.[Online] United States Food and DrugAdministration. 2002, July (revised) [cited2011, March 18] Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

58. Novartis. Lamprene pricing info.[Online] Pharmaworld.com. 2007 [Cited2011, March 18]. Available at:http://www.lamprene.com/index.php?id=4

59. US FDA. Linezolid drug details. [Online]United States Food and DrugAdministration. [cited 2011, March 18]Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LINEZOLID

60. US FDA. Zyvox drug details. [Online]United States Food and DrugAdministration. 2010, June (revised) [cited2011, March 18] Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

61. Espacenet. Substituted oxazine andthiazine oxazolidinone antimicrobials.[Online] European Patent Office. [cited2011, March 22] Available at:http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&adjacent=true&locale=en_EP&FT=D&date=19950316&CC=WO&NR=9507271A1&KC=A1

62. Espacenet. Linezolid-crystal form II.[Online] European Patent Office. [cited2011, March 22] Available at:http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&adjacent=true&locale=en_EP&FT=D&date=20010809&CC=WO&NR=0157035A1&KC=A1

63. Espacenet. Oxazolidinone tabletformulation. [Online] European PatentOffice. [cited 2011, March 22] Available at:http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&adjacent=true&locale=en_EP&FT=D&date=20010927&CC=WO&NR=0170225A2&KC=A2

64. The Global Fund. Price and qualityreporting. [Online] 2011 [cited2011, March 16] Available at:http://www.theglobalfund.org/en/procurement/pqr/

65. Espacenet. Benzoxazine derivatives.[Online] European Patent Office.[cited 2011, March 22] Available at:http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&at=24&locale=en_EP

&FT=D&CC=US&NR=4382892A&KC=A66. Espacenet. Optically activepyridobenzoxazine derivatives andanti-microbial use. [Online] EuropeanPatent Office. [cited 2011, March 22]Available at:http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&at=26&locale=en_EP&FT=D&CC=US&NR=5053407A&KC=A

67. Erturan Z, Uzun M..In vitro activity oflinezolid against multidrug-resistantMycobacterium tuberculosis isolates. ExpeInt J Antimicrob Agents. 2005 July, Vol 26(1):78-80

68. Working group on new TB drugs.Pipeline : View by phase. [Online][cited 2011 March 14] Available from:http://www.newtbdrugs.org/pipeline.php

69. TB Alliance. More than ever: 2010Annual report. [Online] 2010.Available from: http://www.tballiance.org/downloads/publications/TBA021_AR2010.pdf

70. Mukadi YD, Maher D, Harries A.Tuberculosis case fatality rates in high HIVprevalence populations in sub-SaharanAfrica. AIDS 2001;15:143-52.

71. US FDA. Drug product details. [Online]United States Food and DrugAdministration. [cited 2011, March 7]Available at: http://www.accessdata.fda.gov scripts/cder/drugsatfda/index.cfm

72. WHO. Towards Universal Access toDiagnosis and Treatment of Multi-Drug-Resistant and Extensively Drug-ResistantTuberculosis by 2015. WHO ProgressReport. Publication pending 2011.

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Akorn IncLake Forest, Illinois, USAwww.akorn.comSean BrynjelsenVice President, New Business DevelopmentPhone: +1 847 279 6149E-mail: [email protected]

Aspen PharmacareSouth Africa www.aspenpharma.comStavros Nicolaou Senior ExecutivePhone: +27 (0) 11 239 6734E-mail: [email protected]

FATOL ArzneimittelProduction Facility of RIEMSER Arzneimittel AGSchiffweiler, Germany www.fatol.deElke Rinkes International Business CoordinatorPhone: +49 (0) 68 21/ 96 05 17E-mail: [email protected]

HELP S.A.Athens, Greece www.help.com.grJaro MatusiewiczBusiness DevelopmentPhone: +30 210 2847984 E-mail: [email protected]

Jacobus Pharmaceutical Company, IncPrinceton, New Jersey, USALaura R JacobusPhone: +1 (609) 799-8221 ex 207E-mail: [email protected]

LupinIndiawww.lupinworld.com Shrikant Kulkarni Vice President - Exports Phone: +91-22-66402042 E-mail: [email protected]

Mr. Mukul Jerath Sr. Manager - Global TB Phone: +91-22-66402077E-mail: [email protected]

MedochemieLimassol, Cypruswww.medochemie.com Phaedon EllinasPhone: +357 25 867 618E-mail: [email protected]

PanPharmaFougères, Francewww.panpharma.frMichel LE BELLEGOHead of Sales & Contract-Manufacturing Phone: +33.2.99.97.92.12E-mail: [email protected]

PfizerNew York, USAwww.pfizer.comEleanor Levine GebauerDirector, Global AccessPhone: +1 (212) 733-5026Email: [email protected]

Company contacts

DISCLAIMERDR-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 companyprice list nor as a clinical guideline. It is crucial that any purchaser verify pricesand availability as well as quality status directly with the supplier beforeprocurement. Médecins Sans Frontières or The Union have made every effortto ensure the accuracy of prices and other information presented in this report,but MSF or The Union make no representations or warranties, either expressedor implied, as to their accuracy, completeness or fitness for a particularpurpose. Inclusion of a product in this document does not indicate MSF or TheUnion purchases or uses the product. Information in this guide is indicativeonly and not exhaustive, and should be verified with relevant offices whenused for other than reasons of general information. Clinical decisions shouldnot be made based on this document.

ACKNOWLEDGMENTS:MSF and The Union wish to thankmanufacturers and the Global DrugFacility (particularly Caroline Brogenand Kaspars Lunte) for sharing priceinformation for this publication.

Front cover photos:Bruno de CockBrendan Bannon

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

Cover design:TaunusGrafik +1 917 584 8033

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DR-TB Drugs Under the Microscope