THE MSF CAMPAIGN FOR ACCESS TO
ESSENTIAL MEDICINES
In 1999, in the wake of Médecins Sans Frontières (MSF) being
awarded the Nobel Peace Prize, MSF launched the Campaign for
Access to Essential Medicines. Its sole purpose has been to push
for access to, and the development of life-saving and lifeprolonging medicines, diagnostics and vaccines for patients in
MSF programmes and beyond.

THE INTERNATIONAL UNION AGAINSTTUBERCULOSIS AND LUNG DISEASE
The 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, Latin
America, Middle East, North America and South-East Asia regions.
Its scientific departments focus on tuberculosis and HIV, lung
health and non-communicable diseases, tobacco control andresearch.

March 2011

TABLE OF CONTENTS
14
16
17
19
10
12
14

Introduction
The problems that plague DR-TB medicines
Limited number of quality sources
Limited affordability
The neglect of children, and people living with HIV/AIDS
Conclusions: Breaking the vicious circle
Drug Profiles
Group Two:

Injectables
Kanamycin
Amikacin
Capreomycin

Group Three:

Fluoroquinolones
Moxifloxacin
Levofloxacin
Ofloxacin

Group Four:

Oral bacteriostatic second-line agents
Ethionamide
Prothionamide
Cycloserine
Terizidone
PAS

Group Five:

Agents with unclear efficacy
Clofazimine
Linezolid

14
16
18

20
22
24

26
28
30
32
34

36
38

40
41
43
45
47

Annexes
Methodology
Glossary and Abbreviations
References
Company contacts
Disclaimer

3Introduction
Tuberculosis (TB) is a curable disease
that continues to kill nearly 1.4 million
people1 across the globe each year,
and is the main cause of death inpeople living with HIV/AIDS2. Of the
9.4 million new tuberculosis cases eachyear, 440,000 are forms of the disease
that are multi-drug-resistant3, meaning
they can not be treated with the two
primary antibiotics used to treat TB.
Over the last decade, roughly fivemillion people developed drugresistant TB, but less than 1% had
access to appropriate treatment, and
1.5 million died4.
That such an appallingly low
proportion 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 two
years and endure often intolerable side
effects. Partly as a result of thecomplexities of treatment,
programmes must devote considerable
resources to adherence counselling, themanagement of side effects andpsychosocial care, all of which placelarge demands on human resources. In
some countries, the lack of political will
to 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 therefore
extremely vulnerable to disruption. For
some medicines, there is only one
quality-assured source, while for others
there may be several but they all rely
on a single source of the active
pharmaceutical 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 drugsensitive TB. Alarmingly, in recent years
prices have actually been increasing as
some manufacturers put an end to
subsidies that have kept prices lower.

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

THE UNION AND TB

MSF 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; conducting
operational research and clinical trials; organising conferences
and courses; and publishing both a peer-reviewed journal and arange of technical guides. In addition, The Union regularly
monitors MDR-TB project sites and provides technical assistanceon all aspects of MDR-TB management in Africa, Asia, Latin
America and the Middle East. Its clinical trial of a shortened
standardised MDR-TB treatment regimen will begin enrolling
patients in 2011 and has the potential to revolutionise themanagement of MDR-TB.

4

In 2010, MSF treated close to 30,000 people
for tuberculosis, of which 3,300 werechildren under the age of 15. MSF - often
working alongside national health authorities- treats patients for TB in 29 countries in awide variety of settings, ranging from urban
slums to rural areas, prisons or refugee
camps.
In recent years, MSF has worked to increase
the numbers of people it treats with drugresistant tuberculosis from 11 patients in2001 to around 1,000 people across 15
countries in 2010.

“Was it possible that I could live?” - The story of HappinessHappiness Dlamini lives with hereleven year-old son and four-year
old daughter in the village of
Emhlabeni - four hours drive fromMbabane, the capital of
Swaziland. Before getting sick, she
worked as a housekeeper. She isliving with HIV and is also infectedwith multidrug-resistanttuberculosis, which is all too
common in the small southern
African country. One third of those
newly diagnosed with TB in
Swaziland have DR-TB12.
“I had been coughing for a longtime, so after discussion with myfamily, we felt I should go get
tested for TB,” she says. “I wasvery scared when they told me I
had MDR-TB. To me, it meant theend of my life, because everyone
in my community that I knew had
MDR-TB had died.”
Happiness learned that if she wasable to stick to her treatment, she
had a good chance at surviving

Photo © Krisanne Johnson

DR-TB can be cured, but treatment
requires people to take a course of up
to six different antibiotics – as many as
20 pills per day for up to two years,
plus, for the first six months, a daily
painful injection. Patients often endure
intolerable side effects. These can
include nausea, severe vomiting,depression, aggressive behaviour,
hallucinations, vertigo, hearing loss,
diarrhoea and lethargy. Patients
may need to take additional
medication to mitigate these side
effects. Treatment needs to be
tailored to the precise drugs thatwill be effective for a patient,
depending on their drug-resistanceprofile. People's lives are interrupted
by DR-TB treatment, and many findadhering to it too arduous to bear.
Happiness Dlamini from Swaziland
shares what life is like on DR-TB
treatment.

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

MDR-TB. She started treatment
through MSF's community care
MDR-TB programme in Shiselweni
Region, after she was diagnosed in
December 2010. When she started
treatment, 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 later
her daily routine still consists of an
injection and 15 and a half pills.
The side-effects the medicines cause
are harsh - she can barely list all ofthem - and have made her feel
mentally unstable and physically ill.
“It was like I was losing my mind - I
had hallucinations and found myself
banging against things at night,”
she says. “I have sore feet and mylegs cramp up. I have diarrhoea andI often vomit after taking the pills, so
I have to take them again if it was5within 30 minutes to make sure I'm
not defaulting on my treatment.”
Every day, Happiness struggles not
only with the burdens of treatment,
but with the stress of not being able
to provide for her family. And
keeping her distance from herchildren to make sure they don't
get infected is affecting her
relationship with her four-year-old
daughter in particular - little
Nokwenza has now become closer
to her grandmother.
Happiness has responded well totreatment so far and has been
determined to stay the course. But
she does not find it easy to be
optimistic.
“I have to be honest that when it
comes to my future, I am very
unsure,” Happiness says. “I really
don't know what will happen.”

The problems that plague DR-TB medicines
This report provides an overview ofavailable DR-TB medicines, providing
relevant information for each product,
including its sources, quality status andprice, that can aid treatment providers,treatment programmes and national
procurement centres in making
procurement decisions. Transparencyof price and quality information is one
problem that this document also aims
to help overcome. In providing thisoverview, a number of important
problems that hamper access to
medicines are brought to light.
The medicines examined in this report
are those DR-TB drugs classified ingroups 2-5 of the World HealthOrganization's 2008 Guidelines for the
Programmatic Management of Drugresistant Tuberculosis. Certain problems
are more relevant to some drug classes
than others.

GROUPING

DRUGSGroup 1 - First-line oral agents

isoniazid*, rifampicin*,ethambutol*, pyrazinamide*,rifabutin*Group 2 - Injectable agents

kanamycin, amikacin, capreomycin,
streptomycin*

Group 3 - Fluoroquinolones

moxifloxacin, levofloxacin,
ofloxacin

Group 4 - Oral bacteriostatic
second-line agents

ethionamide, prothionamide,
cycloserine, terizidone, paminosalicylic acid (PAS)Group 5 - Agents with unclear
efficacy

clofazimine, linezolid,
amoxicillin/clavulanate*,thioacetazone*,
imipenem/cilastatin*, high-dose
isoniazid*, clarithromycin** this report does not include first-line oral agents, first-line injectable agents, or certain group 5 agents

How countries procure DR-TB drugs
In response to a growing need for
DR-TB treatment - and to prevent
further drug resistance fromdeveloping through improper use
of 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 has
been to provide technical review of
proposed DR-TB treatment
projects, and 'green-light' them ifthey meet certain criteria.
Approved projects then get accessto quality-assured drugs at reduced
prices - since 2002, these havebeen procured through the WHOhosted Global Drug Facility.

From 2000 to end 2010, a
cumulative total of 105,140 patientswere approved for treatment
through the GLC - although lessthan half of these (under 30,000
patients) had actually been started
on treatment by the end of 200972.
Until now, programmes without GLC
approval are not allowed to turn to
the Global Drug Facility to access
WHO quality-assured medicines.
Not surprisingly, nearly one decadeon, only 13% of the estimated DRTB drug market is channelled
through the Global Drug Facility. In
2010, only 12,000 patients wereenrolled in GLC-approved treatment

6

programmes, compared to an
estimated 440,000 new cases and
150,000 deaths3.
Many programmes continue to use
DR-TB drugs from outside the GLC
process, where drug quality may beuncertain, and drug prices may besubstantially higher7. This isespecially concerning in countries
with the highest disease burden.
The GLC Initiative has been
undergoing a reform process since
early 2010 and an intended key
change is to let all programmes
purchase quality-assured medicines
through the GDF13.

Global DR-TB drug market
The global DR-TB market was estimated to be worth $300 million in 2010, with only $125 million procured through the
public sector. Of this, only $40 million was channelled through the Global Drug Facility.
The market has been growing by approximately 5% per year, with India and China taking the largest share, at 63% and17%, respectively17.

1. Limited number of quality sources
Relatively few products for thetreatment of drug-resistant tuberculosis
are included on the WHO List ofPrequalified Medicinal Products orapproved by a stringent drug
regulatory authority such as the US
Food 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 medicines
covered in this report, only six
products (for five different drugs) havebeen prequalified by WHO and only
four sources (for two different
medicines) are recommended forpurchase in 2011 by the Expert Review
Panel14, a joint mechanism of the
Global Fund to Fight AIDS, TB, andMalaria and the GDF that gives
temporary purchase permission for
drugs still under evaluation.
Few quality-assured sources exist.
For many DR-TB drugs, such as
capreomycin, prothionamide,terizidone, PAS and clofazimine, only
one quality-assured source exists. For
others, including ethionamide*,
moxifloxacin and PAS-Sodium, there
are only two quality-assured sources.
Although there has been some recent
progress - with a decrease in thenumber of products that had only one
supplier, down from 11 in 2008 to fourin 20115 - for all of these medicines,
supply is extremely vulnerable todisruption.

The example of kanamycin illustrates
the risks associated with relying on few
sources for a given medicine. In thepast, several manufacturers had
kanamycin registered for use in the US,
although all but one subsequently
ceased production, because of fallingdemand in wealthy countries. Today,
only three quality-assured sources are
identified. Of those, the first was forced
to suspend production because of therelocation of its supplier of active
pharmaceutical ingredient in 2009.
The second also experienced a supply
problem in 2010 and ceased
production for a period of time, leaving
programmes dependent on a third
manufacturer with limited capacity, somuch so that its production is solely
dedicated to GDF procurement,leaving other DR-TB treatment
programmes with no quality-assured
source.
For a number of DR-TB medicines,
multiple producers in Russia, India,
China and other countries are known
to manufacture DR-TB drugs, butwhether they could comply with WHOor stringent regulatory authority
standards is unknown. Part of the
problem of too few quality-assured
sources for international supply could
be resolved by encouraging
manufacturers to improve theircompliance with internationallyrecognised quality standards andsubmit product dossiers for quality
assessment through the WHO
Prequalification Programme or
stringent regulatory authorities.

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

7

One welcome step is that the Global
Drug Facility now has a clear policy,
sending a signal to manufacturers toinvest in quality, by requiring products
to be either quality assured by theWorld Health Organization's
prequalification programme, orapproved by the Expert Review Panel.
The Panel provides time-limited
approval for products that have fewer
than three sources approved by either
the WHO Prequalification or a stringent
regulatory authority. With theimplementation of the GDF qualityassurance policy, price is no longer themain determinant for purchasing
decisions.
Sources of active pharmaceuticalingredients are limited. The
difficulties faced in trying to increase
the number of quality-assured sources
for some DR-TB drugs are to a large
extent due to those associated with the
production of the active
pharmaceutical ingredient (API). For
several drugs, such as capreomycin andkanamycin, only one quality-assured
API source has been identified. In thecase of capreomycin, all quality-assured
finished products identified in thisdocument are reliant on a single sourceof API, again making the entire supplyof capreomycin extremely vulnerable
to disruption. A recent study for the
GDF noted that the supply of API wasvulnerable for amikacin, kanamycin,
prothionamide and clofazimine11.
Part of the problem is due to thecomplexity of production. For

Photo © Bruno de Cockexample, producing the API for the
injectables capreomycin and kanamycin
requires a fermentation process that ismore complex than the synthetic
process. The complexity is further
increased as the API should be sterile.
Some medicines that are active
against DR-TB are not reaching the
DR-TB market. Developed for thetreatment of infectious diseases, somemedicines do not have an approved
indication for use in DR-TB, even though
they have shown efficacy in in-vitro
studies and have been used for many
patients and recommended intreatment guidelines. This is particularly
the case for the latest group of
antibiotics used in DR-TB treatment, thefluoroquinolones (suchas moxifloxacin, levofloxacin andofloxacin).
Although a number of quality-assured
manufacturers 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 GDF
procurement tender. As such, theperspective of higher earnings bytargeting more profitable diseases than
DR-TB acts as a barrier to increasing thenumber of quality-assured sources of
DR-TB medicines.

Getting medicines into countries: Lead times and regulatory constraints
There are additional barriers faced by treatment providers to getting drugs in countries. One is lead times. GDF iscommitted to deliver medicines within 90 days15 after order confirmation. However, this commitment is sometimes
difficult to respect due to long lead time or difficulty of production at manufacturer level. The GDF has thus decided to
put in place a stockpile of DR-TB medicines, with support from UNITAID16.
Delays in drug delivery are also largely due to national regulations, and regulatory issues form a barrier to accessing DRTB 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, registration
can be difficult. When these products are used as a part of a DR-TB treatment regimen, they are essentially being used
“off label” for this indication. This may increase difficulties for manufacturers trying to register their products for theindication of TB in some countries.
Countries should use fast-track registration procedures to facilitate the importation if medicines are quality-assured by
WHO or another stringent drug regulatory authority.

82. Limited affordability
First-line TB treatment costs $19 per
patient for a six-month treatment
course32. Yet the cost of DR-TB
treatment is considerably more
expensive, and this acts as a barrier totreatment scale up. For both drugsensitive and drug-resistant TB, to theprice of the medicines must be added
significant costs in terms of biologicalmonitoring, human resources for
medical and psychosocial care, andtreatment to counter side effects.
The price of DR-TB treatment varies
considerably, as treatment must be
individualised according to a patient's
drug resistance profile. Drugs procured
through the GLC/GDF cost between$4,400 and almost $9,000 per patient
for a standard 18-24 month treatment
course. For drugs purchased outside of
the GLC/GDF, prices may be evenhigher.
These prices are a reflection of
insufficient market competition among
multiple producers, both at the level of
API production, as well as at finishedproduct level. They are also a
consequence of limited demand for
DR-TB drugs, as with low volumes,
manufacturers cannot hope to achieve
economies of scale necessary to bringprices down. This is one area where a
new diagnostic test, by diagnosing
patients more effectively and more

quickly with DR-TB, will increasedemand for more second-line antituberculosis medicines.
The price of four medicines inparticular weigh heavily in theoverall cost of a DR-TB regimen.
Overall costs of the DR-TB regimen are
particularly driven by capreomycin,
moxifloxacin, PAS and cycloserine.
For most DR-TB drugs, patents are
not typically a factor in causing highprices because the medicines weredeveloped so long ago that patents onmost have long run out.
However, moxifloxacin is one notable
exception. Until now, Bayer's
monopoly has kept prices high. But
now that there is one WHO
Prequalified generic moxifloxacin
source available, the situation willchange, and as the number of genericsources increases, the price should fall.
Although patents claiming
moxifloxacin as a compound shouldhave expired in most countries,
subsequent patents could possibly
stand in the way of generic production
and/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 data
exclusivity provisions, as for example
currently demanded by the European
Union as a part of the EU-India Free
Trade Agreement negotiations.
Some DR-TB drug prices haveincreased considerably between 2001
and 2011, including for the medicines
procured through the GDF for GLCapproved treatment programmes. The
prices of amikacin, kanamycin,
cycloserine and capreomycin have all
increased substantially in recent years(see table below).
For kanamycin, the hike in price ispartly due to GDF turning to Meiji after
supply problems affected the
production of more affordable versions
made 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 prices
it was offering the GLC. Since 2003,
the US company has been actively
engaged in technology transfer togeneric manufacturers, and those who
now produce charge substantiallyhigher prices. In fact, the price of
capreomycin is expected to continue
rising, and double in the near future from $4 to $8 per unit - as Eli Lilly's
existing stock at the GDF eventually

Prices available for GLC - approved programmes, in US$
Products

July 2001

March 2011
(lowest price)% Difference
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

StableProthionamide 250mg

0.10

0.10

StablePAS 4g sachet

1.51

1.57

Stable9

Photo © Dieter Telemans

runs out and Akorn's product is used.
The impact on the overall cost of a DRTB regimen is estimated to be around$720.
Prices directly frommanufacturers - the overwhelming
majority of patients who receive DR-TB
treatment are not funnelled throughthe GLC process. They may receive
treatment through national
programmes or NGOs or othertreatment providers, or moreconcerning is on the private market.
No analysis of the private market wasundertaken and is outside the scope of
this report.
MDR-TB patients in Cambodia.

3. The neglect of children and people living with HIV/AIDS
Until today, there has been very little
research 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 expert
opinion, not randomised clinical trials,
with a large number of 'grey areas'
where expert opinions may be
conflicting4.
Children are particularly neglected.
At least 10-15% of total TB cases eachyear occur in children and a similar
percentage can be assumed among
new DR-TB cases in children48. Yet only
two medicines featured in this report(amikacin and levofloxacin) have beendeveloped as paediatric formulations,and these are not widely available. Thismeans that treatment providers who
attempt to treat children must do soby manipulating adult formulations,such as breaking or crushing tablets toapproximate the required dose. This
carries a major risk or over- or underdosing a child.
In addition, safety and efficacy data inchildren have not been established forthe majority of the medicines used in
DR-TB treatment. Only three medicines
in 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 tuberculosis
would need to take the medicine forclose to two years. For cycloserine,different guidelines give different
recommendations so there is no clarity
regarding the safety and efficacy of theuse of this drug in children.
Even when a drug is registered for use
in children and a paediatric formulation
does exist - for amikacin, for example it is not included in the GDF productcatalogue, meaning that GLCapproved programmes cannot
purchase it through the GDF.
The interactions of DR-TB drugs
with AIDS medicines are also
largely unknown. There is precious
little information on how DR-TB
drugs interact with antiretroviral
medicines used to treat HIV/AIDS70 this has not been a priority fordevelopers of HIV drugs as coinfection with TB is today uncommon
in wealthy countries. This isparticularly problematic given that TB
is the biggest killer of people livingwith HIV today2.
For many DR-TB medicines the crucial
research is lacking. For kanamycin,
amikacin and capreomycin, forexample, the potential for renal
10

toxicity when used with tenofovir(the backbone of the WHOrecommended first-line antiretroviralregimen) is unstudied. The medicinesof the fluoroquinolone class moxifloxacin, levofloxacin andofloxacin - are thought to interact
with crucial protease inhibitors likeritonavir and atazanavir (both part ofsecond-line AIDS regimens). Druginteractions are also predicted
between ethionamide andprothionamide and ARVs such asnevirapine and efavirenz. There is
precious little knowledge about
possible interactions for othermedicines, such as terizidone, PAS
and cycloserine.
The adaptability of some DR-TB
medicines for use in resource-poor
settings is also a concern. Many
DR-TB drugs are poorly adapted tothe constraints of health systems in
high-burden settings. PAS requires
refrigeration, which is an added
logistical burden for programmes,
particularly in sub-Saharan Africa. The
use of injectable products likekanamycin and amikacin also imposes
burdens both on the programme, as
qualified staff will be required foradministration of the product, and on
the patient, who must undergo six
months of painful injections.

R&D for TB: A long story of neglect
The medicines used in DR-TB
treatment cause often intolerable
side effects, which can include
nausea, severe vomiting, depression,
aggressive behaviour, hallucinations,vertigo, hearing loss and diarrhoea.
With such a litany of complaints
associated with drug-resistanttuberculosis treatment, many look to
the research and development(R&D) pipelines for a new regimen
to answer these problems.
R&D into TB drugs and diagnostics
were neglected for decades because
the disease primarily affects
developing countries and therefore
did not represent a lucrative market
for the pharmaceutical industry. Thisapplies as much to drug-susceptible
as drug-resistant TB. In the case of
second-line TB medicines, however,the problem is amplified, as thedrugs used are of limited
effectiveness, with success rates of
the current treatment at around 80%
at best.

It is questionable whether this objective
can be achieved within reasonable
timelines. In addition, the most urgent
priority is to improve treatment of
MDR-TB, given length, toxicity andlimited effectiveness of current
treatment.
Among the new drugs, Tibotec's
TMC20719 and Otsuka's OPC6768320
are in most the advanced stages, andhave recently completed Phase IIb
clinical trials in MDR-TB patients. TMC
207 is expected to get accelerated
approval for use in DR-TB treatment as
early as 2012. However, further studies
will be needed to determine if theaddition of the new drug will allow
some of the older drugs to be
removed from the regimen and how
much the treatment regimen can beshortened.
To ensure a range of effective
treatment options in the long-term, alarge number of new drug candidates
with novel mechanisms of action need

to be available to allow for theselection of optimum regimens andmeet the goal of a single therapy
effective against both drug-sensitiveand drug-resistant TB. Thus drug
discovery efforts need to be scaled
up in order to have a healthy
pipeline able to deliver an optimaltreatment regimen.
In the immediate term, it is crucial
to make today's DR-TB treatment as
tolerable as possible for patients.
This entails conducting studies on
how to alleviate the worst side
effects caused by existing drugs, byfor example looking at ways tospace the intake of drugs, optimise
doses, develop alternative, moreuser-friendly formulations (for the
injectables) and study their use inchildren and people living with HIV.
Part of these efforts involve
exploring new combinations ofexisting medicines to reduce theduration of treatment21. A shorter
regimen has already been used in
Bangladesh, 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.
Photo © Krisanne Johnson

After having been at a virtual
standstill for about 40 years, the TB
drug pipeline has seen encouraging
progress in recent years68, withrenewed R&D activities by the Global
Alliance for TB Drug Development(the product development
partnership established in 2000 tofoster development of new TB drugs)
and a few pharmaceuticalcompanies. However, compared toother disease R&D pipelines, TB's
remains fairly limited, and no new
drug has yet reached the market.

compounds in the clinical development
stage and the intention is that some ofthem will be part of a future single
treatment regimen active against both
drug-sensitive and all forms of drugresistant TB18.

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

11

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. Supply
insecurity due to delivery delay or interruption - as for kanamycin in 2010 - means that programmes have been cautious
rather than ambitious about the number of people they aim to treat - a direct disincentive to treatment scale-up.
Low demand for DR-TB drugs is also caused by the difficulties surrounding diagnosis - only 11% of 440,000 new MDR-TB
cases were detected in 2009. Until now, it has taken up to three months to determine a patient's precise drug-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 implemented
more widely, improved diagnosis could contribute to the level of increased demand needed to make the DR-TB drug
market more attractive to drug developers and manufacturers. This, in turn, could lead to additional suppliers entering 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 Green
Light Committee Initiative and the work of the Global Drug Facility may have made an important contribution but have
not yet been able to overcome supply problems and decrease prices. The GLC Initiative and the GDF have been
undergoing a reform process since early 2010 - what is needed is for GDF to take a clear break from its previous short-term
approach and limited focus on risk minimising strategies. The GDF can and should play a stronger market shaping role,guided and supported by users and donors.

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

12

Manufacturers and drug developers:■ Should agree to provide information on prices and pricing conditions in order to improve the transparency on the priceof 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 andexpanded access programmes.
■ Drug developers should study the safety and efficacy of existing and new medicines in paediatric formulations and forpossible 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 thatallow 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 resistancedevelopment 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 should support research todefine a better and shorter DR-TB
treatment regimen with the inclusionof newer drugs.

MDR-TB patient receives care throughMSF in Uzbekistan

13

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

General Information• Therapeutic Class:Aminoglycoside antibiotic• Presentations available: solution
for injection: 1g/4ml, 500mg/2ml,
1g/3ml. As powder for injection: 1g• ATC Code: J01GB0422• Included in the WHO
Guidelines as Group 2 injectableagent23• Included in the 16th edition of
the WHO Model List of Essential
Medicines24 and in the 2nd editionof the WHO Model List of Essential
Medicines for Children25• First approved by U.S. Foodand Drug Administration(FDA): The date of the original
New Drug Application (NDA) is not
publically available on the US FDA
website. The first Abbreviated New
Drug Application (ANDA) wasapproved on 13 February 1973.
The only registered product in the
US today was approved on 17
November 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 information
Price of the lowest unit (i.e. the price of one tablet, capsule or vial)
Manufacturer

Meiji

Panpharma

Macleods

APP Pharma

GDF pooled
procurement
price

Quality status

Approved by SRA

Approved by SRA

Under evaluation

Approved by SRA

GDF Quality
Assurance Policy

1g powder for
injection

xx

0.84*

No price
information givenxx

No price
information given

1g/4ml solution
for injection

No price
information given

xx

xx

xx

2.58
(Meiji)

1g/3ml solution
for injection

xx

xx

xx

Not currently in
productionxx* Price received in Euro and converted to US$ on 7 March 201114

Spotlight on access issues
There is no clinical difference between
kanamycin and amikacin. They have
similar side effect profiles and show
cross reactivity and therefore almost
identical resistance23. The choice of a
National TB Programme or treatment
provider will also therefore depend onother factors including price,
availability and adaptability of theformulation.

Number of quality sources
In the past, kanamycin formulations
from several different manufacturers
were registered in the US. Today,
however, only three kanamycin
products approved by a stringent
regulatory authority were identified inthis report. No sources of kanamycin
are approved through WHO
Prequalification, although one
manufacturer (Macleods) has
submitted a dossier to WHO
Prequalification and has been acceptedfor evaluation.
Despite this, the supply of kanamycin
remains vulnerable to disruption.
Today, only one company (APP
Pharma) has an active registration in
the US - but they have not had any
production since February 2009 due tothe relocation of the API
manufacturer26. In the EU, there is only
one approved manufacturer(Panpharma) but in 2010 they had aproblem with the API resulting in aninterruption in supply. As this was the
only quality-assured source available to
GDF at the time, this resulted in asignificant problem for GLC-approved
programmes and other treatment
providers. The problem has been
rectified but capacity issues remain.
In reaction to the potential shortage of
quality-assured kanamycin, GDF
identified an alternative source inJapan (Meiji). While this helped toensure continual supply while
Panpharma was not in production,
Meiji has limited production capacity

GROUP 2and the price is considerably morethan the Panpharma product. The
supply is also reserved for GDF leaving
other treatment providers with noalternative quality-assured sources.

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

This is a good example of thevulnerability of supply with limited
sources. Additional manufacturers may
exist in China, India, the former Soviet
Union, and other countries, butwhether they comply with WHO
quality standards is unknown.

Adaptability

Active Pharmaceutical
Ingredient
Increasing the number of qualityassured sources for the finishedproduct is to a large extent tributary ofthe difficulties associated with the
production of the active
pharmaceutical ingredient (API).
Kanamycin API is manufactured by aprocess of fermentation. This is a
specialised process, and there are notmany manufacturers globally who
have the capacity to produce qualityassured API produced through thefermentation process - the complexity
is further increased as the API should
be sterile. In today's regulatoryenvironment, the quality assurance of
the API is critical in the approval
process of the finished productthrough WHO Prequalification or astringent regulatory authority.

Kanamycin, like the otheraminoglycosides and capreomycin
cannot be administered orally. This
imposes burdens both on the
programme, as qualified staff will be
required for administration of the
product, and on the patient, whomust undergo six months of painful
injections.
Kanamycin is available in both apowder and a fully liquid formulation;
the latter is more adaptable toresource-limited settings asreconstitution of the powder is not
required.

Paediatrics
The safety and effectiveness in children
has not been established. While there
are dosages published in several
guidelines, there is an urgent need forfurther research (pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.

Evolution in priceHIV co-infection

In 2001, Green Light Committeeapproved programmes were able toaccess kanamycin for US$ 0.36 pervial27. Since then the price has slowly
increased and today the mostaffordable price available through the
GDF, for a fully liquid ampoule, ismore than seven times the priceoffered to the GLC in 2001. The
reason for this is not clear, but partiallythis is related to the unavailability of
the Panpharma product in 2010, andthe identification of Meiji as a quality-

There have been no studies
performed, but based on
pharmacokinetic profiles, the potential
for drug interactions are low. There ishowever potential for additive
toxicities in particular with
antiretrovirals which may cause renal
toxicity like tenofovir28. Further studies
are required to confirm this.

15

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

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

Medochemie

Quality status

Approved by SRA Approved by WHO Approved by SRA
PQ

500mg/2ml
solution for
injection

1.06*

Cipla

Help SANo price
information given* Price received in Euro and converted to US$ on 7 March 2011

16

1.54*

GDF pooled
procurement
price
GDF Quality
Assurance Policy
1.20*(Medochemie)Spotlight on access issues
There is no clinical difference
between kanamycin and amikacin.
They have similar side effect profiles
and show cross reactivity andtherefore almost identical resistance23.
The choice of a National TB
Programme or treatment provider will
therefore depend on other factors
including price, availability andadaptability of the formulation.

GROUP 2Evolution in price

Paediatrics

In 2001, Green Light Committeeapproved programmes were able toaccess amikacin for US$ 0.11 per vialor ampoule27. Since then, the pricehas slowly increased and today themost affordable price available
through the GDF is $1.20 per vial or
ampoule. This is an increase of close
to 1000% since 2001, the reasons forwhich are unclear.

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

Number of quality sources
Several companies have amikacin
approved by stringent regulatory
authorities. In addition, in January
2011, the first generic amikacin from
Cipla was prequalified by WHO. A
further Indian manufacturer (MicroLabs) is expected to submit a dossier
to WHO Prequalification during thecourse of 2011.
There are multiple sources of qualityassured amikacin, possibly because
other approved indications of use
exist for the drug. The supply of
amikacin is therefore secure.

Nevertheless this remains considerably
more affordable than prices paid inrich countries - the British National
Formulary lists a price of $16.49 pervial29,30.

No prices were offered for thisproduct for this report. In addition,
the GDF does not include thisformulation in its product catalogue,
meaning that GLC-approved
programmes cannot order thisproduct for children through the
GDF32.

HIV co-infection

Adaptability
Amikacin, like the otheraminoglycosides and capreomycin
cannot be administered orally. This
imposes burdens both on the
programme, as qualified staff will be
required for administration of the
product, and on the patient, whomust undergo six months of painful
injections.
Amikacin is available in both a powder
and a fully liquid formulation; thelatter is more adaptable to resourcelimited settings as reconstitution of
the powder is not required.

17

There have been no studies
performed, but based on
pharmacokinetic profiles, thepotential for drug interactions arelow. There is however potential for
additive toxicities in particular with
antiretrovirals which may cause
renal toxicity like tenofovir28. Further
studies are required to confirm this.

CAPREOMYCIN (Cm)General Information• Therapeutic Class:polypeptide antibiotic• Presentations available:
1g powder for injection• ATC Code: J01GB0622• First approved by U.S. Foodand Drug Administration(FDA): 2 June 197133• Included in the WHO
Guidelines as a Group 2
injectable agent23• Included in the 16th edition of
the WHO Model List of Essential
Medicines24 and in the 2nd editionof the WHO Model List of Essential
Medicines for Children25

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

Akorn

Macleods

GDF pooled
procurement
price

Quality status

Approved by SRA

Under evaluation

GDF Quality
Assurance Policy

1g powder for
injection

8.00

No price
information given

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

18• Approved indication in the US:
Capreomycin is to be usedconcomitantly with otherappropriate anti-tuberculosis
agents, is indicated in pulmonary
infections caused by capreomycinsusceptible strains of M. tuberculosis
when the primary agents(isoniazid, rifampicin, ethambutol,aminosalicylic acid, andstreptomycin) have been ineffective
or cannot be used because of
toxicity or the presence of resistanttubercle bacilli33

Spotlight on access issues
Number of quality sources
Eli Lilly filed the initial application to
the US FDA in 1971. Since 2003, thecompany has been actively engaged intechnology transfer to three genericmanufacturers (Aspen, Hisun and SIA
International) and today has ceased
production of capreomycin in the US.
None of these manufacturers has yet
received regulatory approval by a SRA
or WHO PQ.
Today, there are no sources ofcapreomycin approved through WHO
PQ. In the US, Eli Lilly's license was soldto Akorn, which today is the only
quality-assured source available to GDF.
An additional manufacturer (Macleods)
has submitted a dossier to WHO
Prequalification and has been acceptedfor evaluation, and Aspen is expected
to submit during the course of 2011.

GROUP 2environment, the quality assurance of
the API is critical in the approval
process of the finished productthrough WHO Prequalification or astringent regulatory authority.
Eli Lilly transferred the technology forcapreomycin API to only one
manufacturer - the Chinese genericproducer Hisun in 2003. Although thishas been a success, with the Hisun API
being approved by the US FDA in June
2006, all manufacturers of qualityassured capreomycin are reliant on thisone source.
Although other API manufacturers
exist, none of them has yet been
approved by a stringent regulatory
authority or by the WHO
Prequalification Programme.

Evolution in price
The supply of quality-assured
capreomycin therefore remains
vulnerable to disruption. Additional
manufacturers may exist in China,
India, the former Soviet Union, andother countries, but whether they
comply with WHO quality standards is
unknown.

Active Pharmaceutical
Ingredient
Increasing the number of qualityassured sources for the finishedproduct is to a large extent tributary ofthe difficulties associated with the
production of the active
pharmaceutical ingredient (API).
Capreomycin API is manufactured by aprocess of fermentation. This is a
specialised process, and there are notmany manufacturers globally who havethe capacity to produce quality-assured
API produced through thefermentation process - the complexity
is further increased as the API should
be sterile. In today's regulatory

In 2001, Green Light Committeeapproved programmes were able toaccess capreomycin for US$ 1.02 pervial27. Since this time, the price has
increased, with prices reported in the
Global Fund Price and Quality
Reporting (PQR) Tool between 2007
and today ranging between $3.21 and$3.64 per vial.64
For a number of years, Eli Lilly
subsidised the price of thecapreomycin for programmes
approved by the Green Light
Committee. Since transferring thetechnology to other manufacturers,
however, the price of capreomycin has
increased by almost 300%. Now that
Eli Lilly has ceased production for thismarket, the price will not be subsidised
anymore and we will see a further
increase in prices.
The price currently quoted by GDF forthis report corresponds to the Eli Lilly
subsidised price as stock is stillavailable. We can therefore expect to19

see a further price increase in the
future as GDF turns to Akorn for
supplies. If the price Akorn charges for
GDF remains the same as the one the
manufacturer provided for thisdocument ($8), the impact on theoverall cost of a drug-resistanttuberculosis treatment containing
capreomycin will be an increase ofaround $720.
Nevertheless the Akorn price remains
considerably more affordable thanprices paid in rich countries - the British
National Formulary lists a price of$40.95 per vial29,30.

Adaptability
Capreomycin, like DR-TB medicinesfrom the aminoglycosides class, cannot
be administered orally. This imposes
burdens both on the programme, as
qualified staff will be required foradministration of the product, and on
the patient, who must undergo six
months of painful injections.

Paediatrics
The safety and effectiveness in children
has not been established. While there
are dosages published in several
guidelines, there is an urgent need forfurther research (pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children aged
under five, so that dosages can beclarified and child adapted
formulations developed to be able todeliver these dosages to children.

HIV co-infection
There have been no studies performed,
but based on pharmacokinetic profiles,
the potential for drug interactions arelow. There is however potential for
additive toxicities in particular with
antiretrovirals which may cause renal
toxicity like tenofovir28. Further studies
are required to confirm this.

MOXIFLOXACIN (Mfx)
General Information• Therapeutic Class:
Fluoroquinolone• Presentations available:
400mg tablet• ATC Code: J01MA1422• First approved by U.S. Foodand Drug Administration(FDA): 12 October 199971• Included in the WHO
Guidelines as a Group 3
Fluoroquinolones23• Not included in the 16th editionof the WHO Model List of Essential
Medicines24 nor in the 2nd editionof the WHO Model List of Essential
Medicines for Children25• Approved indication in the US:
Moxifloxacin was initially approved
for the indications of bacterial
sinusitis and community acquired
pneumonia. This was further
expanded to include acutebacterial exacerbation of chronic
bronchitis, uncomplicated andcomplicated skin and skin structure
infection and complicated intraabdominal infections35

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

Macleods

Bayer

Cipla

Quality status

Under evaluation Approved by WHO Approved by SRA
PQ

400mg tablet

No price
No price
information given information given

20

No price
information given

GDF pooled
procurement
price
GDF Quality
Assurance Policy
1.70(Cipla)GROUP 3

Spotlight on access issues
Number of quality sources

Approved Indication

For many years, Bayer was the only
quality-assured source of moxifloxacin
available. 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 will
therefore be relatively secure in thenear future (although price remains abarrier).

While moxifloxacin has been shown tobe effective against Mycobacterium
Tuberculosis (Mtb)36 and has been
included in many guidelines for use in
DR-TB, it does not have an indication
approved by any stringent regulatory
authority. When moxifloxacin is used asa part of a DR-TB treatment regimen, itis therefore essentially being used “offlabel” for this indication. This may
increase complexities for manufacturers
trying to register their products for theindication of TB in some countries.

In addition, we can expect to see
further sources of quality-assured
moxifloxacin, because other approved
indications 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 when
the patent expires.
Additional manufacturers may exist in
China, India, the former Soviet Unionand other countries, but whether they
comply with WHO quality standards is
unknown.

In August 2005, Bayer and TB Alliancesigned an agreement to conduct a
global clinical development
programme, aiming to registermoxifloxacin for a first-line TB
indication. Three Phase II trials havebeen completed, and a Phase III trial isongoing.
Other actors, including The Union, arecurrently involved in clinical trials
looking at the use of moxifloxacin in a
regimen to shorten the treatment of
MDR-TB21.

Evolution in priceWith the entry of a quality-assured
generic into the market the price has
reduced considerably. Prior to this the
only option available was Bayer andprices for this product reported in the
Global Fund Price and Quality
Reporting (PQR) Tool between 2009
and today range between US$ 3.97
and $5.03 per tablet.64
This shows that some developing
countries are therefore paying prices
higher than those paid in rich countries- the British National Formulary lists a
price of $4.03 per tablet29,30. With moregeneric manufacturers expected toenter the market, we could expect tosee this price continue to fall.

Patents
Although patents covering themoxifloxacin molecule have now
expired in most countries, subsequent
patents claiming a crystal monohydrate
form of moxifloxacin appear to standin the way of generic production. Suchpatents, due to run until 2016, havebeen granted in several countries
including China, Russia, South Africaand Ukraine.
In India, where this patent waswithdrawn by Bayer, additional patents
on other pharmaceutical forms havebeen granted but do not appear to be
blocking generic manufacture.

Paediatrics
The safety and effectiveness in children
has not been established. While there21

are dosages published in several
guidelines, there is an urgent need forfurther research (pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children aged
under five, so that dosages can beclarified and child adapted formulations
developed to be able to deliver thesedosages to children. As there is no
paediatric formulation available today,
paediatric doses are obtained bymanipulating adult formulations toachieve target doses. Today the only
quality-assured adult source available
through the GDF does not have a breakline to allow for accurate fractioning of
the dose.
One alternative is to use anextemporaneously preparedmoxifloxacin oral suspension, thesubject of a stability study published in
200938. 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 available
in many settings where DR-TB is
prevalent. This solution is far from ideal
and there is therefore a need for acommercially available paediatricformulation.

HIV co-infection
No interaction studies have been
performed, but based on theknowledge of the metabolism ofmoxifloxacin, levels of the drug may be
reduced by ritonavir and increased byatazanavir. Further research is needed
to assess this.
Protease inhibitors and efavirenz may
prolong QT interval so concomitant use
with moxifloxacin should be cautious,with electrocardiogram monitoring.
Oral absorption of fluoroquinolones are
reduced by buffered drugs, so doses
should be separated from didanosinebuffered tablets28.

LEVOFLOXACIN (Lfx)
General Information• Therapeutic Class:
Fluoroquinolone• Presentations available:
250mg, 500mg and 750mg
tablets, 25mg/ml oral solution• ATC Code: J01MA1222• Included in the WHO
Guidelines as a Group 3
Fluoroquinolones23• Included in the 16th edition of
the WHO Model List of Essential
Medicines24 and in 2nd edition of
the WHO Model List of Essential
Medicines for Children25.
Levofloxacin is considered a better
alternative to ofloxacin based on
availability and programme
considerations• First approved by U.S. Foodand Drug Administration(FDA): 20 December 1996. The
paediatric formulation (25mg/ml
oral solution) was approved on 21
October 200440

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

Cipla

Macleods

GDF pooled
procurement
price

Quality status

Under evaluation

Under evaluation

GDF Quality
Assurance Policy

250mg tablet

No price
No price
information given information given

0.05(Macleods)

500mg tablet

No price
No price
information given information given

0.08(Macleods)

22• Approved indication in the US:
Levofloxacin was initially approved
for the indications of acutemaxillary sinusitis, acute bacterial
exacerbations of chronic bronchitis,
community-acquired pneumonia,
uncomplicated skin and skinstructure infections, complicatedurinary tract infections (UTI), andacute pyelonephritis. This was
further expanded to include
uncomplicated UTI, chronic
bacterial prostatitis, and treatment
of inhalational anthrax (postexposure)40

Spotlight on access issues
Number of quality sources
Two manufacturers have dossiers
submitted and accepted for evaluation
by WHO Prequalification. These Cipla(250mg) and Macleods (250mg and
500mg) sources have already beenassessed by the Expert Review Panel for
the GDF and the Global Fund and are
currently listed as purchasable in 2011
with Global Fund money.

GROUP 3

DR-TB, it does not have an indication
approved by any stringent regulatory
authority. When levofloxacin is used as apart of a DR-TB treatment regimen, it istherefore essentially being used “offlicense” for this indication. This may
create problems for manufacturers
trying to register their products for theindication of TB in some countries.

twice a day dosing for children between
six months and 17 years. Other
publications suggest twice a day dosing
for under five years, while the WHO
guidelines suggest a once a day dosing.
This can be confusing to National TB
Programmes and dangerous for children.
There is a need for a further clarification
and a consensus on the dosing of smallchildren.

Patents
An additional manufacturer (MicroLabs) is expected to submit to WHO
Prequalification during the course of
2011. The supply of levofloxacin istherefore relatively secure.
In addition, there are multiple sources ofquality-assured levofloxacin, because
other approved indications of use exist
for the drug. Indeed, a further 13
manufacturers have obtained US FDA
tentative approval for levofloxacin,
waiting to enter the US market when
the patent expires in the US in June
2011. However, none of theseproducers have applied for WHO
Prequalification, nor have made theirproducts available to GDF.

Patents claiming levofloxacin wereoriginally filed in 198165 and 198666 by
Daiichi Seiyaku, now a subsidiary ofDaiichi Sankyo, and licensed to Janssen.
Although 20-year patents expired in2001 and 2006 respectively, patent
protection has been extended until June
2011 in several European countries andthe US.
As the patent will expire soon,
manufacturers are already registering
their 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-approved
programmes.

Evolution in price

Paediatrics

The prices reported in the Global FundPrice and Quality Reporting (PQR) tool
between 2007 and today has remainedat US$ 0.05 per 250mg tablet, and hasvaried between $0.05 and $0.10 per
500mg tablet34.

Levofloxacin has been approved in the
US for children aged over six months,
but only for use in children for acuteinfections. The safety in paediatricpatients treated for more than 14 days
has not been studied. Because children
with DR-TB may be treated with thisdrug up for up to two years, there is
therefore a need for more safety data on
the use of levofloxacin for extended
periods of time in children.

This remains considerably more
affordable than prices paid in richcountries - the British National
Formulary lists a price of $2.36 per
250mg tablet and $4.21 per 500mg
tablet29,30. The price of levofloxacin does
not appear to be an issue.

Approved Indication
While levofloxacin has been shown tobe effective against Mycobacterium
Tuberculosis (Mtb)36 and has been
included in many guidelines for use inChildren metabolise levofloxacin fasterthan adults and smaller children need toreceive doses twice a day rather thandaily as recommended for adults. Thiscan be difficult to implement
programmatically if strict directly
observed therapy is followed. The USapproved product information suggests

23

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 levofloxacin
oral suspension39. This suspension allows
for 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 formulations
are manipulated in order to achievetarget doses. Today the only qualityassured source available through GDF
does not have a break line to allow for
accurate fractioning of the dose. Both ofthese solutions are far from ideal andthere is therefore a need for thepaediatric formulation to be made more
widely available.

HIV co-infection
No interaction studies have been
performed, but based on the knowledgeof the metabolism of levofloxacin, nointeractions are predicted. Further
research is needed to assess this.
Protease inhibitors and efavirenz may
prolong QT interval so concomitant use
with levofloxacin should be cautious,with electrocardiogram monitoring.
Oral absorption of fluoroquinolones isreduced by buffered drugs, so doses
should be separated from didanosinebuffered tablets28.

OFLOXACIN (Ofx)General Information• Therapeutic Class:
Fluoroquinolone• Presentations available:
200mg, 300mg, 400mg tablet• ATC Code: JJ01MA0122• First approved by U.S. Foodand Drug Administration(FDA): 28 December 199071• Included in the WHO
Guidelines as a Group 3
Fluoroquinolones23• Included in the 16th editionof the WHO Model List of Essential
Medicines24 nor in the 2nd editionof the WHO Model List of Essential
Medicines for Children25

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

Cipla

Macleods

GDF pooled
procurement
price

Quality status

Under evaluation

Under evaluation

GDF Quality
Assurance Policy

200mg tablet

No price
No price
information given information given

0.06(Macleods)

400mg tablet

No price
No price
information given information given

0.06(Macleods)

24• Approved indication in the US:
Ofloxacin is approved for theindications of acute bacterial
exacerbations of chronic bronchitis,
acute uncomplicated uretheral andcervical gonorrhea, nongonococcal urethritis and cervicitis,
acute pelvic inflammatory disease
and uncomplicated skin and skinstructure infections41

Spotlight on access issues

GROUP 3

Number of quality sources

Approved Indication

HIV co-infection

Today there is no ofloxacin approved
by WHO PQ, but three manufacturers(including Cipla and Macleods) havedossiers submitted and accepted forevaluation, and an additional
manufacturer (Micro Labs) is expected
to submit during the course of 2011.
The supply of ofloxacin will therefore
be relatively secure in the near future.

While ofloxacin has been shown to beeffective against Mycobacterium
Tuberculosis (Mtb)36 and has been
included in many guidelines for use in
DR-TB, it does not have this indication
approved by any stringent regulatory
authority. When ofloxacin is used as apart of a DR-TB treatment regimen, itis therefore essentially being used “offlicense” for this indication. This may
create problems for manufacturers
trying to register their products forthe indication of TB in some countries.

No interaction studies have been
performed, and based on themetabolism of ofloxacin, interactions
are not predicted. However one
source suggests there may be apotential interaction with atazanavirand lopinavir. There is an urgent needfor further research to clarify theseinconsistencies regarding druginteractions to guide clinicians on
drug dosing51.

In addition, there are multiple sourcesof quality-assured ofloxacin, because
other approved indications of use
exist 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 market
and several others on the EU market,
but none of them have made theirproducts available to GDF.

Evolution in priceIn 2001, Green Light Committeeapproved programmes were able toaccess ofloxacin for US$ 0.33 pertablet27. Since then, the price has
decreased dramatically with prices
reported in the Global Fund Price andQuality Reporting (PQR) Tool between
2007 and today ranging between$0.03 and $0.06 per 200mg tablet
and between $0.05 and $0.07 per
400mg tablet64. These prices remain
considerably more affordable thanprices paid in rich countries - theBritish National Formulary lists a priceof $1.09 per 200mg tablet and $0.89
per 400mg tablet29,30.

Paediatrics
The safety and effectiveness inchildren has not been established.
While there are dosages published inseveral guidelines, there is an urgent
need for further research(pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.
As there is no paediatric formulation
available today, children's doses are
obtained by manipulating adultformulations to achieve target doses.
Today the only quality-assured source
available through GDF does not havea break line to allow for accurate
fractioning of the dose.

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

25

Protease inhibitors and efavirenz may
prolong QT interval so concomitant
use with ofloxacin should be cautious,with electrocardiogram monitoring.
Oral absorption of fluoroquinolones
are reduced by buffered drugs, sodoses should be separated fromdidanosine-buffered tablets28.

ETHIONAMIDE (Eto)
General Information• Therapeutic Class:carbothionamides group, derivativeof isonicotinic acid23• ATC Code: J04AD0322• Included in the WHO
Guidelines as a Group 4 oral
bacteriostatic second-line agent23• Included in the 16th edition of
the WHO Model List of Essential
Medicines24 and in 2nd edition of
the WHO Model List of Essential
Medicines for Children25• Presentations available: 250mg
tablet• First approved by U.S. Foodand Drug Administration(FDA): 30 April 196571• Approved indication in the US:
ethionamide is primarily indicatedfor the treatment of active
tuberculosis in patients with
M. tuberculosis resistant to isoniazidor rifampicin, or when there is
intolerance on the part of thepatient to other drugs42

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

Lupin

Quality status

Under evaluation

250mg tablet

0.09

Cipla

Macleods

PfizerUnder evaluation Approved by WHO Approved by SRA
PQ
No price
information given

26

No price
information given

3.50

GDF pooled
procurement
price
GDF Quality
Assurance Policy
0.09(Macleods)

Spotlight on access issues
Prothionamide is the propyl analog of
ethionamide. There is complete crossresistance between ethionamide andprothionamide and the two are usedinterchangeably43.

Number of quality sources
Today only two ethionamide products
are quality-assured; one is prequalified
by WHO (Macleods) and Pfizer has
the marketing license for ethionamide
in the US and Canada. Such a limited
number of quality-approved sourcesmeans this product is relatively
vulnerable to supply disruption.
The situation is likely to improve as afurther two manufacturers (Lupin,
Cipla) have submitted dossiers to
WHO Prequalification and have been
accepted for evaluation. The Cipla
product has already been assessed by
the Expert Review Panel for the GDF
and the Global Fund and is currently
listed as purchasable in 2011 with
Global Fund money. An additional
manufacturer (Micro Labs) is expected
to submit during the course of 2011.
Additional manufacturers may exist in
China, India, the former Soviet Unionand other countries, but whether they
comply with WHO quality standards is
unknown.

GROUP 4Evolution in priceHIV co-infection

The current price available directly
through manufacturers or through the
GDF shows little evolution over the
past ten years. In 2001, Green Light
Committee-approved programmes
were able to access ethionamide for
US$0.10 per tablet - the price today isidentical27. The price of ethionamide
does not appear to be an issue.

There have been no studies
performed, but based on
pharmacokinetic 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 for
additive toxicities in particular with
antiretrovirals which may cause
hepatotoxicity including efavirenz andnevirapine28.

Pfizer has the marketing license forethionamide in the US and Canada
and does not currently have a pricing
structure for other markets.

Paediatrics
The safety and effectiveness inchildren has not been established.
While there are dosages published inseveral guidelines, there is an urgent
need for further research(pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.
As there are no paediatricformulations commercially available
today, dosages for children are
obtained by manipulation of adultformulations. The one quality-assured
source available today is a film-coatedtablet that is not breakable, whichmeans that fractioning the tablet is
not accurate.

27

PROTHIONAMIDE (Pto)
General Information• Therapeutic Class:carbothionamides group, derivativeof isonicotinic acid23• ATC Code: J04AD0122• Included in the WHO
Guidelines as a Group 4 oral
bacteriostatic second-line agent23• Not included in the 16th editionof the WHO Model List of Essential
Medicines24 nor in the 2nd editionof the WHO Model List of Essential
Medicines for Children25• Presentations available: 250mg
tablet• 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 registration
process in Germany on 14 June
200550Price (in US$) and quality information
Price of the lowest unit (i.e. the price of one tablet, capsule or vial)
Manufacturer

Lupin

Fatol

GDF pooled
procurement
price

Quality status

Under evaluation

Approved by SRA

GDF Quality
Assurance Policy

250mg tablet

0.08

0.14*

0.14*
(Fatol)* Price received in Euro and converted to US$ on 7 March 201128

• Approved indication inGermany: Treatment of all forms
and stages of pulmonary andextra-pulmonary tuberculosis as
second-line drug in the case ofproven multidrug-resistance of thepathogens against first-line drugs;
treatment of diseases caused by socalled ubiquitous (atypical)
mycobacteria; treatment of leprosy
in the context of modified therapy
regimens52

Spotlight on access issues
Prothionamide is the propyl analog of
ethionamide. There is complete crossresistance between ethionamide andprothionamide and the two are usedinterchangeably43.

Number of quality sources
Today there is only one
prothionamide product approved bya stringent regulatory authority (Fatol
product in Germany) and none isprequalified by WHO. Such a limited
number of quality-approved sourcesmeans this product is relatively
vulnerable to supply disruption.
The situation is likely to improve as afurther manufacturer (Lupin) has
submitted a dossier to WHO
Prequalification and has been
accepted for evaluation, and an
additional producer (Micro Labs) is
expected to submit during the courseof 2011.
Additional manufacturers may exist in
China, India, the former Soviet Unionand other countries, but whether they
comply with WHO quality standards is
unknown.

GROUP 4Evolution in priceHIV co-infection

The current price available directly
through manufacturers or through the
GDF shows little evolution over the
past ten years. In 2001, Green Light
Committee-approved programmes
were able to access prothionamide for
US$0.10 per tablet - the price today isalmost identical27. The price ofprothionamide does not appear to be
an issue.

There have been no studies
performed, but based on
pharmacokinetic 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 for
additive toxicities in particular with
antiretrovirals which may cause
hepatotoxicity including efavirenz andnevirapine28.

Paediatrics
The safety and effectiveness inchildren has not been established.
While there are dosages published inseveral guidelines, there is an urgent
need for further research(pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.
As there are no paediatricformulations commercially available
today, dosages for children are
obtained by manipulation of adultformulations. The only quality-assured
source available today does have a
break line, which facilitates breaking
the tablet in half. Howeverprothionamide has a very unpleasanttaste and breaking the tablet is not
ideal. There is a need for a paediatricformulation to be made available.

29

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

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

Quality status
250mg capsule

Lupin

Purdue GMP

GDF pooled
procurement
price

Under evaluation Approved by WHO Approved by WHO Approved by SRA
PQ
PQ

GDF Quality
Assurance Policy

0.60

Aspen

Macleods

0.78

No price
No price
information given information given30

0.59 and 0.78
(Macleods andAspen)

Spotlight on access issues

GROUP 4

Number of quality sources

Evolution in price

Paediatrics

Eli Lilly filed the initial application to
the US FDA in 1964. Since 2003, thecompany has been actively engaged
in technology transfer to three
generic manufacturers (Aspen, Purdue
GMP and SIA International) and in2008 ceased production of
cycloserine. Two of thesemanufacturers (Aspen & Purdue
GMP) now produce quality-assured
cycloserine.

In 2001, Green Light Committeeapproved programmes were able toaccess cycloserine for US$ 0.14 per
capsule27. Since this time the price has
slowly increased, with prices reported
in the Global Fund Price and Quality
Reporting (PQR) Tool between 2007
and today ranging between $0.48
and $0.68 per capsule34.

The British National Formulary
provides doses for children aged 2 to18 while the US FDA states that thesafety and effectiveness in children
has not been established. This is aclear example of different guidelines
providing different recommendations.
There is an urgent need for further
research (pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.

In additional, another manufacturer(Macleods) has cycloserine approved
by WHO Prequalification and threeother manufacturers (including Lupin
and Cipla) have submitted dossiers to
WHO Prequalification and have been
accepted for evaluation.
The supply of quality-assured
cycloserine is therefore relatively
secure.

For a number of years, Eli Lilly
subsidised the price of the cycloserine
for programmes approved by theGreen Light Committee. Sincetransferring the technology to othermanufacturers, however, the price of
cycloserine has increased by morethan 300% to $0.59 per capsule.
This remains considerably more
affordable than prices paid in richcountries - the British National
Formulary lists a price of $5.43 per
capsule29,30.

Active Pharmaceutical
IngredientAs there are no paediatricformulations commercially available
today, dosages for children are
obtained by manipulation of adultformulations. All of the quality-assured
sources available today are capsules,
which means that it is not possible toaccurately fraction the capsule.

HIV co-infection

Until 2006, the only quality-assured
source for the active pharmaceuticalingredient was Eli Lilly.

The metabolism of cycloserine is notcompletely understood, and henceinteractions are unpredictable28. Thereis a need for more research into theinteractions between antiretrovirals
and cycloserine.

Eli Lilly started the technology transfer
for the API to Shasun, India, in 2003 a
process that was concluded in 2006.
This was a success with the Shasun
API being approved by the US FDA in
June 2008.

31

TERIZIDONE (Trd)General Information• 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 editionof the WHO Model List of Essential
Medicines24 nor in 2nd edition of
the WHO Model List of Essential
Medicines 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 inGermany: Treatment oftuberculosis in adults and juveniles
aged 14 or older54

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

Fatol

GDF pooled
procurement
price

Quality status

Approved by SRA

GDF Quality
Assurance Policy

250mg capsule

1.68*

1.65*
(Fatol)* Price received in Euro and converted to US$ on 7 March 201132

GROUP 4

Spotlight on access issues
Terizidone is a combination of two
molecules of cycloserine, and as suchhas a similar mode of action as
cycloserine. There is complete crossresistance to cycloserine54. It is being
used in some countries instead of
cycloserine, and assumed to be as
efficacious; however, there are no
direct studies comparing the two
drugs, and terizidone is therefore notyet recommended by WHO23.

Number of quality sources
Today there is only one qualityassured source of terizidone available.
There are no manufacturers withdossiers submitted to WHO PQ, andno manufacturers likely to submit
dossiers in 2011. The supply of
quality-assured terizidone therefore
remains extremely vulnerable todisruption.
Additional manufacturers may exist in
China, India and the former Soviet
Union and other countries, butwhether they comply with WHO
quality standards is unknown.

Evolution in priceHIV co-infection

No price for terizidone was reported
in the Global Fund Price and Quality
Reporting (PQR) Tool.

As terizidone is a combination of acouple of molecules of cycloserine
and the metabolism of cycloserine is
not completely understood,
interactions are unpredictable28. Thereis a need for more research into theinteractions between antiretrovirals
and terizidone.

Paediatrics
The safety and effectiveness inchildren has not been established.
While there are dosages published inseveral guidelines, there is an urgent
need for further research(pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.
As there are no paediatricformulations commercially available
today, dosages for children are
obtained by manipulation of adultformulations. The only quality-assured
source available today is a capsule,which cannot be accurately
fractioned.

33

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

General Information• Therapeutic Class:salicylic acid -anti folate23• ATC Code: for PAS: J04AA01
For 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 editionof the WHO Model List of Essential
Medicines24 and in the 2nd editionof the WHO Model List of Essential
Medicines for Children25. PASSodium is not included in either
document.

• Presentations available:
PAS: 4g sachet. PAS-Sodium: 60%
weight for weight granules 9.2g
sachet and 100g jar; powder forsolution 5.52g sachet (equivalent
to PAS 4g sachet)• First approved by U.S. Foodand Drug Administration(FDA): PAS-Sodium was firstregistered in a tablet formulation in
the US on 8 March 1950. There areno manufacturers of PAS-Sodium
on the market in the US today. The
only product on the market today
in the US is PAS and this was
registered on 30 June 199455• Approved indication in the US:
PAS is indicated for the treatmentof 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

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

Quality status

Jacobus

Olainfarm

Macleods

Approved by SRA Approved by WHO Approved by SRA
PQ

GDF pooled
procurement
price
GDF Quality
Assurance Policy

1.57

xx

xx

1.57
(Jacobus)

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

No price
information givenxx

No price
information given

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

No price
information given

xx

24.00
(2.21)*(Macleods)

PAS-Sodium powder forsolution- 5.52g
sachetxx

xx

No price
information given

1.50(Olainfarm)

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

34

GROUP 4

Spotlight on access issues
Para-aminosalicylate sodium (PAS Sodium) is the sodium salt of paraaminosalicylic acid (PAS). 1.38g of
PAS-Sodium is approximately
equivalent to 1g of PAS56. None of thequality-assured sources of either PAS
or PAS-Sodium come in the same
formulation 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 multiple
formulations exist in one treatment
programme.

Heat-stable PAS-Sodium is available
today range in price between $1.5
and $2.21 for an equivalent dose ofPAS.
While the price of PAS and PASSodium has remained relatively stablein recent years, the medicine accounts
for between 25 and 50% of the total
cost of a patient's treatment overall
cost, depending on which medicines
and which products are used. A
reduction in the price of PAS and PASSodium would therefore have a large
impact on the overall cost oftreatment.

Number of quality sources
Today there is only one qualityassured source of PAS (Jacobus), andtwo quality-assured sources of PASsodium (Macleods and Olainfarm),with no products in the pipeline. Thismeans the supply of quality-assured
product is vulnerable.
The PAS-Sodium formulation fromMacleods was approved by WHO PQ
in 2009, but the unexpectedly large
demand for this product led tocapacity problems, resulting in longlead times for orders. This should berectified in 2011.
Additional manufacturers may exist in
China, India, the former Soviet Unionand other countries, but whether they
comply with WHO quality standards is
unknown.

Evolution in priceIn 2001, Green Light Committeeapproved programmes were able toaccess PAS for US$1.51 per 4g
sachet27. Since this time the price has
slowly increased, with prices for thisproduct reported in the Global FundPrice and Quality Reporting (PQR)
Tool between 2007 and today
ranging from $1.88 and $2.00 per 4g
sachet.

Adaptability
The PAS marketed by Jacobus, must
be stored at temperatures below
15°C. This is problematic for manysettings where DR-TB is prevalent, as
maintaining a functional cold chain
requires a certain level of investment
both in infrastructure and humanresources.
The product information states “thepackets may be stored at room
temperature for short periods oftime”. This should be clarified to givetreatment providers guidance on theexact length of time the product may
be stored above 15°C before
dispensing to patients, without risk ofdegradation. The availability of a PAS
product that can be kept at room
temperature for a determined periodof time will have positive implications,especially where programmes are
moving to a decentralised approachand may not have access to cold
chain.
The PAS-Sodium products do not
require any special storage conditions.

35

Paediatrics
The safety and effectiveness inchildren has not been established.
While there are dosages published inseveral guidelines, there is an urgent
need for further research(pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.
As there are no paediatricformulations commercially available
today, dosages for children are
obtained by manipulation of adultformulations. As all the available
formulations are either granules or
powders, measuring the exact dose
for a child is difficult and requires
calibrated scales to be available at the
point of dispensing. The PAS-Sodium
product from Macleods that is
supplied in the 100g jar is however
supplied with a graduated measuring
cup to allow for some estimations ofdose, but this is still not accurateenough.
An additional complexity is that
dosages are not given for PASSodium, and that doses have to be
calculated based on the content of
PAS 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-infection
There have been no studies
performed, but based on thepharmacokinetic profile of the PAS,drug interactions are unlikely. Studies
should be performed to confirm this28.

CLOFAZIMINE (Cfz)
General Information• Therapeutic Class:
Phenazine Derivative23• ATC Code: J04BA0122• Included in the WHO
Guidelines as a Group 5
medicine; agents with unclear
efficacy23• Included in the 16th edition of
the WHO Model List of Essential
Medicines (as an anti-leprosy
medicine)24 and in the 2nd editionof the WHO Model List of Essential
Medicines for Children (as an antileprosy medicine)25• Presentations available: 50mg
and 100mg soft-gel capsules

Price (in US$) and quality information
Price of the lowest unit (i.e. the price of one tablet, capsule or vial)
Clofazimine is a Group 5 medicine which today represents a very small market,
as they are essentially used in patients with XDR-TB. While there is a qualityassured source available, Novartis was not contacted regarding a price for thisproduct. This medicine does not exist in the GDF product catalogue.

36• First approved by U.S. Foodand 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

Spotlight on access issues
Clofazimine was first synthesised in
1954 as an anti-TB compound. The
drug was thought to be ineffective
against TB but in 1959 effectivenessagainst leprosy was demonstrated.
After clinical trials the product was
launched in 1969 and marketed by
Novartis for use in leprosy.
Even though clofazimine has no
official indications for the treatment of
DR-TB, clinical data on use in TB has
been published and the drug is
recommended by WHO.

Number of quality sources
Today there is only one source
approved by a stringent regulatory
authority. This product is produced by
Sandoz for Novartis. Additional
manufacturers may exist in China,
India, the former Soviet Union andother countries, but whether they
comply with WHO quality standards is
unknown.
Clofazimine was not included in the10th Invitation to Manufacturers to
submit an Expression of Interest (EoI)
for product evaluation by WHO
Prequalification (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 Invitation
to manufacturers to submit an
Expression of Interest for productevaluation issued by the Expert
Review Panel in January 2011.
With no market for this product inwealthy countries, there is no reason
for a manufacturer to seek
authorisation through a stringent
regulatory authority. It is therefore
imperative that WHO Prequalification
includes clofazimine in the next EoI,
to send a clear message tomanufacturers that the product isneeded.

GROUP 5

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

Evolution in priceIn late 1999, Novartis signed a
Memorandum of Understanding(MoU) with the WHO leprosy
programme for a donation of
clofazimine and rifampicin47. In
November 2005, this donation was
extended until the end of 2010.
For patients who require this drug, it
can be purchased through certain
private pharmacies, but the cost isquite high, at US$ 0.86 for the 50mg
capsule and $1.43 for the 100mg
capsule in Switzerland, for example58.

Paediatrics
The 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 several
guidelines, there is an urgent need forfurther research (pharmacokinetics,
pharmacodynamics, safety data), into
the use of this drug in the younger
populations, in particular children
aged under five, so that dosages can
be clarified and child adapted
formulations developed to be able todeliver these dosages to children.
Today there is a 50mg soft-gel capsuleavailable, but this formulation makes
it impossible to fraction the dose, andclinicians are put in a difficult position
to 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.

37

HIV co-infection
There have been no studies
performed, but clofazimine is a weak
inhibitor of CYP3A4, and so proteaseinhibitor and etravirine concentrations
may be increased.
Further studies are required to confirm
this28.

LINEZOLID (Lzd)General Information• Therapeutic Class:Oxazolidinone antibiotic• ATC Code: J01XX0822• Included in the WHO
Guidelines as a Group 5
medicine; agents with unclear
efficacy23• Not included in the 16th editionof the WHO Model List of Essential
Medicines24 nor in the 2nd editionof the WHO Model List of Essential
Medicines for Children25• Presentations available: 600mg
tablet, 100mg/5ml powder forsuspension

Price (in US$) and quality information
Price of the lowest unit (i.e. the price of one tablet, capsule or vial)
Linezolid is a Group 5 medicine which today represents a very small market, as
they are essentially used in patients with XDR-TB. While there is a qualityassured source available, Pfizer was not contacted regarding a price for thisproduct. This medicine does not exist in the GDF product catalogue.

38• First approved by U.S. Foodand Drug Administration(FDA): 18 April 200059• Approved indication in US:
Linezolid is indicated for treatmentof susceptible strains of designatedmicroorganisms for the following
conditions, nosocomial
pneumonia, complicated anduncomplicated skin and skinstructure infections. It is notindicated for the treatment ofGram-negative infections andcommunity acquired pneumonia60

Spotlight on access issues
Even though linezolid has beenclassified by WHO as an agent with
unclear efficacy, it has been shown tohave in-vitro activity against
Mycobacterium Tuberculosis. Data has
been presented at international
conferences and small case series
reports have been published on its
use in treatment of DR-TB67. Linezolid
is associated with a relatively highnumber of adverse effects, including
myelosuppression, anaemia andperipheral and optical neuropathies.
Linezolid does however play animportant role in patients with XDRTB. Pfizer and Astra Zeneca are
currently investigating othermedicines in the oxazolidinone groupin the hope of developing a more
efficacious and safer molecule thanlinezolid.

GROUP 5the joint GDF/Global Fund Invitation
to manufacturers to submit an
Expression of Interest for productevaluation issued by the Expert
Review Panel in January 2011.
As linezolid has a market in wealthy
countries, manufacturers with SRA
approval should be approached tomake their products available for the
DR-TB market. It is imperative that
WHO Prequalification includes
linezolid in the next EoI to send aclear message to manufacturers that
this product is also needed for the TB
market.

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

Paediatrics
Pharmacokinetic studies have been
completed in children from birth,and dosages are approved by the US
FDA. Safety data is based on trials,
where patients took linezolid for 28
days. As children with DR-TB may betreated with this drug for up to two
years, there is a need for more safety
data 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 staff
to accurately measure the required
water needed to suspend the powder
and access to clean, safe water. The
reconstituted product can be stored
at room temperature.

Number of quality sources
Today only one manufacturer, Pfizer,
is approved by a stringent regulatory
authority. A further four
manufacturers (Teva, Mylan,
Glenmark and Gate Pharma) havetentative approval from the US FDA,
waiting to enter the US market when
the patent expires.
Additional manufacturers may exist in
China, India, the former Soviet Unionand other countries, but whether they
comply with WHO quality standards is
unknown.
Linezolid was not included in the 10th
Invitation to Manufacturers to submit
an Expression of Interest (EoI) for
product evaluation by WHO
Prequalification (August 2010 revised February 2011). Because ofthis, there are no manufacturers withdossiers currently under evaluation.
The drug was however included in

An indicative price is given in the
British 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 be
critical to ensure price reductions.

Patents
The basic patent claiming linezolid
was first filed in 1993 by Upjohn
Company in the US and is due toexpire in May 201561. Similar patents
were also granted in China, thePhilippines and South Africa.
Upjohn Company also filed patents
claiming crystal forms62 and to a tablet
formulation63 of linezolid in 2001 in
many developing countries including
Argentina, Brazil, China, Colombia,
India, EAPO countries, Mexico,
Ukraine and South Africa.

39

HIV co-infection
There have been no studies
performed, but interactions areunlikely. There may be increase risk of
myelosuppression and mitochondrial
toxicities with long-term use incombination with certain
antiretrovirals (zidovudine, stavudine,
didanosine).28 Further studies are
required to confirm this.

Methodology
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 antituberculosis product listed on the
WHO List of Prequalified Medicinal
Products or quality-approved by astringent regulatory authority
according to MSF or The Union’s
knowledge. The data were collected
up to March 2011.

Price information: Prices are listed
where manufacturers agreed to share
information. A number ofmanufacturers, including Cipla,
Macleods, Bayer, Meiji, and Olainfarm
did not have prices available or did
not agree to publish prices, and no
responses were received from Eli Lilly,
Mylan, Chao Centre and APP Pharma.
Prices paid for by the Global Drug
Facility pooled procurement
mechanism are also listed, althoughthese prices are reserved for projects
that have received approval from theGreen Light Committee.
Prices are given in US$, rounded up
to the nearest second decimal point,and correspond to the lowest unit
price (i.e. the price of one tablet,
capsule or vial). When prices thatvaried according to packaging (e.g.
blisters or bottle) were received froma manufacturer for the same
formulation, the lowest price wasselected. Prices received in currencies
other than US$ were converted on
7 March 2011 using the currency
converter site www.oanda.com. Prices
listed are 'ex-works'.
The prices listed in this publication
are the ones provided by the
manufacturers. The prices paid by thepurchaser might be higher because of
add-ons (such as import taxes anddistribution mark-ups), or may belower after negotiations. The
document 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 regulatory
authority are listed in the price tables
as 'approved'. Products that areundergoing review by either the
WHO Prequalification or by astringent regulatory authority arelisted in the price tables as 'underevaluation'. Submissions to WHO
Prequalification are confidential andall companies mentioned that havethe dossier accepted for review havegiven permission to do so. Productsthat have not yet been submitted to
WHO Prequalification or to astringent regulatory authority havenot been included in the table.
Products procured by the Global
Drug Facility comply with the GDF's
Quality Assurance policy. This deems
eligible for GDF procurement all
products that are included on the
WHO List of Prequalified Medicinal
Products, that are approved by astringent regulatory authority, or thatare approved by the Expert Review
Panel (ERP) also used by the Global
Fund. The GDF quality assurance
policy can be found at:
http://www.stoptb.org/gdf/drugsuppl
y/quality_sourcing_process.asp
As the information on the WHO Listof Prequalified Medicinal Products is
updated regularly, the list should be
consulted for up-to-date information
regarding quality:
http://apps.who.int/prequal/

1 WHO guidelines for the Programmatic Management of Drug-resistant Tuberculosis - Emergency update 200840

Glossary and abbreviations
Abbreviated New Drug
Application (ANDA)
An Abbreviated New Drug
Application (ANDA) contains data
that, when submitted to FDA's Center
for Drug Evaluation and Research,
Office of Generic Drugs, provides forthe review and ultimate approval of ageneric drug product. Generic drug
applications are called "abbreviated"because they are generally not
required to include preclinical(animal) and clinical (human) data toestablish safety and effectiveness.
Instead, a generic applicant must
scientifically demonstrate that its
product 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 of
substances intended to be used in the
manufacture of a pharmaceutical
dosage form and that, when so used,becomes an active ingredient of thatpharmaceutical dosage form2.
CultureBacterial culture is a laboratory
method to multiply bacteria in order
to 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 environment
where they usually grow (e.g. for TB,
the human body).
Drug resistance
When a drug used to treat
tuberculosis is in fact ineffective
against a strain of M. tuberculosis, thebacteria is said to be resistant to thedrug (as opposed to drug-susceptible
or drug-sensitive).

Drug-susceptible/drug-sensitive TB
Bacteria 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. The
strains of TB which are sensitive to all
first-line drugs are called drugsusceptible.
Ex works
A commercial term (incoterm)
meaning that the seller delivers when
the 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 any
collecting vehicle.
Expert Review Panel (ERP)
An independent technical bodycomposed of external technicalexperts, hosted by the WHO
Department of Essential Medicines
and Pharmaceutical Policies. Their
purpose is to review the potential
quality risk of using antiretroviral,
anti-TB and antimalarial products
which are not yet WHO prequalified
or authorised by a stringent
regulatory authority, and to give
advice to the Global Fund and the
Global Drug Facility whether
procurement of such products can be
authorised.
Extensively drug-resistant TB
see XDR-TB
Extra-pulmonary TB
Form of TB where M. tuberculosis
infect parts of the body other thanthe lungs. This is most commonly thelymph nodes, bones, central nervous
system, cardiovascular andgastrointestinal systems.
First-line drugs
The 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 TB
and patients usually tolerate them
well.
Global Drug Facility (GDF)
A mechanism hosted by WHO to
expand access to, and availability of,quality-assured anti-TB drugs anddiagnostics through pooled
procurement. Products procured
comply with the GDF's Quality
Assurance policy. This deems eligible
for GDF procurement all productsthat are included on the WHO List ofPrequalified Medicinal Products, thatare approved by a stringent
regulatory 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 save
lives. To date, it has committed US$
21.7 billion in 150 countries tosupport large-scale prevention,
treatment and care programs against
the three diseases3.
Green Light Committee (GLC)
The GLC Initiative helps countries
gain access to quality-assured secondline anti-TB drugs so they can provide
treatment for people with multidrugresistant tuberculosis in line with the
WHO 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).
Microscopy
Microscopy is currently the mostcommonly used technique todiagnose TB. Two to three sputum

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

41

samples are taken from the patient
and the sample will be stained andlater read under the microscope. If TB
bacilli 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 TB
that are resistant to (at least) the twomost powerful first-line antibiotics
used to treat TB, namely rifampicin
and isoniazid, are said to havemultidrug-resistant TB, or MDR-TB
Mycobacteria
Types of bacteria, of the genus
Mycobacterium, that cause diseases
such as TB and leprosy.
M. Tuberculosis
A pathogenic bacterial species of thegenus Mycobacterium and thecausative agent of most cases of TB.
First discovered in 1882 by Robert
Koch.
New Drug Application (NDA)
When the sponsor of a new drug
believes that enough evidence on the
drug's safety and effectiveness has
been obtained to meet FDA's
requirements for marketing approval,
the sponsor submits to FDA a new
drug application (NDA). The
application must contain data from
specific technical viewpoints forreview, including chemistry,
pharmacology, medical,
biopharmaceutics, and statistics. If
the NDA is approved, the productmay be marketed in the UnitedStates. For internal tracking purposes,
all NDA's are assigned an NDA
number4.
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 close
as possible to the site of patient care.
The driving notion behind point-ofcare testing is having a test as
convenient to the patient as possible
and giving immediate results that canlead to prompt initiation oftreatment.
Pulmonary TB
Form of TB where M. tuberculosis
bacteria are infecting the lungs.
QT Interval
In cardiology, the QT interval is ameasure of the time between thestart of the Q wave and the end of
the T wave in the heart's electricalcycle. This represents the total
duration of electrical activity of theventricles. A prolonged QT interval isa biomarker of life-threatening
ventricular tachyarrhythmias including torsdes de pointes.
Second-line drugs
Second-line drugs are used when thefirst-line drugs are no longer effective
to cure a patient. In the case oftuberculosis, they are less effective
and have many more side-effects
than first-line drugs. This report looks
at the sources and prices of secondline 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 International
Conference 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 legallybinding mutual recognition
agreement including Australia,
Norway, Iceland and Liechtenstein.
(as may be updated from time totime)5.
TB Alliance
The TB Alliance is a not-for-profit,
product development partnershipaccelerating the discovery anddevelopment of new TB drugs thatwill shorten treatment, be effective
against susceptible and resistantstrains, be compatible with
antiretroviral therapies for those HIVTB patients currently on suchtherapies, and improve treatment oflatent infection. The TB Alliance iscommitted to ensuring that approved
new drug regimens are affordable,
widely adopted and available to those
who need them.
Tentative FDA approval
Is awarded by the US Food and Drug
Administration (FDA) to a drug
product that has met all required
quality, safety and efficacy standards,
but is not eligible for marketing in the
US because of existing patent
protection. Tentative approval does
make the product eligible forpurchase outside the US under the
PEPFAR programme6.
WHO Prequalification (PQ)
The Prequalification Programme, set
up in 2001, is a service provided by
the World Health Organization(WHO) to facilitate access to
medicines that meet unified
standards of quality, safety andefficacy for HIV/AIDS, malaria andtuberculosis7.
XDR-TB
Patients, who have MDR-TB and also
show resistance to second-line drugs,
including at least one from the classknown as fluoroquinolones and oneof the injectable drugs, are describedas suffering from extensively drugresistant TB or XDR-TB.

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

42

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Company contacts
Akorn Inc
Lake Forest, Illinois, USA
www.akorn.com
Sean Brynjelsen
Vice President, New Business Development
Phone: +1 847 279 6149
E-mail: sean.brynjelsen@akorn.com

Lupin
India
www.lupinworld.com
Shrikant Kulkarni
Vice President - Exports
Phone: +91-22-66402042
E-mail: shrikantkulkarni@lupinpharma.com

Aspen PharmacareSouth Africa
www.aspenpharma.com
Stavros Nicolaou
Senior Executive
Phone: +27 (0) 11 239 6734
E-mail: nicolaous@aspenpharma.com

Mr. Mukul Jerath
Sr. Manager - Global TB
Phone: +91-22-66402077
E-mail: mukuljerath@lupinpharma.com

FATOL Arzneimittel
Production Facility of RIEMSER Arzneimittel AG
Schiffweiler, Germany
www.fatol.de
Elke Rinkes
International Business Coordinator
Phone: +49 (0) 68 21/ 96 05 17
E-mail: rinkes@riemser.de
HELP S.A.
Athens, Greece
www.help.com.gr
Jaro Matusiewicz
Business Development
Phone: +30 210 2847984
E-mail: j.matusiewicz@help.com.gr

Jacobus Pharmaceutical Company, Inc
Princeton, New Jersey, USA
Laura R Jacobus
Phone: +1 (609) 799-8221 ex 207
E-mail: LRJACOBUS@aol.com

Medochemie
Limassol, Cyprus
www.medochemie.com
Phaedon Ellinas
Phone: +357 25 867 618
E-mail: phaedon.ellinas@medochemie.com
PanPharma
Fougères, France
www.panpharma.fr
Michel LE BELLEGO
Head of Sales & Contract-Manufacturing
Phone: +33.2.99.97.92.12
E-mail: MLeBellego@panpharma.fr
PfizerNew York, USA
www.pfizer.com
Eleanor Levine Gebauer
Director, Global AccessPhone: +1 (212) 733-5026
Email: Eleanor.j.levine@pfizer.com

46

ACKNOWLEDGMENTS:
MSF and The Union wish to thankmanufacturers and the Global Drug
Facility (particularly Caroline Brogen
and Kaspars Lunte) for sharing priceinformation for this publication.
Front cover photos:
Bruno de Cock
Brendan Bannon
Design/artwork:
Sue Grant/ Twenty 3 Crows+44 (0)1848 200331
Cover design:
TaunusGrafik+1 917 584 8033

DISCLAIMER
DR-TB drugs under the microscope - The sources and prices of medicines for drugresistant tuberculosis is a pricing guide and cannot be regarded as a company
price list nor as a clinical guideline. It is crucial that any purchaser verify prices
and availability as well as quality status directly with the supplier before
procurement. Médecins Sans Frontières or The Union have made every effort
to ensure the accuracy of prices and other information presented in this report,
but MSF or The Union make no representations or warranties, either expressedor implied, as to their accuracy, completeness or fitness for a particularpurpose. Inclusion of a product in this document does not indicate MSF or The
Union purchases or uses the product. Information in this guide is indicative
only and not exhaustive, and should be verified with relevant offices whenused for other than reasons of general information. Clinical decisions should
not be made based on this document.