DR-TB DRUGSUNDER THE MICROSCOPE
SOURCES AND PRICES FOR DRUG-RESISTANT
TUBERCULOSIS MEDICINES
4th Edition – March 2016www.msfaccess.org

THE MSF ACCESS CAMPAIGNIn 1999, on the heels of Médecins Sans Frontières (MSF) being awarded the Nobel
Peace Prize – and largely in response to the inequalities surrounding access to
HIV/AIDS treatment between rich and poor countries – MSF launched the AccessCampaign. Its sole purpose has been to push for access to, and the development of,life-saving and life-prolonging medicines, diagnostics and vaccines for patients in
MSF programmes and beyond.
MSF has been involved in tuberculosis (TB) care for 30 years, often working
alongside national health authorities to treat patients in a wide variety of settings,
including chronic conflict zones, urban slums, prisons, refugee camps and rural
areas. MSF’s first programmes to treat multidrug-resistant TB opened in 1999,
and the organisation is now one of the largest NGO treatment providers for
drug-resistant TB. In 2014, the organisation treated over 23,000 patients with
TB, including 1,800 patients with drug-resistant TB.

LATEST RESOURCES FROM MSF ON TB
Out of Step (2015): TB policies in 24 countries
Out of Step presents the results of a survey of 24 countries conducted by Stop TB
Partnership and MSF, tracking the latest TB policies, guidelines and tools acrossfive areas. The results of this survey provide a snapshot of the world’s readinessto defeat the TB epidemic.
www.msfaccess.org/content/report-out-step-2015-tb-policies-24-countries

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

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

Médecins Sans Frontières | March 2016

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

SUMMARY ANALYSIS		
2

Introduction

		3

DR-TB drug and regimen pricing trends		
6

Barriers to access for key DR-TB drugs

		
9The road to better treatment and new regimens		12

Policy recommendations		
13

Methodology

TABLE OF CONTENTSTABLE OF CONTENTS

DRUG PROFILESGROUP TWO: INJECTABLES		
14

Amikacin		
16

Kanamycin		
18

Capreomycin

GROUP THREE: FLUOROQUINOLONES
20

Moxifloxacin

		
22

Levofloxacin

GROUP FOUR: ORAL BACTERIOSTATIC SECOND-LINE AGENTS
24

Ethionamide		25Prothionamide		26

Cycloserine		28

Terizidone		30

PAS and PAS-sodium

GROUP FIVE: AGENTS WITH UNCLEAR EFFICACY
32
		
34

Clofazimine
Linezolid

NEW DRUGS:		36

Bedaquiline

		38

Delamanid

ANNEXES40
		Annex 1: Summary table of all prices		
41

Annex 2: Conditions of offer, as quoted by companies		42

Annex 3: Company contacts

		
43

References

		46

Abbreviations

		
47

Glossary

DR-TB Drugs Under the Microscope

1

INTRODUCTIONINTRODUCTION
This report – now in its fourth edition – analyses the barriers and factors affecting access totreatment regimens for drug-resistant tuberculosis (DR-TB), including new and repurposed
drugs. We provide detailed pricing profiles of key DR-TB drugs, using manufacturer responses
to standardised questionnaires and the Global TB Drug Facility website.
Access to successful DR-TB
treatment remains low. World HealthOrganization (WHO) reports that
only half of notified MDR-TB patientswere successfully treated and cured
in 2014, using routine treatment.1
Encouragingly, early results from MSF
and other implementers’ operational
research in treating extensively drugresistant (XDR) TB using the new
drugs, bedaquiline and delamanid,
in combination with promising
repurposed drugs, indicate that muchhigher cure rates can be achieved
than with existing regimens (culture
conversion rates between 75% and
97% are seen2, compared to 26%
with existing regimens1). However, a
few years after these two new drugs– bedaquiline and delamanid, the firstnew drugs in nearly half a century –were conditionally approved to treat
TB, barely two percent of those who
could benefit from these treatments
have access to them.2 WHO also
reports on a deadly and persistentdiagnostic gap: among estimated
DR-TB cases, only about a quarter ofpeople were diagnosed in 2014.1
TB is now the leading infectious
disease killer worldwide and there isa critical need for more effective andmore affordable DR-TB treatment
regimens. Despite individual drug
price decreases, overall regimen
prices remain a barrier to sufficient
treatment scale up. The price for
DR-TB regimens that can be obtained
from the Global Drug Facility (GDF),
range from US$1,023a – $4,646b
for the lowest-priced regimens, as
of February 2016. The full price ofpreferred DR-TB regimens range fromabout $1,800c to $4,600d. There are

additional barriers to accessing DR-TB
drugs beyond their prices, including alack of registration in many countries,
not being included on national
Essential Medicine Lists (EML) anda lack of appropriate country-levelguidance for programmatic use.3
Even when it is possible to procure
the needed drugs, they may not be
indicated for TB use (e.g. linezolid andclofazimine), which contributes to areluctance on the part of national TB
programmes to incorporate the drugs
into national protocols that would
enable wider access.

STOP PRESS
This report went to print justbefore the Global Drug Facility
was due to update its prices for
DR-TB drugs by 1 April 2016,
once the yearly manufacturer
consultation was finalised. For
the most up-to-date information
on GDF prices for DR-TB drugs,
please consult the Global Drug
Facility, www.stoptb.org/gdf/
drugsupply/drugs_available.asp

To increase the chance of a cure forpeople with DR-TB, the deadly gaps
in diagnosis and access to effective,
affordable, tolerable treatment options
must be closed.
A smarter DR-TB medicines market
can help. This requires having
enough quality-assured suppliers tomeet demand and to foster pricelowering competition. WHO andexperts can contribute to smarter

DR-TB markets by streamlining thenumber of second-line drug options
recommended, in line with medical
outcomes, so that the market isn’t
unnecessarily split. Data from ongoingand pending clinical trials should help
inform decisions to cull certain drugs
that have onerous side effects while
offering little benefit to patients, andshould help with fast-tracking othernew and repurposed drugs that can
improve patient outcomes. GDF could
better consolidate demand if there
were fewer second-line drug options.
WHO and experts should also workwith manufacturers to better forecast
demand of streamlined drug options.
With more countries relying upondomestic funds to purchase TB and
DR-TB medicines, the Global Fundto Fight AIDS, Tuberculosis andMalaria (GFATM) should implement
clear transition strategies to ensure
countries can secure the purchaseof quality-assured first- and secondline TB medicines, even after they
graduate from support. The GDF
should explore ways to evolve its
business model in order to bid innational public tenders for countries
that purchase outside of the GDF. For
countries purchasing outside of the
GDF, the importance of continuing toprocure and use quality-assured drugs
is vital. By publishing pricing data inthis report, we hope to contributeto countries’ ability to negotiate thelowest procurement price possiblefor quality-assured DR-TB drugs.
Countries that are able to obtainaffordable, sustainable access toneeded DR-TB drugs have a betterchance of reducing the growing
number of DR-TB cases.

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

2

Médecins Sans Frontières | March 2016

CURRENT PRICES: IMPROVEMENTS, BUT CHALLENGES PERSIST
Recent reductions in the prices of most
DR-TB drugs have brought preferredregimen prices down to a range ofabout $1,800-$4,600 per treatment
course (without any Group 5 or new
drugs included) (see Table 1). This isa marked improvement compared to
our first Under the Microscope report in2011, when drugs procured throughthe Green Light Committee (GLC)/GDF cost between $4,400 and almost$9,000 per patient for a standard 1824 month treatment course.4 However,at up to $4,600 per treatment course,
DR-TB treatment regimens are still
unaffordable, limiting countries’
abilities to respond to the growing
spread of drug resistance.

A key factor in DR-TB drug pricedecreases is the joint GFATM-GDF
Expert Review Panel mechanism,
which since 2009 has been successfully
attracting new manufacturers ofquality-assured DR-TB medicines tothe market. Competition from genericmanufacturers of quality-assured finishedproducts has reduced prices for linezolid,
capreomycin, and levofloxacin (SeeTable 2). Additional drivers of pricereductions of DR-TB drugs over the
past three years vary. For example,
higher order volumes helped reduce
the lowest global price of DR-TB drug
linezolid. In the case of cycloserine, while
the number of manufacturers of thefinished product remains the same, there

are now more manufacturers of theactive pharmaceutical ingredients (API),
contributing to the drug’s lower price.
Notable exceptions to the trend of
decreasing drug prices are clofazimine,amikacin, prothionamide andethionamide, whose prices haveremained steady, and kanamycin
and PAS-sodium, whose prices haveincreased since 2013. Additionally,some countries – especially middleincome countries – that purchaseoutside of the GFATM-GDF mechanism
may still lack the competitive markets
of multiple manufacturers needed toaccess similarly low prices. (See Box:
Spotlight on linezolid in South Africa.)

DR-TB DRUG AND REGIMEN PRICING TRENDS

DR-TB DRUG AND
REGIMEN PRICING TRENDSTABLE 1: 2015 PRICES FOR DR-TB DRUG REGIMENS*
Regimen dose

Lowest unit pricefor a quality-assured
source (US$)

Lowest cost for
regimen (US$)

Highest unit pricefor a quality-assured
source (US$)

Highest cost for
regimen (US$)

Capreomycin 1g vial

1 pill a day for8 months

3.80

912.008.00

1920.00

Cycloserine 250mg capsule

3 pills a day for
24 months

0.19

403.920.60

1296.00

Ethionamide 250mg tablet

3 pills a day for
24 months

0.06

133.920.10

211.68Moxifloxacin 40mg tablet

1 pill a day for
24 months

0.44

314.640.66

475.20Pyrazinamide 400mg tablet**4 pills a day for
24 months

0.02

55.58

0.02

67.68

Total cost1820.06

3970.56

By replacing cycloserine with PAS, the price changes to…
PAS 4g sachet /PAS-sodium 60% w/w
granules 9.2g sachet

2 sachets a day
for 24 months

Total cost

1.31

1919.523335.66

1.69

1919.524595.08*Prices sourced from MSF questionnaire sent to manufacturers, September 2015, and from the April 2015 GDF catalogue for TB drugs.
** Price obtained from GDF catalogue

DR-TB Drugs Under the Microscope3

DR-TB DRUG AND REGIMEN PRICING TRENDSTABLE 2: KEY DR-TB DRUGS PRICE TRENDS
Drug

Presentation

Change in # of manufacturers from 2013

Change in lowest identified
price from 2013 to 2015

Capreomycin

1g powder vial

▲ number of finished product manufacturers by 3
(5 manufacturers in 2015)▼by 24%

Linezolid

600mg tablet▲ number of finished product manufacturers by 1
(3 manufacturers in 2015. In January 2016, this figure
went back to 2, awaiting the final assessment of the
WHO Prequalification Programme for one source)▼by 22%

Levofloxacin

250mg tablet

No change in number of finished productmanufacturers (5 manufacturers in 2015) *▼by 16%

Levofloxacin

500mg tablet

No change in number of finished productmanufacturers (5 manufacturers in 2015) *▼by 25%

Cycloserine

250mg capsule▲ number of API sources by 2 (3 sources for
cycloserine API in 2015)▼by 52%* The cause(s) of price drops for levofloxacin are unknown, but it is possible that these result from an increased demand for the drugs, either for a TB
indication or for other uses.

SPOTLIGHT ON ACCESS TO LINEZOLID IN SOUTH AFRICA
Multiple studies have shown that
inclusion of linezolid in the treatment
of XDR-TB, including for people coinfected with HIV, improves culture
conversion rates and treatment
outcomes.5,6 However in South
Africa, high prices charged by aduopoly of suppliers have restricted
access, keeping linezolid out of reachof many XDR-TB patients.

Control Council (MCC), registered

In late 2014, at the urging ofpatients, clinicians, and civil society
organisations, South Africa’s
regulatory body, the Medicines

significant price reductions. As ofpharmaceutical company Hetero’s
generic linezolid. The Hetero
product is marketed in South Africa
through an arrangement with
Sanofi. Pharmaceutical company
Pfizer’s linezolid product had
previously held a monopoly on
the market. However, this limitedcompetition has not resulted in
November 2015, in the private
market, Pfizer was selling a 600mg
daily tablet of linezolid for about© MSF

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

4

Médecins Sans Frontières | March 2016

$62 (ZAR855) per pill, while Hetero’s
product cost about $47 (ZAR655)
per pill.7 Public sector prices offeredby the two suppliers are discounted,
but remain too high to have been
accepted by national tenders.
Further competition is needed tobring prices down.
In South Africa, it is significantly
less expensive for MSF to import
Hetero’s linezolid through our own
supply channels, at a price of $7.90
per pill (ZAR109), than to source
linezolid at the Sanofi and Pfizer
prices offered to South African
provinces, which cost 46% to 96%
more, respectively.7 South Africa
receives support from the Global
Fund to Fight AIDS, Tuberculosis
and Malaria, has one of the largest
TB burdens in the world, and has
a high demand for linezolid8; theSouth African government should
be offered prices comparable to the
GDF, where linezolid costs between$5.35 and $5.48 per pill.
Note: All rand to dollar conversions calculated
at November 2015 rates.

MSF believes that the total price for a
full treatment course should be no morethan $500. However, DR-TB
regimen costs remain high and variable
despite the fact that prices could
potentially be universally much lower
if they were based on production costs
plus profit margins. A recent study
developed target price ranges for DRTB drugs based on estimated costs ofactive pharmaceutical ingredients (API),
excipients, formulation, packaging,
and a reasonable profit margin (a‘cost-plus’ model).9 The study notesthat treatment courses such as theone used in the nine-month STREAM
regimen, also known as the ‘Bangladesh
regimen’ (see Glossary) (see Box:
Clinical trials landscape), are currently
priced between just over $800 to morethan $1,800 per treatment course,
but could be priced as low as $100$400 per treatment course basedon a ‘cost-plus’ model (see Table 3).
For the individual drugs clofazimine,linezolid, bedaquiline, delamanid, andmoxifloxacin, the estimated ‘target’
prices per patient per month (pppm)
that could be achievable with robust
generic competition are listed below,
along with the current price available
from GDF.
To move closer to these targets weneed better drug forecasting at country
level. WHO and GDF could play aleading role in promoting harmonised
approaches across actors – including

the Global Fund and othernon-governmental organisations
who provide TB care – in providing
technical support at country level todevelop forecasts for DR-TB medicines.
Other price-decreasing measures could
include promoting more competition
for linezolid suppliers, encouraging
new generic manufacturers for
clofazimine, and measures toencourage generic production ofdelamanid and bedaquiline, whether
via voluntary licences negotiated by
the Medicines Patent Pool or throughthe use of public health safeguards
by governments seeking to foster
production or access to low-cost
generic versions.

© Lana Abramova

In February 2016, Otsuka and the
GDF announced a price of $1,700
per treatment course, available to
Global Fund-eligible countries throughthe GDF.31 Given that delamanid
is just one drug that needs to be
combined with multiple other drugs
to form a DR-TB regimen, this price isprohibitively expensive for most highburden MDR-TB countries and not
all high burden countries are eligible
for this price. In addition to the highprice, the registration of delamanid
remains an issue; without broad
registration and an affordable priceby the company, it will be difficult for
countries to scale up treatment of DRTB and ensure the people who needthis drug can receive it.

DR-TB DRUG AND REGIMEN PRICING TRENDSTARGET PRICES:OPPORTUNITIES FOR DRAMATIC FUTURE PRICE DECREASESJAYNA, WHO IS 28 AND
A MOTHER OF THREE,IS BEING TREATED FOR
XDR-TB IN THE RUSSIAN
FEDERATION. FIRSTDIAGNOSED WITH TB
IN 2008, JAYNA HAS
HAD SEVERAL RELAPSESSINCE. THIS TIME, HER
TREATMENT INCLUDESBEDAQUILINE, AND
AFTER JUST ONE WEEK,SHE STARTED TO
FEEL BETTER. SHEIS TOLERATING THE
TREATMENT WELL AND
IS EXPERIENCING NO
SIDE EFFECTS.

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

Linezolid

Bedaquiline

Delamanid

Moxifloxacin

Target price range(pppm US$)*

6.20-16.40

4.90-12.80

8.80-16.40

3.50-8.60

3.50-9.40

Current lowest GDF
price (pppm US$)

66

161

150

283.3313*Price per patient per month. Source: Gotham D et al. Target generic prices for novel treatments for drug-resistant tuberculosis.
15th European AIDS Conference, Barcelona, abstract PS2/4, October 2015.

DR-TB Drugs Under the Microscope

5

BARRIERS TO ACCESS FOR KEY DR-TB DRUGSBARRIERS TO ACCESSFOR KEY DR-TB DRUGSIn addition to price barriers, several other factors impede access to new TB drugs and repurposed drugs
developed for other indications that have been proven, or are thought to be, effective against TB. Barriers
include a lack of clinical data, a lack of registration in countries, and a lack of a TB indication.

NEW DR-TB DRUGSLONG-AWAITED CLINICAL TRIAL RESULTS
Bedaquiline (marketed by Janssen) anddelamanid (marketed by Otsuka) wereconditionally approved in 2012 and2013 respectively based on their phase
IIb clinical data, but completion andpublication of phase III data are stillcritically important. Delamanid’s phase
III clinical trial completed enrolment inNovember 2013, with results expected
in 2017. Bedaquiline’s phase III clinical
trial, which expands on the existing

STREAM trial10 looking at the efficacyof shorter treatment regimens, has yet
to commence.
Also of great importance are theresults of a long-awaited drug-druginteraction study (AIDS Clinical Trials
Group’s A5343 trial), to examine
possible effects of the two new drugs
on the heart (QT prolongation, see
Glossary for additional details), which

has not started despite being planned
since 2014.11 To compensate forthe lack of manufacturer-initiated,
regimen-based clinical research,a number of trials run by NGOs,
including MSF, and other non-profit
product development partnerships areunderway or planned to test new DRTB regimens containing bedaquiline
or delamanid12 (see Box: MDR-TB
Clinical Trial Landscape).

MSF OPERATIONAL EXPERIENCE
MSF reports positive clinical patient outcomes withbedaquiline-containing regimens and repurposed
drugs in Armenia and Chechnya, Russian Federation,
where we are supporting some of the largest
cohorts of XDR-TB patients receiving bedaquiline in
the world. Between April 2013 and March 2015,
60 patients received bedaquiline from MSF in
Armenia. In the cohort of 38 patients who started
before July 2014, 24 (80%) displayed sputum culture
conversion at six months; in Chechnya, 27 out of
36 (75%) MSF patients who have completed six
months of treatment are culture negative. Serious
adverse events were reported in four patients in
the Armenian cohort, one attributed to bedaquiline
QT effects without clinical consequences for thepatient, who completed bedaquiline treatment.
Similarly successful culture conversion rates werereported for non-MSF compassionate use cohorts
in France and South Africa (97% and 77%,
respectively).13 Additional information from thecohort in South Africa demonstrated similar safety
and efficacy even when bedaquiline was given in
combination with antiretroviral therapy (ART) to
TB/HIV co-infected people (59.3% of the cohort
were TB/HIV co-infected), another sign that
bedaquiline has the potential to transform DR-TB
treatment in the coming years.14

6

Médecins Sans Frontières | March 2016

© Lana Abramova

I don’t know why I got tuberculosis,
people here in the mountains don’t get
tuberculosis. I could hardly tolerate thetreatment. I was nauseous, I vomited
and couldn’t eat. I survived by miracle, I
thought I was going to die. But after eightmonths the new drugs appeared and Dr
Animesh said: ‘You should take thesedrugs, you won’t die’. He’s a good doctor.
Thanks to all of them I recovered.
SAPIKHAT, 53, TALKS ABOUT HER TREATMENT FOR
XDR-TB, WHICH INCLUDED BEDAQUILINE. SHE LIVESWITH HER HUSBAND, A TEACHER, AND THEIR THREE
CHILDREN IN A REMOTE MOUNTAIN VILLAGE IN
CHECHNYA. SAPIKHAT PREVIOUSLY ENDURED MULTIPLE
HOSPITALISATIONS AND LUNG SURGERY TO TREAT HER
TB; SHE NOW RECEIVES AMBULATORY CARE.

Outside of clinical trials, approximately
700 patients have accessed bedaquiline
through compassionate use and about
2,300 have received bedaquiline aspart of routine use as of January 2016.
Only about 180 patients have received
delamanid outside clinical trials.15
It is critical that new drugs
be incorporated into routine,
programmatic DR-TB treatment
protocols. There is clear guidance from
WHO regarding how to incorporate
bedaquiline and delamanid into theroutine management of patients with
DR-TB. For this to become a reality,
there are some important barriers
that need to be addressed: the drugs
need to be registered in country, withcountries allowing import waivers
in the meantime; countries need to
update their treatment guidelines toreflect the WHO recommendations;adequate pharmacovigilance systems
need to be introduced; and theaccompanying drugs needed to forma regimen with the new drugs need tobe affordable and available in country.
These are not insurmountable hurdles
and a number of countries are taking
strides to ensure that patients have theopportunity to access the new drugs,
particularly bedaquiline.
South Africa has committed to treating
3,000 DR-TB patients per year withregimens including bedaquiline;16
however, this target was not met
in 2015, with just 1,009 patients
starting treatment with bedaquiline
during the year, as of November
2015. This is in part due to a delayedtransition between Janssen’s national
compassionate use programme,
which ended in December 2014, andstandard procurement by provinces.
Free access to bedaquiline throughcompassionate use ended before
provinces had managed to adequatelyplan for the cost of bedaquiline inannual budgets,17 leading to several
months’ delay in starting new patientson treatment. As more facilities inSouth Africa gain experience initiating

DR-TB patients on bedaquilinecontaining regimens, the 3,000-patient
target should be achievable in 2016,
with even more ambitious numbers
feasible in the future.
Bedaquiline has been granted
conditional or full marketing
authorisation by the National Medicine
Regulatory Agency (NMRA) in nine of
the 27 high MDR-TB burden countries,and submission is pending in nineothers. In the case of delamanid,
Otsuka has received conditional
approval or full marketing authorisationin Japan, South Korea, and in Europe
by the European Medicines Agency,
but delamanid is not registered inany high burden countries, including
four countries considered to have ahigh burden of MDR-TB where Otsuka
carried out clinical trials with the
drug. To date, it has not been possible
for countries to plan for widespread
programmatic use of delamanid due toa lack of registration and the lack of asystem to procure the drug for use.

BARRIERS TO ACCESS FOR KEY DR-TB DRUGSSLOW SCALE UP OF ROUTINE AND COMPASSIONATE USE OF NEW DRUGSDRUG DONATION PROGRAMMES FOR BEDAQUILINE AND DELAMANID
Janssen and Otsuka have announced drug donation programmes for bedaquiline and delamanid, respectively.
In December 2014, USAID and Janssen Therapeutics announced a donation programme for bedaquiline, withthe official agreement signed in March 2015. The terms of this agreement specify that 30,000 treatment courses
will be donated over a four-year period to more than 100 Global Fund to Fight AIDS, Tuberculosis and Malaria(GFATM) -eligible low- and middle-income countries through Stop TB Partnership’s Global Drug Facility (GDF).18
In October 2015, USAID announced Georgia as the first recipient of donated bedaquiline.19
Not all countries are eligible for these donations, however. For example, South Africa is ineligible, and there appears
to be a quota on the number of treatments to be supplied to Commonwealth of Independent States (CIS) countries
through the drug donation programme.
In April 2015, Otsuka announced its “FighTBack Initiative” to provide donations of delamanid to 20% of diagnosed
MDR-TB patients by 2020.20 Despite requests for additional details about the programme, little information is
publicly available eleven months later. Based on the joint announcement with GDF at the end of February 201631, it
remains unclear how Otsuka will implement this donation.
MSF advocates for fair commercial terms for medicines and avoids medical products donations wherever possible.
However, faced with a lack of an alternative source of delamanid for patients in our TB treatment programmes,
MSF exceptionally accepted a donation of 400 treatments of delamanid from Otsuka. MSF maintains that medical
product donation programmes are not a solution to access challenges and present a number of complications forsustainable access to essential medicines.21

DR-TB Drugs Under the Microscope

7

BARRIERS TO ACCESS FOR KEY DR-TB DRUGSDRAWBACKS OF MEDICAL PRODUCTS DONATION PROGRAMMESThere are a number of reasons why
donations fail to ensure sustainable
access to medical products, which is
widely acknowledged by medicinespurchasers like MSF, internationalorganisations like WHO, and inacademic literature. Below aresome of the key points of concern
regarding drug donations: nsustainability: Continued
Udonations are entirely dependent
on the choices of the donor.
Insufficient scale: In general,
donations can only meet a fractionof a country’s disease burden.
I ndication restrictions: Drugindications may be overly narrow,preventing countries from using
drugs in ways that meet publichealth objectives.
I nadequate consultation withrecipient countries: Donations
may not meet the public healthneeds of recipients.
 ountry eligibility concerns:
C
Potential recipients may be

excluded from programmes forreasons that are irrelevant topublic health needs.

preventing competitive genericmarkets from emerging.

B urdensome requirements
for recipients: Programmes
may impose added logisticaland operational burdens tostrained health systems withonerous requirements concerning
pharmacovigilance, monitoring,evaluation, etc.

Temporary ‘solution’:Donations may temporarily
reduce public pressure aroundthe underlying access problems,
making it harder to expand
access to the drug in the future.
Additionally, donations areusually time-limited, so they are
inherently not durable solutions.

T ime delays: Lengthy donation
negotiations may prolong theperiod in which patients cannot
access the medicine.

Potential distortion of rational
use: Donated, but less effective,
medicines may be used over more
effective medicines.

C osts incurred by recipient
countries: Recipients often mustbear the costs of sorting, storing,
distributing, and potentiallydestroying expired donatedmedicines, ironically making
ostensibly free drugs quite costly.

Market priming: Donor recipients
may be pressured to purchase adrug from the donor once the
donation has ended.

A nti-competitive impacts
on drug markets: Genericmanufacturers may be dissuaded
from entering a recipient country,

Disincentivising future
biomedical R&D: Other firms
may be disincentivised fromengaging in future research anddevelopment to create improved
medicines for lack of a viable
commercial market.

REPURPOSED DR-TB DRUGSGroup 5 drugs (clofazimine, linezolid,
imipenem/cilastatin) show promisein treating DR-TB but still lack DR-TB
indications and conclusive clinicaldata, which leads to problems
registering, procuring, importing,and dispensing these drugs foroff-label use.13

MDR-TB INDICATED DRUGSON THE WHO ESSENTIAL
MEDICINES LISTIn April 2015, WHO released the19th edition of its Essential Medicines
List (EML). For the first time, thisEML includes MDR-TB indications forbedaquiline, delamanid, and linezolid,
which should spur governments
to update their national EMLs.13 A
thorough literature review allowed
experts to justify the addition oflinezolid to the WHO EML with a
TB indication, despite the lack ofregistered indication for this particulardisease. Although clofazimine is still
8

Médecins Sans Frontières | March 2016not listed on the WHO EML as a TB
medicine, it is included in the WHO
Prequalification Programme’s invitation
to manufacturers of API and FinishedPharmaceutical Products in reference
to second-line anti-tuberculosis
medicines.22 This should be understoodby generic manufacturers as anincentive to develop clofazimine
products, and to pursue WHO
prequalification or registration by astringent regulatory authority (SRA),
as required by the GFATM.

INDICATION AND
REGISTRATIONCHALLENGES
Another major access problem is theseverely limited national registrationof repurposed DR-TB drugs. For
example, while linezolid may beregistered in some countries forother antibiotic-resistant Grampositive bacterial infections, it cannot
be registered with a TB indicationin any country due to the lack ofofficial indication. Clofazimine is
not registered anywhere with a
TB indication23, although it may
be registered by 2020 in the US,
following the US Food and Drug
Administration’s review of an orphan
drug filing and specific clinical trials
by Novartis. Without a registered TB
indication, countries may be reluctant
to incorporate Group 5 drugs into
national TB management guidelines,
and may even face challenges
purchasing the drug for DR-TB use.
Both of these medicines should be
registered with TB indications assoon as possible, with a particularemphasis on registration in high MDRTB burden countries. In the interim,countries should consider granting
import waivers for these medicinesthat are still unregistered nationally,
whenever manufacturers obtain either
WHO Prequalification Programmeapproval or registration by a stringent
regulatory authority (SRA).

Treatment of DR-TB is on the cusp ofchange, with multiple new drug trials
planned or underway (see Box: MDRTB Clinical Trial Landscape). Given theopportunity for improvement, WHOshould further improve regimens bystreamlining recommended treatment
options, moving away from using
injectable agents and drugs withpoor side effect profiles (such asPAS, ethionamide and cycloserine),and proactively working with

manufacturers to ensure sufficient
supply for clofazimine, linezolid andother promising drugs.
There are numerous potential regimens
to treat DR-TB using drugs from fourgroups (Groups 2–5). While some levelof customisation is needed to ensurethat the patient receives the best
regimen for their resistance pattern, toomuch variation leads to fragmentationof an already small market.e

For example, Group 4 contains drugs
from the same class, prothionamide andethionamide, which are both thioamides24
and for which there is very little evidence
to support the use of one over the other.
This same issue occurs with Group 4 drugs
cycloserine and terizidone which are also
in the same class of antibiotic. Both drugs
are recommended in the WHO guidance
but there is a note that terizidone has
limited programme and effectiveness datacompared to cycloserine.

MDR-TB CLINICAL TRIAL LANDSCAPE
A number of clinical trials areplanned or underway to assess
combinations of repurposed and
new TB drugs for optimal treatment
regimens.12 These include: TREAM I Trial: This is a USAIDS
funded, Union-sponsored andMedical Research Council
UK-implemented randomised
clinical trial looking at a ninemonth combination of existing
TB drugs for the treatment of
MDR-TB.25 The study regimen
is ethambutol, pyrazinamide,
moxifloxacin and clofazimine
throughout, supplemented
by kanamycin, prothionamide
and high-dose isoniazid in thefirst four months. Participating
patients are randomised to the
STREAM regimen or the optimised
background MDR-TB regimen. The
trial includes patients co-infectedwith HIV. Trial countries include
Ethiopia, Mongolia, Vietnam andSouth Africa25 and the results may
be ready by 2018.
S
 TREAM II Trial: This phase III trial
compares six-month and nine-month
bedaquiline-containing regimens
against the WHO recommended
and STREAM I regimens. The six
month regimen adds bedaquiline to
the STREAM I regimen and the ninemonth regimen replaces kanamycin
with bedaquiline to give an all-oral
regimen for MDR-TB. Enrolment is
expected to begin in March 2016.
NEXT Trial: This phase III trial iscurrently enrolling participantsin South Africa to evaluate a newtreatment regimen for patients with
MDR-TB through an open-label,randomised, controlled trial of a sixto nine-month injection-free regimen
containing bedaquiline, linezolid,
levofloxacin, ethionamide/high dose
isoniazid, and pyrazinamide.
NiX TB Trial: This phase III open-label
study assessing the safety and efficacy
of bedaquiline given only with othernew drugs (pretomanid and linezolid)
to patients with XDR-TB or treatment
intolerant/non-responsive MDR-TB,
including patients co-infected with
HIV, is recruiting participants inSouth Africa.
 ATB NC-005 Trial: This phase II
G
open-label partially randomised
trial to evaluate the efficacy, safety
and tolerability of combinationsof bedaquiline, pretomanid andpyrazinamide during eight weeks
of treatment in adults with newly
diagnosed drug-sensitive TB (DS-TB),or bedaquiline, moxifloxacin,
pretomanid and pyrazinamide for
MDR-TB recruited participants, inSouth Africa, Tanzania and Uganda.
Recruitment has been completed.26
STAND Trial: A phase III study
to assess the efficacy, safety
and tolerability of a six-month
combination of moxifloxacin,
pretomanid and pyrazinamide in
subjects with MDR-TB. Also has a
DS-TB arm with the same regimen,
but for a shorter duration. Recruitment
is currently suspended.27

THE ROAD TO BETTER TREATMENT AND NEW REGIMENSTHE ROAD TO BETTERTREATMENT AND NEW REGIMENS B-PRACTECAL Trial: MSF isT
sponsoring this phase II-III trial,
which intends to evaluate the safety
and efficacy of short treatment
regimens containing bedaquiline
and pretomanid in combination
with existing and repurposed TB
drugs for adults with MDR-TB, in
partnership with the London Schoolof Hygiene and Tropical Medicine
and other leading international
research organisations. Recruitment
is planned for spring 2016,beginning in Uzbekistan.28
 ndTB Trial: MSF is collaboratingewith Partners in Health (PIH) andInteractive Research & Development(IRD) as part of the ‘endTB project’,
which will evaluate five experimental
regimens containing bedaquiline
and/or delamanid by enrolling 750
participants in five countries.29

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

DR-TB Drugs Under the Microscope

9THE ROAD TO BETTER TREATMENT AND NEW REGIMENS

3P PROJECT
Today, finally, there is a relatively
robust late-stage TB drug pipeline
with several drugs showing
promising results. Nevertheless,the TB research and development(R&D) pipeline’s potential todeliver therapeutic solutions for TB
and DR-TB remains insecure. The
challenges of TB drug and regimen
development persist, in large part,due to the way that drugs arefinanced and incentivised.
Relying on monopoly-based rewards
to spur innovation discourages
information sharing, promotes
inefficient duplication and leaves us

incentivises R&D through thepromise of financial rewards if certain
objectives are met (i.e. throughprizes); and 3. The project pools
resulting intellectual property (IP) to
ensure open collaborative research
and fair licensing for competitive
production and affordability of the
final products. Changing the modelby which TB drugs are promoted andpaid for can result in major publichealth gains with more efficiently
and affordably developed treatment
regimens of new drugs, which canbe used in combination and without
deadly delays. Learn more about the3P Project at: www.msfaccess.org/3P

I was told that if
I followed treatment,
I would get cured.
So I tried to follow
treatment, I took
medicines, I had
intravenous fluids.
I followed treatment
strictly. But the
medicines produced
side effects, all mybones ached becauseof these pills, I had
an allergy.
MOVSAR, 49, FROMNOVYE ATAGI, CHECHNYA,DESCRIBES HIS STRUGGLES
WITH MDR-TB TREATMENT.
DESPITE BEING TREATEDFOR TB IN 2010 AND MDRTB IN 2011, MOVSAR WASDIAGNOSED WITH XDR-TB
IN 2014. HE WAS ONE OF
MSF’S FIRST PATIENTSTO BE TREATED WITH
BEDAQUILINE. DESPITE
BEING DIABETIC, MOVSARTOLERATES THE NEW
TREATMENT WELL AND HAS
IMPROVED CONSIDERABLY.

10

with unaffordable single drug end
products. For TB this means thatthe early pipeline is weak and large
companies are withdrawing from
TB R&D due to a perceived lackof a market. This is why MSF andpartners propose the 3P (Push-PullPool) Project, to deliver affordable,
effective new TB treatment regimens
faster.30 The 3P Project uses an open
collaborative approach to drug
development, and novel approaches
to financing and coordinating R&D
through three key features: 1. The
project pushes upfront funding tofinance R&D activities (i.e. throughgrants); 2. The project pulls or

Médecins Sans Frontières | March 2016

© Lana Abramova

Bedaquiline

Delamanid

Clofazimine

Linezolid

Yes for DR-TB

WHO EMLYes for DR-TB

Yes for DR-TB

Yes, but for leprosy(WHO has beenin discussion with
Novartis since 2008
to address indication)

Registration• Conditional approval• Restricted use
pre-XDR/XDR• Registered in 9,
pending in 9, of 27
high burden countries• Conditional approval• Broader recommendation
than Bdq (includes
MDR-TB with an increased
risk of poor outcome)•R eg. in Japan, Europe,
S. Korea

Not registered for TB
in any country

Not registered for TB in
any country

Indication

DR-TB

DR-TB

Indication limited
to leprosy

No TB indication

Lowestglobal price$150 per patient, permonth (pppm)$283.33 pppm

$66 (procured on a
named-patient basisonly) 100mg pppm

$161 pppm

Access conditions• Donation programme
launched April 2015
through USAID/GDF
for 30,000 treatment
courses over 4 years
for all GFATM-eligible
countries. Quota for
CIS countries• Access in Russia andselect CIS countries via
Pharmstandard (ex.
at $1,351/treatment
course, Feb 2016 for an
order in Uzbekistan)• IP barriers until 2029
that limit genericcompetition ordevelopment of FDCs
• Not clear if Janssen will
engage in bilateral or
Medicines PatentPool-led voluntary
licence negotiations• International donation
programme (FighTBack)announced in April 2015
to give access to 20%
of all diagnosed andtreated MDR-TB patientsby 2020; details remain
unclear;• Access to Global Fundeligible countries at one
single public price• Patent barriers(compound andsecondary patents) inplace until 2031 that limit
generic competition ordevelopment of FDCs
• Slow discussions withgeneric companies
for potential voluntary
licence• Single producerof quality-assured
clofazimine• In April 2014,
US FDA agreed
to review a filingunder orphan drug
designation by
Novartis for phase II
clinical trial of Cfz;
could possibly
lead to registration
with TB indication
by 2020• Secondary patents could
preclude importation of low-cost
generics until 2021 in somecountries, although likely thatgeneric producers will challenge
or ignore the secondary patents

Recommendations• Proactive plan to movefrom donation tosustainable, affordable
price ASAP, especiallyfor MICs• A lower, single priceoffered to all LICs andMICs• Reduction of IP
barriers through use of
TRIPS flexibilities or a
voluntary licence thatis negotiated throughthe MPP• High-burden TB
countries’ NMRAs mustprioritise registration• Janssen must prioritise
high-burden country
registration• Rapidly commencetrials looking at
combining Bdq withother new drugs and in
shorter regimens• Rapidly start phase III
and paediatric trials• Otsuka to clarify future
donation plan(s) in
the framework of the
FighTBack initiative• Otsuka to publish anaccess plan for nonGlobal Fund eligible
countries (e.g. RussianFederation) and thosetransitioning out from
Global Fund support (e.g.
Georgia)• Reduction of IP barriers
through use of TRIPS
flexibilities or a voluntary
licence that is negotiatedthrough the MPP• Otsuka rapidly pursues
registration in highburden TB countries andclinical trial countries;
until then Dlm should
be widely accessible
through compassionate
use or other early accessprogrammes• Rapidly commence trials
looking at combining Dlmwith other new drugs andin shorter regimens•N ovartis should
continue pursuing a
TB indication for Cfz(current outcomes
expected 2020)•A better price offered
to countries•T ech transfer for
API production toallow sustained
availability; prioritisereformulation to apresentation moresuited to hot andhumid environments,
and allowing dosing
adaptation•C urrent andfuture genericmanufacturersof active
pharmaceuticalingredients andfinished productof Cfz should
pursue WHO
prequalification• Inclusion on the
WHO EML for TB•P fizer, Hetero register Lzd inall high-burden TB countries asa priority•Q uality-assured suppliers offer
prices on par with GDF prices to all
high-burden countries that procure
linezolid outside of GDF channels•M acleods pursue the assessmentof its linezolid with WHO PQ•C ountries update their national
EML with Lzd for TB based on the
April 2015 WHO EML update•M anufacturers pursue a TB
indication for this drug using theliterature review gathered by the
WHO EML expert committee•N ew generics companies (US FDA
tentatively approved) register Lzd
in high burden TB countries•C ivil society and GDF push formore competitors to improveaffordability and price transparency•A better price offered to countries•U se TRIPS flexibilities to remove
secondary patents in countries
where treatment scale up isneeded and where secondary
patents may interfere with entryof generics

DR-TB Drugs Under the Microscope

THE ROAD TO BETTER TREATMENT AND NEW REGIMENSTABLE 4: ACCESS STATUS AND RECOMMENDATIONS FOR KEY DR-TB DRUGS

11

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

AFFECTED COUNTRY
GOVERNMENTS SHOULD:
 cale-up optimal TB andS
DR-TB treatment, including useof Group 5 medicines, per WHO
recommendations;
 egister Group 5 TB medicines (linezolid,Rclofazimine, imipenem/cilastatin) andnew drugs bedaquiline and delamanid,
and in the meantime allow importwaivers for these medicines; pdate national treatment guidelines
Uand national EML to match the latest
WHO recommendations;E nsure adequate planning andfunding so that all diagnosed drugresistant patients (MDR- and XDR-TB)
are started on treatment with DR-TB
medicines that are compliant with
WHO quality standards;
 et-up adequate regulations forS
compassionate use or expanded
access programmes for new
pre-registered drugs; andE xercise full use of public healthflexibilities enshrined ininternational intellectual property
rules for pharmaceuticals, as wellas other measures available topromote competition and improveaccess and affordability for key
DR-TB medicines.

THE GLOBAL FUND
TO FIGHT AIDS,
TUBERCULOSIS AND
MALARIA SHOULD:
E ncourage countries to upgrade
national guidelines to meet WHO
recommendations; and llow countries to carry on procuringA
quality-assured TB medicines atthe lowest possible price once theytransition out from GFATM support.

12

Médecins Sans Frontières | March 2016

THE GLOBAL DRUG
FACILITY SHOULD:
 ush for alternative quality-assuredP
supplier(s) for clofazimine (2015-2016);
 romote more competition forPlinezolid suppliers;
 romote best practices on drugP
forecasting at country level, in orderto provide manufacturers with clearer
volumes to be ordered with theobjective of driving down prices of
DR-TB medicines; andE xplore options allowing GDF
bidding to national public tenders.

WORLD HEALTHORGANIZATION SHOULD:
 ursue data collection which couldPlead to the addition of clofazimine to
the WHO EML list (Q1 2017);
 romote fast track registrations ofPGroup 5 medicines for TB (e.g. WHO
PQ collaborative registration forprequalified medicines but also for
those registered by SRAs); and rovide guidance on whether
PGroup 4 drugs can be streamlined,
such as recommending only one
drug from each class where there
are currently two drugs in thesame class. (e.g prothionamide/
ethionamide, terizidone/cycloserine).

PHARMACEUTICALCOMPANIES SHOULD:
 ubmit for registration Group 5 TB
S
medicines (linezolid, clofazimine,
imipenem/cilastatin) and new drugs
bedaquiline and delamanid in all
high-burden countries;
 fizer and Sanofi should immediately
P
offer more affordable prices forlinezolid in South Africa; B Alliance should develop aTcompassionate use program forpretomanid;
Offer affordable, sustainable
commercial prices, not limited tocountries’ income tiers, and whereapplicable, negotiate non-exclusive,
broad voluntary licences with theMedicines Patent Pool. Problematic
donation programmes are not asustainable answer to access to
drugs; and efer to Table 4 for additionalRdrug-specific recommendations.

CIVIL SOCIETY SHOULD:
E nsure countries are procuring
quality-assured medications for
DR-TB programmes; and ressure governments to upgradePnational policies, including
ensuring that treatment guidelines
and EML are in line with WHO
recommendations.

DONORS SHOULD:
 upport countries’ upgrading ofSnational TB programmes’ guidelines
and national EML to meet WHO
recommendations; andE nsure that DR-TB drugs procured
with donor funding are compliant
with WHO quality standards.

ALL STAKEHOLDERSSHOULD: upport the 3P Project, an alternativeS
model of TB drug developmentthat promotes more efficient, more
effective and more affordable TB
treatment regimens.

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

DATA COLLECTION
Questionnaires were sent tocompanies listed on the Global Fund
List of Tuberculosis pharmaceuticalproducts,i producing at least one
anti-tuberculosis product either listedon the WHO List of Prequalified
Medicinal Products or approvedby a stringent regulatory authority(SRA) or temporarily approved by
the Expert Review Panel (ERP) of the
Global Fund. The data were collected
up to September 2015.

PRICE INFORMATION
Prices are listed where manufacturers
agreed to share information.
A number of manufacturers, including:• Bayer, Glenmark, Ipca did not wish
to contribute to the publication;• Hisun, Lupin, Meiji, Microlabs,
Mylan, Novartis, Pfizer, Panpharma,
Reimser-Fatol, Otsuka and Teva did
not have prices available or did notagree to publish prices;• no response was received from
Medochemie; and• no contact for Biocom was available.
Prices are given in US dollars (US$),rounded up to the nearest third
decimal point, and correspond to thelowest unit price (i.e. the price of one
tablet, capsule or vial). When pricesthat varied according to packaging(e.g. blisters or bottle) were received
from a manufacturer for the same
formulation, the lowest price wasselected. Prices listed are ‘ex-works’
except for prices provided by Apotex(CIF, Toronto, Canada) - see Annex 2for details, and the Glossary for an
explanation of incoterms.
The prices listed in this publication
are the ones provided by the
manufacturers. The prices paid by thepurchaser might be higher becauseof add-ons (such as import taxes anddistribution mark-ups), or may belower after negotiations or as a resultof effective procurement procedures.
Prices offered by the Global Drug
Facility (GDF) pooled procurement
mechanism are also ‘ex-works’ andcorrespond to the lowest and highest
prices referenced per medicine on
GDF website.ii Note that prices in the
GDF price catalogue can fluctuateduring the year if, for example, along-term agreement with different
suppliers comes to an end. In
addition, this year a range of prices
is provided per medicine without
specific figures per manufacturer.

QUALITY INFORMATION
Products that are either listed on the
WHO List of Prequalified Medicinal
Products or approved by a stringent
regulatory authority are listed in theprice tables as ‘approved’. Productsthat are undergoing review by either
WHO Prequalification, by a stringent
regulatory authority, or that havebeen reviewed and listed by the ERPof the Global Fund, are listed in theprice tables as ‘under evaluation’.
Products that have not yet been
submitted to WHO Prequalificationor to a stringent regulatory authority
have not been included.

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

METHODOLOGYMETHODOLOGY

Submissions to WHO Prequalification
are confidential and all companies
mentioned that have a dossier accepted
for review have given MSF thepermission to disclose this information.
As the information on the WHO Listof Prequalified Medicinal Products is
updated regularly, the list should be
consulted for up-to-date information.iii
Products procured by GDF comply
with the GDF’s Quality Assurance
policy. iv This deems eligible for
GDF procurement all products thatare included on the WHO List ofPrequalified Medicinal Products,that are approved by a stringent
regulatory authority, or that areapproved by the joint GDF/Global
Fund Expert Review Panel (ERP).
The ERP is an independent technicalbody whose purpose is to review
the potential quality risk of using
medicines which are not yet WHOprequalified or authorised by astringent regulatory authority, andgive advice to the Global Fund andthe Global Drug Facility whether
time-limited procurement of suchproducts can be authorised. The
list of ERP reviewed products fortuberculosis can be consulted on
The Global Fund website.v

STOP PRESS
This report went to print justbefore the Global Drug Facility
was due to update its prices for
DR-TB drugs by 1 April 2016,
once the yearly manufacturer
consultation was finalised. For
the most up-to-date information
on GDF prices for DR-TB drugs,
please consult the Global Drug
Facility, www.stoptb.org/gdf/
drugsupply/drugs_available.asp

v. http://www.theglobalfund.org/en/procurement/quality/pharmaceutical/#A_B

DR-TB Drugs Under the Microscope

13

AMIKACIN ( Am ) GROUP 2

AMIKACIN ( Am )GROUP 2

GENERAL INFORMATION• Therapeutic Class:Aminoglycoside antibiotic.

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

• ATC Code: J01GB06.36• Included in the WHO Guidelines
as a Group 2 injectable agent.37• First approved by US FDA: The
date of the original New Drug
Application (NDA) is not publicly
available on the US FDA website.
The first Abbreviated New Drug
Application (ANDA) was approved
on 22 January 1981.39• Included in the 19th edition of
the WHO Model List of Essential
Medicines23 and in the 5th editionof the WHO Model List of Essential
Medicines for Children.38• Approved indication in the US:
Amikacin is indicated for the short-term
treatment of serious infections due tosusceptible strains of Gram-negative
bacteria, including bacterial septicaemia(including neonatal sepsis), serious
infections of the respiratory tract,bones and joints, central nervous
system (including meningitis) andskin and soft tissue; intra-abdominal
infections (including peritonitis);burns and post-operative infections(including post-vascular surgery).40

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

14

CadilaCipla

Pharmatex

VianexGDF pooled procurement

Quality status

Under evaluation
by WHO PQ

WHO PQ
approved

SRA approved

SRA approved

GDF Quality Assurance Policy

500mg/2ml
solution for
injection

0.980

1.600

0.678

2.500

0.678 - 0.805

Médecins Sans Frontières | March 2016

There is little clinical difference between kanamycin and amikacin. As they have similar side effect profiles and showhigh levels of cross-resistance, factors including price, availability and adaptability of formulations will influencenational TB programmes or treatment providers when selecting these drugs.
Capreomycin should be used if aminoglycosides are contra-indicated or poorly tolerated; may be effective in cases
showing resistance to amikacin and kanamycin.
Number of quality sources
There are several stringent
regulatory authority-approved
sources of amikacin. In 2011, a
generic source of amikacin (Cipla)
was prequalified by WHO for the
first time. An additional three
products are currently undergoing
WHO prequalification, including a
1g/vial and a 500mg/vial.
Suitability for use indeveloping country settings
Amikacin, like other aminoglycosides
and capreomycin, cannot be
administered orally and is usually
given intramuscularly (IM) but can begiven intravenously (IV). This imposes

DR-TB Drugs Under the Microscopeburdens both on patients andtreatment programmes, as qualified
staff need to administer the product.

manufacturer contacted for the

Amikacin is available in bothpowder and liquid formulations;the latter is more adaptableto resource-limited settings asreconstitution is not required.

approved source available (e.g.

Paediatrics
Amikacin is licensed for use inneonates, infants and children.

have been performed, but based

There is a smaller dosage(100mg/2ml) available whichallows for more accurate dosing
in children. This formulation is
not part of the portfolio of any

low. However, there is potential for

AMIKACIN ( Am ) GROUP 2

SPOTLIGHT ON ACCESS ISSUES

publication. There is at least one
stringent regulatory authorityBristol-Myers Squibb) but it is notavailable through the GDF.
HIV co-infection
No antiretroviral interaction studies
on pharmacokinetic profiles, thepotential for drug interactions are
additive toxicities, in particular with
antiretrovirals which may cause renal
toxicity, such as tenofovir. Further
studies are required to confirm this.

15

KANAMYCIN ( Km ) GROUP 2

KANAMYCIN ( Km )GROUP 2

GENERAL INFORMATION• Therapeutic Class:Aminoglycoside antibiotic.
• ATC Code: J01GB04.36• Included in the WHO Guidelines
as a Group 2 injectable agent.37• Included in the 19th edition of
the WHO Model List of Essential
Medicines 23 and in the 5th editionof the WHO Model List of Essential
Medicines for Children.38• Presentations available: solution for
injection – 1g/4ml. As powder for
injection – 1g/vial.
• First approved by US FDA: The dateof the original New Drug Application(NDA) is not publicly available on the
US FDA website. The first Abbreviated
New Drug Application (ANDA) wasapproved on 13 February 1973.
The only currently registeredproduct in the US was approvedon 17 November 2002.

• Approved indication in the US:
Kanamycin is indicated in the
short-term treatment of serious
infections caused by susceptible
strains of micro-organisms.41

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

16

Macleods

Meiji

Panpharma

GDF pooled procurement

Quality status

Under evaluation
by WHO PQ

SRA approved

SRA approved

GDF Quality Assurance Policy

1g powder for
injection

1.000

xx

Manufacturer did notagree to publish prices

1.000- 1.721

1g/4ml solution
for injectionxx

Manufacturer did notagree to publish prices

xx

2.560

Médecins Sans Frontières | March 2016

There is little clinical difference between kanamycin and amikacin. As they have similar side effect profiles andshow high levels of cross-resistance, factors including price, availability and adaptability of formulations will
influence national TB programmes or treatment providers when selecting these drugs.
Capreomycin may be effective in cases showing resistance to kanamycin.
Number of quality sources
In the past, kanamycin formulations
from several different manufacturers
were registered in the US. However,as Fresenius Kabi has discontinued
production, only two kanamycin
sources are currently approved by astringent regulatory authority: Meiji(in Japan) and Panpharma (approvedin Latvia and Lithuania). Panpharma
and Meiji did not agree to having
their prices published. Meiji notedthat all supply goes through GDF.
No sources of kanamycin are
WHO-prequalified, although one
manufacturer (Macleods) disclosedthat they have submitted a dossierfor WHO prequalification for the
1g/vial and 500mg/vial formulations
which are currently under review.
A price was available in September
2015 from Macleods only for the
1g/vial. Two additional sources for1g/vial and three additional sourcesof 500mg/vial are undergoing
WHO prequalification.33
The supply of kanamycin remains
vulnerable, with only two sources(Panpharma and Meiji) available for
TB procurement, both of which haveexperienced production limitations.
Panpharma resolved issues withactive pharmaceutical ingredient(API) production which had resulted
in an interruption of supply to several
national TB programmes in 2010,
although production only resumed
in late 2011. Meiji was identified by

DR-TB Drugs Under the Microscope

GDF as an alternative source in 2010;
however their limited production
capacity means availability ofkanamycin is insufficient to coverglobal needs. Further challenges
in the production of the active
ingredient occurred in 2015 requiringextra manufacturing steps to ensure
the sterility of the API, leading todelays in supply and a 21% increasein the price of the finished product.

Suitability for use indeveloping country settings
Kanamycin, like otheraminoglycosides and capreomycin,
cannot be administered orally andis usually given intramuscularly(IM) but can be given intravenously(IV). This imposes burdens both on
patients and treatment programmes,
as qualified staff need to administerthe product.

Additional manufacturers exist in
China, India, in countries fromthe former Soviet Union, and inother countries, but it is unknown
whether they comply with WHO
quality standards.

Kanamycin is available in bothpowder and liquid formulations;the latter is more adaptableto resource-limited settings asreconstitution is not required.

Active Pharmaceutical
Ingredient
Issues with the production of the
API remain a barrier in increasing
the number of quality-assured
sources for the finished product.
Kanamycin API is manufactured
by a specialised process offermentation. There are few
manufacturers globally who
have the capacity to produce
quality-assured API through thisfermentation process, and thecomplexity is further increased
as the API should be sterile. The
quality assurance of the API is a key
factor and is often what prevents
companies from securing approvalof the finished product through
WHO Prequalification or a stringent
regulatory authority.

KANAMYCIN ( Km ) GROUP 2

SPOTLIGHT ON ACCESS ISSUES

Paediatrics
The safety and efficacy of kanamycinin children has not been established.
While dosages are published in several
guidelines 42,43, there is need forfurther research (in pharmacokinetics,
pharmacodynamics and safety data)
into the use of this drug in younger
populations, in particular in children
aged under five years.
HIV co-infection
No antiretroviral interaction studies
have been performed, but based on
pharmacokinetic profiles, the potential
for drug interactions are low.
However, there is potential for
additive toxicities, in particular with
antiretrovirals which may cause renal
toxicity, such as tenofovir. Further
studies are required to confirm this.

17

CAPREOMYCIN (Cm) GROUP 2

CAPREOMYCIN (Cm)GROUP 2

GENERAL INFORMATION• Therapeutic Class:
Polypeptide antibiotic.

• Presentations available:• ATC Code: J04AB30.36• First approved by US FDA:

1g powder for injection.

• Included in the WHO Guidelines
as a Group 2 injectable agent.37• Included in the 19th edition of
the WHO Model List of Essential
Medicines23 and in the 5th editionof the WHO Model List of Essential
Medicines for Children.38

2 June 1971.43• Approved indication in the
US: Capreomycin is to be usedconcomitantly with othercapreomycin-susceptible strains ofM. tuberculosis when the primaryagents (isoniazid, rifampicin,
ethambutol, aminosalicylic acid, andstreptomycin) have been ineffective,
or cannot be used because of
toxicity or the presence of resistanttubercle bacilli.43

appropriate anti-tuberculosis
agents; it is indicated for use inpulmonary infections caused by

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

Quality status

1g powder for
injection

18

Akorn

Aspen

Hisun

Macleods

VianexGDF pooled procurement

SRA approved

WHO PQ
approved

WHO PQ
approved

Under evaluation
by WHO PQ(ERP approved
until 31/10/2016)

SRA approved

GDF Quality
Assurance Policy

8.100

Manufacturer
did not agree
to publish
prices

4.150

6.000

3.800 - 4.700

8.000

Médecins Sans Frontières | March 2016

Capreomycin shows moderate cross-resistance to amikacin and kanamycin and can be used when there isresistance to either one of these drugs.
With PAS and linezolid, capreomycin remains one of the three medicines which weigh heavily in the overall
cost of a DR-TB regimen.
Number of quality sources
There are currently five qualityassured sources available: Akorn,
who bought Eli Lilly’s US licence;
Vianex, a manufacturer based in
Greece, received stringent regulatory
authority approval in Spain in 2011;
Hisun, a China-based manufacturer,
received WHO prequalification in
2014; Macleod’s, which received ERP
approval in 2014; and Aspen, which
received WHO prequalification in
December 2015.
With five quality-assured sources now
available for TB procurement, thesupply of capreomycin has improved
and the price has decreased by nearlya quarter (24%) since 2013. Twofurther companies have submitted adossier for WHO prequalification.
Evolution in priceFor a number of years, Eli Lilly
subsidised the price of capreomycin
for GLC-approved programmes,
charging US$1.02 per vial until a set
volume had been ordered, and $4.00

DR-TB Drugs Under the Microscope

per vial thereafter. The price at whichcountries can procure capreomycin
increased considerably since Eli Lilly
stopped production and transferredtechnology to other companies(Aspen, Hisun, and SIA International).
GDF currently procurescapreomycin at $3.80 to $4.70 pervial. Even with new quality-assured
sources having entered the market,
the price of capreomycin remains
higher than the Eli Lilly-subsidised
product, despite a price decreaseof 24% since 2013.
Suitability for use indeveloping country settings
Capreomycin, similar to amikacin
and kanamycin from theaminoglycosides class, cannot be
administered orally and is usually
given intramuscularly (IM), but
can also be given intravenously(IV). This imposes burdens
both on patients and treatment
programmes, as qualified staff
need to administer the product.

Paediatrics
The safety and efficacy of
capreomycin in children has
not been established.

CAPREOMYCIN (Cm) GROUP 2

SPOTLIGHT ON ACCESS ISSUES

While dosages are published inseveral guidelines, there is need forfurther research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug in younger
populations, in particular in children
aged under five years.
HIV co-infection
No antiretroviral interaction
studies have been performed, but
based on pharmacokinetic profiles,
the potential for drug interactions
is low.
However, there is potential for
additive toxicities, in particular with
antiretrovirals which may cause
renal toxicity such as tenofovir.
Further studies are required toconfirm this.

19

MOXIFLOXACIN (Mfx) GROUP 3

MOXIFLOXACIN (Mfx)
GROUP 3

GENERAL INFORMATION•T herapeutic Class: Fluoroquinolone.
•A TC Code: J01MA14.36• Included in the WHO Guidelines
as a Group 3 Fluoroquinolone.37•M entioned as an alternative tolevofloxacin for tuberculosis in the
19th edition of the WHO Model List of

Essential Medicines.23 Not included in
the 5th edition of the WHO Model Listof Essential Medicines for Children.38• Presentations available: 400mg tablet.
• First approved by US FDA:
12 October 1999.45• Approved indication in the US:
Moxifloxacin was initially approved forthe indications of bacterial sinusitis andcommunity-acquired pneumonia. Thiswas further expanded to include acutebacterial exacerbation of chronic bronchitis,
uncomplicated and complicated skin andskin structure infection, and complicatedintra-abdominal infections.46

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

20

Cipla

HeteroMacleods

Microlabs

Sunpharma

GDF pooled
procurement

Quality status

WHO PQ
approved

SRA approved

WHO PQ
approved

Underevaluation by
WHO PQ

WHO PQ
approved

GDF Quality
Assurance Policy

400mg tablet

0.600

0.660

0.580

Manufacturer
did not agree topublish prices

0.510

0.437-0.540

Médecins Sans Frontières | March 2016

Moxifloxacin use is increasing due to the key role that fluoroquinolones play in the treatment of drug-resistantforms of tuberculosis.
Based on 2011 WHO DR-TB programmatic guidelines, the use of later generation fluoroquinolones, such as
moxifloxacin and levofloxacin, are preferred to ofloxacin (inferior performance and higher risk of resistance).
There is, however, potential for cross-resistance between the later generation fluoroquinolones.
Number of quality sources
Bayer was the only quality-assured
source of moxifloxacin available
for many years. In November
2010, Cipla’s product became
the first generic moxifloxacin to
be prequalified by WHO, and in2013 two more sources (Macleods
and Sun Pharmaceuticals) wereprequalified. One additional source(Hetero) is SRA approved. Currently
seven manufacturers are underevaluation by WHO PQ.
With additional quality-assured
sources entering the market,
access to moxifloxacin appears to
be relatively secure for the time
being. Prices, which in the past
represented a barrier to access,are continuously decreasing; since2013, the lowest price on themarket has decreased by 27%.
Approved indication
While moxifloxacin has been shown
to be effective against M. tuberculosis
and has been included in manytreatment guidelines for DR-TB, it
has not yet received an approved
TB indication by any stringent
regulatory authority.
Patents
In India, the Markush andcompound patent applications were
not eligible for product patents
under the 1970 Patent Act, andthe crystal monohydrate form was
rejected after a pre-grant opposition
was filed by Ranbaxy Laboratories.
As a result, the drug has been ingeneric production in India forseveral years and is registered by anumber of generic manufacturers

DR-TB Drugs Under the Microscopewith the Indian Central Drugs
Standard Control Organisation, anumber of whom have filed andobtained WHO pre-qualification
and/or US FDA approval.
The basic Markush and compound
patents which covered themoxifloxacin molecule have started
to expire around the world, andgeneric companies have worked
around the secondary patents on
the crystal monohydrate form47 andthe process of preparing an oral
tablet formulation.48 As a result,generics are now available in the
US (launched in February 2014)49,
Canada and South Africa. Genericversions have now been registeredin South Africa and are suppliedfor DR-TB treatment through thenational TB programme as part of
the government tender awarded
in 2011. Generic versions are also
marketed in the Russian Federation.
Paediatrics
The safety and efficacy of moxifloxacin
in children has not been established.
While dosages are published in several
guidelines 42,43, there is an urgent needfor further research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug in younger
populations, in particular in children
aged under five years. Existingstudies show substantially lower
serum concentrations in children
compared to adults at the currently
recommended doses, probably due
to faster elimination.50
As there is no paediatric formulation
available, paediatric doses are

obtained by manipulating adultformulations to achieve target
doses. This requires a certain level oftraining, supervision and resources,
which may not be available in many
resource-limited settings where
DR-TB is prevalent.

MOXIFLOXACIN (Mfx) GROUP 3

SPOTLIGHT ON ACCESS ISSUES

HIV co-infection
No antiretroviral interaction
studies have been performed, but
based on the metabolism rate ofmoxifloxacin, levels of the drug may
be reduced by the use of ritonavir
and increased by atazanavir. Further
research is needed to assess this.
Protease inhibitors and efavirenz
may prolong QT interval, so
caution is advised in concomitant
use with moxifloxacin, withelectrocardiogram monitoring
recommended.
Oral absorption of fluoroquinolones
is reduced by buffered drugs, sodoses should be separated fromdidanosine-buffered tablets.
Special caution
Moxifloxacin can affect cardiac
conduction (QT prolongation). QT
prolongation can infrequently resultin a serious (rarely fatal) fast/irregularheartbeat, known as torsades
de point. This is an importantconsideration, as several new (suchas bedaquiline and delamanid) andrepurposed TB drugs (clofazimine)
have a similar risk, and it is unclear
if this will be an additive effect.
This is an effect seen in this classof drugs, but is most pronouncedwith moxifloxacin.

21

LEVOFLOXACIN (Lfx) GROUP 3

LEVOFLOXACIN (Lfx)
GROUP 3

GENERAL INFORMATION• Therapeutic Class: Fluoroquinolone.
• ATC Code: J01MA12.36• Included in the WHO Guidelines
as a Group 3 Fluoroquinolone.37• Included in the 19th edition of
the WHO Model List of Essential
Medicines23 and in the 5th editionof the WHO Model List of Essential
Medicines for Children.38 Levofloxacin
is considered a better alternative

to ofloxacin, based on availability andprogramme considerations.
• Presentations available: 250mg, 500mg
and 750mg tablets; 25mg/ml oral solution.
• First approved by US FDA:
20 December 1996. The paediatricformulation (25mg/ml oral solution) wasapproved on 21 October 2004.51• Approved indication in the US:
Levofloxacin was initially approved forthe indications of acute maxillarysinusitis, acute bacterial exacerbationsof chronic bronchitis, communityacquired pneumonia, uncomplicatedskin and skin structure infections,complicated urinary tract infections(UTI), and acute pyelonephritis.
This was further expanded toinclude uncomplicated UTI, chronic
bacterial prostatitis, and treatment of
inhalational anthrax (post-exposure).51

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

Cipla

HeteroLabatec

Macleods

Microlabs

GDF pooled
procurement

QualitystatusWHO PQ
approved

WHO PQ
approved

SRA approved

SRA approved

WHO PQ
approved

WHO PQ
approved

GDF Quality
Assurance Policy

250mg
tablet0.090*

0.061

0.059

1.538

0.043

0.057

0.033-0.055

500mg
tablet0.130*

0.110

0.105

2.315

0.078

0.092

0.059-0.097

750mg
tablet0.150*

xx

0.240

xx

0.128

xx

0.100

* Inconterm CIF

22

Médecins Sans Frontières | March 2016

There is potential for cross-resistance between the later generation fluoroquinolones. Based on 2011 WHO
DR-TB programmatic guidelines, the use of later generation fluoroquinolones, such as moxifloxacin andlevofloxacin, are preferred to ofloxacin.
Number of quality sources
Levofloxacin 250mg and 500mg
oral formulations produced by
Cipla were prequalified by WHO
in December 2011, with Microlabs
following in October 2012, Apotex
in June 2013 and Macleods in
October 2014. Currently, an
additional four manufacturers forthe 250mg product, and threemanufacturers for 500mg, are underevaluation by WHO Prequalification.
A significant number of genericversions have been approved bystringent regulatory authorities,
since patents expired in the US
and in Europe in 2011.
The first 750mg formulation(produced by Apotex) was
prequalified by WHO in June 2013,
followed by Macleods, prequalifiedin October 2014.
Evolution in price
The price of levofloxacin does notappear to be an issue, and it hascontinued to fall over recent years.
Approved indication
The 2011 WHO programmatic
guidelines for DR-TB recommend use

DR-TB Drugs Under the Microscopeof later generation fluoroquinolones,
including levofloxacin. However,levofloxacin does not have a TB
indication approved by any stringent
regulatory authority.
Patents
Patents on levofloxacin held by Daiichi
Sankyo in the US and in several
European countries expired in 2010.
Other patents in the US and inseveral European countries claiming
levofloxacin expired in June 2011.
Paediatrics
The US FDA has approved levofloxacin
for use in children aged over six
months, but only for acute infections.
The safety of levofloxacin in children
treated for more than 14 days has
not been studied; as this drug may betaken for up to two years, there is anurgent need for more safety data on
the use of levofloxacin for extended
periods in children.
While there are two manufacturersof the paediatric formulations(25mg/ml oral solution) available
in the US, these are not widely
available elsewhere.

Currently, the majority of DR-TB
programmes prepare paediatricdoses by manipulating adultformulations to achieve target
doses. This requires a certain level oftraining, supervision and resources,
which may not be available in many
resource-limited settings where DRTB is prevalent.

LEVOFLOXACIN (Lfx) GROUP 3

SPOTLIGHT ON ACCESS ISSUES

HIV co-infection
No antiretroviral interaction studies
have been performed, but based on
the metabolism rate of levofloxacin,no interactions are expected.
However, further research is needed
to assess this.
Protease inhibitors and efavirenz
may prolong QT interval, so caution
is advised in concomitant use withlevofloxacin, with electrocardiogram
monitoring recommended.
Oral absorption of fluoroquinolones
is reduced by buffered drugs, sodoses should be separated fromdidanosine-buffered tablets.

23

ETHIONAMIDE (Eto) GROUP 4

ETHIONAMIDE (Eto)
GROUP 4

GENERAL INFORMATION• Therapeutic Class: Carbothionamidesgroup, derivative of isonicotinic acid.
• ATC Code: J04AD03.36• Included in the WHO Guidelines
as a Group 4 oral bacteriostatic
second-line agent.37• Included in the 19th edition of the WHO
Model List of Essential Medicines23 andin the 5th edition of the WHO Model
List of Essential Medicines for Children.38• Presentations available: 250mg and
125mg tablets.
• First approved by US FDA: 30 April 1965.52• Approved indication in the
US: ethionamide is primarily
indicated for the treatment ofactive tuberculosis in patientswith M. tuberculosis resistant
to isoniazid or rifampicin, or
where the patient is intolerant
to other drugs.52

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

GDF pooled
procurement

Under evaluation
by WHO PQ (ERP
approved until
02/07/2016 )WHO PQ
approved

GDF Quality
Assurance Policy

xx

0.112

xx

xx

0.066

xx

0.082

0.062-0.080

Cipla

Lupin

Macleods

Quality status

WHO PQ
approved

WHO PQ
approved

WHO PQ
approved

125mg tablet

xx

xx

250mg tablet

0.098

Manufacturer
did not agree topublish prices

SPOTLIGHT ON ACCESS ISSUES
Prothionamide is the propyl analog of ethionamide. There is complete cross-resistance between the two drugs
and they are used interchangeably.
Number of quality sources
The supply and number ofsources of ethionamide 250mg
is gradually improving, withfour WHO-prequalified products
available. In addition, Macleods
has developed a 125mg paediatricformulation which was approvedby the GDF/Global Fund Expert
Review Panel (ERP) in July 2015.
Evolution in price
The price of ethionamide does
not appear to be an issue.

24

Médecins Sans Frontières | March 2016

Paediatrics
The safety and efficacy of
ethionamide in children has
not been established.
While dosages are publishedin several guidelines, there
is an urgent need for further
research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug inyounger populations, inparticular in children aged
under five years.

HIV co-infection
While no antiretroviral interaction
studies have been performed,
pharmacokinetic profiles suggestthat drug interactions withethionamide are possible.
There is the possibility of additive
toxicities with antiretrovirals
which may cause hepatotoxicity,
including efavirenz and nevirapine.
With the potential for interactions withsome classes of antiretrovirals, there isan urgent need for further studies.

GROUP 4

GENERAL INFORMATION• Therapeutic Class: Carbothionamidesgroup, derivative of isonicotinic acid.
• ATC Code: J04AD01.36• Included in the WHO Guidelines
as a Group 4 oral bacteriostatic
second-line agent.37•M entioned as an alternative toethionamide for tuberculosis in the
19th edition of the WHO Model List of

Essential Medicines.23 Not included in
the 5th edition of the WHO Model Listof Essential Medicines for Children.38• Approved indication in Germany:
Treatment of all forms and stagesof pulmonary and extra-pulmonary
tuberculosis as second-line drug inthe case of proven multidrug
resistance of the pathogens against
first-line drugs; treatment of diseases
caused by so-called ubiquitous(atypical) mycobacteria; treatmentof leprosy in the context of modified
therapy regimens.54• Presentations available: 250mg tablet.
• First approved by German Federal
Institute for Drugs and Medical
Devices (BfArM): First marketed inGermany in the 1970s but registeredin the framework of posterior
registration on 14 June 2005.53

PROTHIONAMIDE (Pto) GROUP 4

PROTHIONAMIDE (Pto)

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

Lupin

Microlabs

Olainfarm

GDF pooled
procurement

Quality status

SRA approved

WHO PQ approved

WHO PQ approved

SRA approved

GDF Quality
Assurance Policy

250mg tablet

Manufacturer did notagree to publish prices

Manufacturer did notagree to publish prices

0.120

0.100

0.130-0.178

SPOTLIGHT ON ACCESS ISSUES
Prothionamide is the propyl analog of ethionamide. There is complete cross-resistance between the two drugs
and they are used interchangeably.
Number of quality sources
In February 2013, Microlabs was thefirst manufacturer to secure WHO
Prequalification for prothionamide,
followed by Lupin in June 2014.
There are now four quality-assured
sources for the drug, given the two
existing sources approved by stringent
regulatory authorities (Germany’s
Fatol and Latvia’s Olainfarm).
An additional manufacturer has
submitted its dossier for WHO
prequalification.

Paediatrics
The safety and effectiveness ofprothionamide in children has notbeen established. The paediatricformulation of ethionamide
should be considered instead ofprothionamide.
While dosages are published in several
guidelines, there is an urgent needfor further research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug in younger
populations, in particular in children
aged under five years.

HIV co-infection
While no antiretroviral interaction
studies have been performed,
pharmacokinetic profiles suggestthat drug interactions withprothionamide are possible.
There is the possibility of additive
toxicities with antiretrovirals which
may cause hepatotoxicity, including
efavirenz and nevirapine.
With the potential for interactions withsome classes of antiretrovirals, there isan urgent need for further studies.

Continued overleaf
DR-TB Drugs Under the Microscope

25

CYCLOSERINE (Cs) GROUP 4CYCLOSERINE (Cs)
GROUP 4

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

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

26

Dong A

Macleods

Microlabs

Strides

GDF pooled
procurement

Under evaluation
by WHO PQ (ERP
approved until
24/07/2016)

GDF Quality
Assurance
Policy0.600

0.187-0.330

Quality status

WHO PQ approved

WHO PQ approved

WHO PQ approved

Under evaluationof WHO PQ

250mg
capsulePrice was notavailable at timeof data collection

0.216

0.390

Manufacturer
did not agree topublish prices

Médecins Sans Frontières | March 2016

Number of quality sources
Eli Lilly, the original licence holderof cycloserine, actively engaged
in technology transfer to three
generic manufacturers (Aspen,
Chao Center/Purdue GMP andSIA International) and ceased
production in 2008.
There are currently four WHOprequalified sources of cycloserine,
including Dong A, Macleods, andBiocom, the latter having secured
approval in August 2013. In addition,
Cipla received WHO prequalificationin December 2015, however prices
for this publication were collected in
September 2015 and the price for
Cipla’s product is not available forthis edition. In addition, Chao
Center/Purdue have received
approval from a stringent regulatory
authority but are supplying theNorthern American market.
Strides received joint GDF/
Global Fund Expert Review Paneltemporary approval (until July2016), making them eligible for
Global Fund procurement.
Three other manufacturers havesubmitted dossiers for WHO
prequalification.

Active Pharmaceutical
Ingredient
Until 2006, the only quality-assured
source for the active pharmaceuticalingredient of cycloserine was Eli
Lilly. The company completed atechnology transfer for the API to
Indian manufacturer Shasun in 2006.
Shasun API was subsequently US
FDA approved in June 2008 and was
WHO-prequalified in May 2013.
There are currently three API
manufacturers (Dong A, Shasun
and Macleods), and Enzychem ofSouth Korea was expected to file
API PQ in June 2015; this additional
manufacturer will make cycloserine
API supply more sustainable.
Evolution in priceIn the last three years, with thearrival of more quality-assured
sources of API for cycloserine,
the finished product price has
decreased from between US$0.39
and $0.78 per unit, to between$0.19 and $0.60 per unit. The
lowest unit price for a qualityassured source of cycloserine has
dropped by 52% in three years,
resulting in a considerable fall in
the cost of treatment regimens
containing this drug.

Paediatrics
The British National Formulary
provides doses for children aged
2 to 18 years, while the US
FDA states that the safety andeffectiveness of cycloserine inchildren has not been established.

CYCLOSERINE (Cs) GROUP 4

SPOTLIGHT ON ACCESS ISSUES

There is an urgent need for further
research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug in younger
populations, in particular inchildren aged under five years.
As there is no paediatricformulation available, paediatricdoses are obtained bymanipulating adult formulations
to achieve target doses. Thisrequires a certain level of training,supervision and resources, which
may not be available in many
resource-limited settings where
DR-TB is prevalent.
HIV co-infection
The metabolism of cycloserine
is not completely understood,
and therefore interactions with
antiretrovirals are unpredictable.
There is a need for more research
into potential interactions between
antiretrovirals and cycloserine.

Continued overleaf
DR-TB Drugs Under the Microscope

27

TERIZIDONE (Trd) GROUP 4

TERIZIDONE (Trd)
GROUP 4

GENERAL INFORMATION• Therapeutic Class: Analog of D-alanine.
• ATC Code: J04AK03.36• Included in the WHO Guidelines
as a Group 4 oral bacteriostatic
second-line agent.37• Mentioned as an alternative tocycloserine in the 2015 WHO

Model List of Essential Medicines for
Adults;23

not included in the 2013

Model List of Essential Medicines forChildren.38•P resentations available: 250mg capsule.
• First approved by German Federal
Institute for Drugs and Medical Devices(BfArM): First marketed in Germany inthe 1970s and is still in the process ofposterior registration. The filing date
for this process was 1 January 1978.54• Approved indication in Germany:
Treatment of tuberculosis in
adults and adolescents aged 14
years or older.54

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

28

Fatol

Macleods

GDF pooled procurement

Quality status

SRA approved

Under evaluation by WHO PQ

GDF Quality Assurance Policy

250mg capsule

Manufacturer did not agree topublish prices

0.850

1.588-1.666

Médecins Sans Frontières | March 2016

Terizidone is a combination of two molecules of cycloserine, and as such has a similar mode of action as cycloserine.
There is complete cross-resistance to cycloserine and, in some countries, the drug is used instead of cycloserine.
Number of quality sources
Germany’s Fatol is currently
the sole quality-assured sourceof terizidone. One additional
manufacturer (Macleods) has
submitted dossiers for WHO
prequalification.
Additional manufacturers exist, but
it is unknown whether they comply
with WHO quality standards.
Paediatrics
The safety and effectiveness ofterizidone in children has notbeen established.

DR-TB Drugs Under the Microscope

While dosages are publishedin several guidelines 42,43, there
is an urgent need for further
research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug in younger
populations, in particular inchildren aged under five years.
As there is no paediatricformulation available, paediatricdoses are obtained bymanipulating adult formulations
to achieve target doses. Thisrequires a certain level of training,supervision and resources, which

may not be available in many
resource-limited settings where
DR-TB is prevalent.

TERIZIDONE (Trd) GROUP 4

SPOTLIGHT ON ACCESS ISSUES

HIV co-infection
As terizidone is a combination of
two molecules of cycloserine andthe metabolism of cycloserine is notcompletely understood, interactions
with antiretrovirals are unpredictable.
There is a need for more research
into potential interactions between
antiretrovirals and terizidone.

29

PARA-AMINOSALICYLIC ACID (PAS) and PARA-AMINOSALICYLATE SODIUM (PAS-sodium) GROUP 4
30

PARA-AMINOSALICYLIC ACID (PAS) and
PARA-AMINOSALICYLATE SODIUM (PAS-sodium)GROUP 4

GENERAL INFORMATION• Presentations available: PAS: 4g• Therapeutic Class: Salicylic acid anti-folate.

sachet. PAS-sodium: 60% weight• ATC Code: for PAS: J04AA0136; forPAS-sodium: J04AA02.36

for weight granules 9.2g sachet and100g jar; powder for solution 5.52g• Included in the WHO Guidelines – PAS: asa Group 4 oral bacteriostatic second-line
agent; PAS-sodium: not included.37

sachet (equivalent to PAS 4g sachet).
• First approved by US FDA:

• PAS is included in the 19th edition of the WHO
Model List of Essential Medicines23 and in the
5th edition of the WHO Model List of Essential
Medicines for Children.38 PAS-sodium is
not included in either document.

PAS-sodium was first registered in atablet formulation on 8 March 1950.
Currently, only PAS is available in
the US, with the product registeredon 30 June 1994.56

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

Jacobus

GDF pooled procurement

Quality status

SRA approved

GDF Quality Assurance Policy

4g sachet

1.500

1.333

PAS-SODIUM

Macleods

Olainfarm

GDF pooled procurement

Quality status

WHO PQ
approved

WHO PQ
approved

GDF Quality
Assurance Policy

60% w/w granules– 9.2g sachet

1.690

xx

1.690

60% w/w granules– 100g jar

18.360xx

18.360

Powder fororal solution –5.52g sachet

xx

1.400

1.370

Médecins Sans Frontières | March 2016

• Approved indication in the US:
PAS is indicated for the treatmentof tuberculosis in combination
with other active agents. It is
most commonly used in patientswith multidrug-resistant TB or insituations when therapy with isoniazid
and rifampicin is not possible due
to a combination of resistance
and/or intolerance.56

With capreomycin and linezolid, PAS is one of the three medicines which weigh heavily in the overall cost of a
DR-TB regimen.
Para-aminosalicylate sodium (PAS-sodium) is the sodium salt of para-aminosalicylic acid (PAS), with 1.38g ofPAS-sodium equivalent to approximately 1g of PAS.
Number of quality sources
There is currently only one qualityassured source of PAS (Jacobus),
and two quality-assured sourcesof PAS-sodium (Macleods andOlainfarm), with no other sourcesin the pipeline.
With three quality-assured sourcesof PAS and PAS-sodium now
available for procurement, supply
has improved, but is still consideredvulnerable, particularly as thedifferent formulations available are
not easily interchangeable.
Evolution in price
The price of PAS has stagnated formore than three years. The lowest
price for a quality-assured source

DR-TB Drugs Under the Microscopeof PAS-sodium has stagnated,while the second source price has
increased by 30% since 2013.
Prices of both PAS and PASsodium remain a concern, and no
additional quality-assured sources
have been identified since 2011.
Paediatrics
The safety and effectiveness of PAS
and PAS-sodium in children has notbeen established.
While dosages are published in several
guidelines42,43, there is an urgent needfor further research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug in younger
populations, in particular in children
aged under five years.

As there is no paediatric formulation
available, paediatric doses are
obtained by measuring the adult
granular formulations. Jacobus
supplies a graduated dosage
scoop for PAS, and Macleods offers
measuring spoons for PAS-sodium,
both of which allow for a moreaccurate paediatric dosage. Thesespoons are product-specific andcannot be interchanged.
HIV co-infection
No antiretroviral interaction studies
have been performed, but basedon the pharmacokinetic profile ofPAS, drug interactions are unlikely.
Studies should be performed toconfirm this.

PARA-AMINOSALICYLIC ACID (PAS) and PARA-AMINOSALICYLATE SODIUM (PAS-sodium) GROUP 4

SPOTLIGHT ON ACCESS ISSUES

31

CLOFAZIMINE (Cfz) GROUP 5

CLOFAZIMINE (Cfz)
GROUP 5

GENERAL INFORMATION• Therapeutic Class: Phenazine Derivative.
•A TC Code: J04BA01.36• Included in the WHO Guidelines
as a Group 5 medicine (agentswith unclear efficacy).37• Included in the 19th edition of the
WHO Model List of Essential Medicines(as an anti-leprosy medicine)23 andin the 5th edition of the WHO Model
List of Essential Medicines for Children

Clofazimine is indicated in the(as an anti-leprosy medicine),38 but

treatment of lepromatous leprosy,

not yet included for TB indication.

including dapsone-resistant• Presentations available: 50mg
and 100mg soft-gel capsules.
• First approved by US FDA:
15 December 1986.57

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

32

Novartis

GDF pooled procurement

Quality status

SRA approved

GDF Quality Assurance Policy

50mg soft-gel
capsuleManufacturer did not agree
to publish prices

0.547-0.713

100mg soft-gel
capsuleManufacturer did not agree
to publish prices

1.095-1.267

Médecins Sans Frontières | March 2016

• Approved indication in US:

lepromatous leprosy and lepromatous
leprosy complicated by erythemanodosum leprosum.57

Clofazimine is a Group 5 medicine which is mainly used in patients with pre-XDR-TB and XDR-TB. With no official
indication for DR-TB, and owing to its effectiveness in TB having not been clearly established, in 2014 Novartis
filed an Investigational New Drug application with the US FDA linked to a clinical development programme forclofazimine for a potential DR-TB indication. The 2011 WHO programmatic guidelines37 recommend the use ofclofazimine for patients with MDR or XDR-TB, when there are no other options available.
However, clofazimine is a key component of a shortened nine-month regimen, and recent systematic reviewssuggest that clofazimine could be considered as an additional therapeutic option in the treatment of DR-TB.58
Novartis does not make this drug available for DR-TB treatment on the basis of a lack of efficacy and safety data,and owing to concerns over liability for off-label use. Because the company donates clofazimine to WHO as partof a multi-drug co-blistered therapy for leprosy59, Novartis did not submit a price for this publication.

CLOFAZIMINE (Cfz) GROUP 5

SPOTLIGHT ON ACCESS ISSUESAs TB programmes’ demand for this drug has increased, WHO has been in discussion with Novartis since 200860
to address the liability for off-label use and patient safety of clofazimine when used to treat TB, and for the drug
to become available for MDR and XDR-TB treatment.
Eight years on, the difficulties in accessing clofazimine for DR-TB treatment remain acute61, with no plan fortechnology transfer for the finished product formulation to another manufacturer having been announced.
Novartis needs to ensure a secure, affordable supply of clofazimine for use in DR-TB treatment, or provide
the necessary details for a technology transfer to allow another manufacturer to take over the supply of
quality-assured clofazimine. The evaluation of a DR-TB indication for clofazimine will take several years.
In the meantime, as recommended by WHO, clofazimine is needed for patients with MDR or XDR-TB thathave not been cured with other options.
Number of quality sources
Clofazimine produced by Sandoz
India for Novartis is currently thesole quality-assured source of the
drug. Although there are additional
manufacturers in India and Europe,
there has been very little effort toidentify a second potential qualityassured source in order to ensure
access to clofazimine for DR-TB.

Evolution in pricePrice is not currently a barrier forpatients to access clofazimine,
but rather Novartis’s restrictive
approach to the supply of this drug,
which it reserves exclusively forleprosy treatment.
The GDF catalogue lists clofazimine
at 100mg and 50mg strengths.
The product can be procured for
non-leprosy use on a named-patientbasis only. With this caveat, it can beprocured at a price of US$1.10 per
100mg capsule and $0.55- $0.71 per
50mg capsule through Pharmaworld,a supplier in Switzerland.63,64

In order to send a clear message
to manufacturers that clofazimine
is needed, the drug was includedin the WHO Prequalification 13th
Expression of Interest in August
2015. Clofazimine is also includedin the joint GDF/Global Fund
Invitation to Manufacturers to
submit an Expression of Interest for
the evaluation of products by theExpert Review Panel.62

Paediatrics
The safety and effectiveness ofclofazimine in children has notbeen established.

As demand for clofazimine is
expected to grow in light of
the increased use of shortened
regimens, there is a need foralternative quality-assured sourcesof the drug other than the existingNovartis product, which is noteasily available.

While dosages are publishedin several guidelines, there
is an urgent need for further
research (pharmacokinetics,
pharmacodynamics, safety data)
into the use of this drug in younger
populations, in particular in children
aged under five years.

DR-TB Drugs Under the Microscope

A 50mg soft-gel capsule is currently
available, but this formulation
makes it impossible to fraction thedose for children.
HIV co-infection
Clofazimine may have a significant
drug-drug interaction with someantiretrovirals. No studies have been
performed, but clofazimine is a weak
inhibitor of the CYP3A4 metabolism
pathway and may increase levels ofprotease inhibitors and etravirine.
Special caution
Clofazimine can affect cardiac
conduction (QT prolongation).
QT prolongation can infrequently
result in a serious (rarely fatal)
fast/irregular heartbeat, known
as torsades de point. This is an
important consideration as several
other drugs, such as moxifloxacin,delamanid and bedaquiline have asimilar risk and it is unclear if thiswill be an additive effect.

33

LINEZOLID (Lzd) GROUP 5

LINEZOLID (Lzd)
GROUP 5

GENERAL INFORMATION• Therapeutic Class:Oxazolidinone antibiotic.
• ATC Code: J01XX08.

• Approved indication in US: Linezolid isof the WHO Model List of Essential
Medicines23 and in the 5th editionof the WHO Model List of Essential
Medicines for Children with atuberculosis indication.38

36• Included in the WHO Guidelines
as a Group 5 medicine (agentswith unclear efficacy).37

indicated for treatment of susceptible
strains of designated microorganisms
for nosocomial pneumonia; andcomplicated and uncomplicated skinand skin structure infections. It is• Presentations available: 600mg tablet;
100mg/5ml powder for suspension.

• L inezolid has been included forthe first time in the 19th edition

not indicated for the treatment ofGram-negative infections and• First approved by US FDA: 18 April 2000.57

community-acquired pneumonia.65

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

PfizerGDF pooled procurement

Quality status

SRA approved

Under evaluation
by WHO PQ

SRA approved

GDF Quality
Assurance policy

600mg tablet

5.800

5.500

Manufacturer did not agree
to publish prices

5.350-5.480

100mg/ml powder
for suspension

xx

xx

Manufacturer did not agree
to publish pricesxx

SPOTLIGHT ON ACCESS ISSUESWith capreomycin and PAS, linezolid is one of the three medicines which weigh heavily in the overall cost of a DR-TB regimen.
Although linezolid has no official indication for DR-TB treatment, the 2011 WHO programmatic guidelines
recommend the use of linezolid as a Group 5 drug37 for patients with MDR or XDR-TB, when there are no otheroptions available. In April 2012, a systematic review outlined the efficacy of linezolid in DR-TB treatment.66 Data has
also been presented at international conferences, and small case series reports have been published.67 The literature
review has allowed the WHO Expert Committee to add linezolid to the WHO EML with a DR-TB indication.
Linezolid has a relatively high number of adverse side effects, including myelosuppression, anaemia, and irreversible
peripheral and optical neuropathies. Nonetheless, linezolid plays a pivotal role in the treatment of patients with XDRTB.68 The use of linezolid is expected to grow with the increased use of new drugs bedaquiline and delamanid, due tothe importance of not adding a single (new) drug to a failing regimen, and due to linezolid’s lack of a QT effect.
Number of quality sources
Currently two manufacturers –Pfizer and Hetero – are approvedby a stringent regulatory authority.
In addition, Macleods and one
further source are under WHO
PQ evaluation.
Teva had a ‘First To File’ status forlinezolid with the US FDA – which
provides 180 days of generic drug
exclusivity on the market before

34

Médecins Sans Frontières | March 2016

other generic companies can enter
the market with their own products– and subsequently launched theirgeneric linezolid on the US market atthe end of June 2015, with no plans
to supply other markets. A further
five manufacturers (Mylan, Glenmark,Amneal, Alkem and Gate Pharma)
have tentative approval from the US
FDA. The primary patent on linezolid
expired at the end of 2014 in mostcountries, including in the USA.

Nevertheless, due to Teva’s ‘First
to File’ status giving them market
exclusivity on linezolid for six
months, other generic companies
will be able to market their own
product only from January 2016;
Mylan has since launched theirgeneric linezolid.69
Apotex Canada is also anothersource of quality-assured linezolid
supplying only the CanadianLinezolid is included in the 13th
WHO Prequalification Expression ofInterest (since August 2015) withtwo dosages, 600mg coated tablet
and 150mg dispersible tablet.
In case of severe anaemia andsevere peripheral neuropathy,
patients should be switched from a
600mg to a 300mg dose; there isa need for 600mg scored tablets or
300mg strength tablets.
Evolution in price
Although the primary patent has
expired in the US and most othercountries, the cost of the drug is
extremely high. Patients failingconventional DR-TB treatment but who
could have a chance to survive throughthe use of linezolid are often denied
this option due to the prohibitively
expensive cost of the drug.
In South Africa, for example, theprice of Pfizer-produced linezolid in
the private sector is ZAR655 (US$47)
per tablet. With the treatment
duration using linezolid lasting
on average four to six months,
this takes the cost per patient oflinezolid alone to around $10,000
to $15,000 – to which the cost ofother medicines in the regimen
needs to be added. Considering
the current commitment by theSouth African Ministry of Health tostart 3,000 patients on bedaquiline
before the end of 2016, and theneed of linezolid as a companion
drug to bedaquiline, the high cost oflinezolid will remain a limiting factor
for scale up.
The availability of more qualityassured generic sources of linezolid
and the increase in order volumes
have changed matters somewhat.
Although the price has decreased
by 22% since 2013, the price still
remains high, with the current
lowest price at $5.35 per tablet.

Patents
The basic patent claiming linezolid
was filed by Upjohn Company*in the US in 1993 and expired in
201470 in the US and China. In
South Africa, the key patents onlinezolid71 also expired in 2014.
Upjohn Company also filed patents
in the US on a crystalline form
II which will expire in the US by2021.72 The crystalline form patenthas been rejected in Brazil, haslapsed in South Africa, and hasceased in China, but it remains
valid in India until 2021.73
There is also a tablet formulation
patent filed in the US in 2001.74
This tablet formulation patent has
been granted in India and China75,
and will remain valid until 2021.
However, the same patent on thetablet formulation has lapsed inSouth Africa due to non paymentof fees76, has lapsed and been
withdrawn from the European
Patent Office77, and has lapsed in
Brazil due to non payment of fees.78
In India, the basic compound patent
could not be filed in 1993 since
India’s patent law did not allow forpharmaceutical product patenting
at the time. However, as mentioned
above, the patent applications on
the crystalline form II and the tablet
formulation, which have been
rejected, lapsed, withdrawn or ceasedin other countries, have been granted
in India and will only expire in
2021.79 However, none of these block
generic competition. Several Indian
generic companies produce the API
and have been marketing genericversions of linezolid for several years.
More recently, a patent on aprocess which is more economical
for the preparation of linezolid
has led to a legal dispute among
generic companies. Symed Labs –a subsidiary of Hetero Drugs – hasenforced its API process-related
patents (IN213062 and IN213063)
against Glenmark, Alkem andother companies, and successfully
obtained injunctions against them.
This patent dispute was finallysettled when Alkem and Glenmark
committed to not infringe thepatented process in the productionof linezolid. Currently Hetero
Drugs therefore holds considerable
control over the most efficient
process of API production.80
As of November 2015, theMedicines Patent Pool (MPP) has
a mandate to negotiate voluntary
licences for TB drugs. There isno indication yet whether Pfizer
or other companies that own
secondary patents will provide
broad, public health-friendly
voluntary licences to the MPP thattake into account all remaining
secondary patents for linezolid
which may block some genericproducers – especially those in
China and India – in producing andentering into a particular market.

LINEZOLID (Lzd) GROUP 5

market. The availability of additional
quality-assured sources for DR-TB
patients is required to address theneeds of DR-TB programmes foraffordable sources of this product.

Paediatrics
Pharmacokinetic studies have been
completed in children from birth,and dosages are approved by the
US FDA exclusively for infections
with gram-positive bacteria
resistant to other antibiotics.
A paediatric formulation exists as asolution for suspension, produced
by Pfizer. The reconstituted
product can be stored at room
temperature. Although linezolid
150mg dispersible tablet has been
introduced in the Expression ofInterest of the WHO PQ, no dossier
has been submitted yet.
There is a need for further safety
and efficacy data on the use oflinezolid for extended periods inchildren with DR-TB.
HIV co-infection
No antiretroviral interaction
studies have been performed but
interactions are unlikely. Theremay, however, be an increased
risk of myelosuppression andmitochondrial toxicities withlong-term use in combination withcertain antiretrovirals (zidovudine,stavudine, didanosine). Further
studies are required to confirm this.

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

DR-TB Drugs Under the Microscope35

BEDAQUILINE (Bdq) NEW DRUG/GROUP 5

BEDAQUILINE (Bdq)
NEW DRUG/GROUP 5
GENERAL INFORMATION•T herapeutic Class: diarylquinoline(first-in-class) with bactericidal
and sterilising activity against
Mycobacterium tuberculosis orother mycobacterial species.81

MDR-TB in June 201383; bedaquiline
was allocated to Group 5 drugs.

•A TC Code: J04AK05.82• Bedaquiline has been included
for the first time in the 19thedition of the WHO Model Listof Essential Medicines.23•W HO issued interim guidelines on
the use of bedaquiline to treat• Presentations available:
100mg tablet.

• First conditionally approved by
US FDA: 28 December 2012.84• Approved indication in US: Treatmentof multidrug-resistant pulmonary
tuberculosis in adults. Bedaquiline isindicated for treatment of pulmonary
multidrug-resistant tuberculosis aspart of combination therapy only
when an effective treatment regimen
cannot otherwise be provided.85

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

GDF pooled procurement

Quality status

SRA approved*

GDF Quality Assurance policy

100mg tablet

Tiered pricing based on disease burden andaffordability. Please refer to both GDF and/or
USAID donation program.

Free of charge (donation)* Bedaquiline received US FDA accelerated approval on the basis of phase IIb clinical trial data.

SPOTLIGHT ON ACCESS ISSUES
Bedaquiline received conditional approvalby the US FDA in late December 2012
based on Phase II clinical trial data.
Janssen Pharmaceuticals are required tosubmit additional clinical data for the
drug to receive full FDA approval.86
The first compound in the diarylquinoline
class, bedaquiline’s novel mechanism ofaction inhibits mycobacterial adenosine
5’-triphosphate (ATP) synthase. The
drug is intended as part of combination
therapy for DR-TB, and it inhibits bothactively replicating and non-replicating
wild-type and resistant M. tuberculosis.
In placebo-controlled studies of MDR
and XDR-TB patients (including
those co-infected with HIV), 79%of patients given bedaquiline had
negative TB cultures after 24 weeks.
Culture conversion happened 33%
faster in patients taking bedaquiline
as compared to the standard WHOrecommended MDR-TB regimen.87,83
There are concerns around safety
however. During drug trials, 10 out of
79 patients in the bedaquiline groupdied, compared to 2 out of 81 patients

36

Médecins Sans Frontières | March 2016

in the standard treatment group.
Although many of these deaths are
attributed to TB itself, the difference issignificant and a source of concern, andneeds careful future monitoring as theuse of bedaquiline increases. Assessingthese concerns should form part ofphase III trials.
WHO issued interim guidelines on theuse of bedaquiline to treat MDR-TB
in June 2013.83 The scale up ofprogrammatic use of bedaquiline has
been slow but is increasing, with just over
2,300 patients on bedaquiline as part ofprogrammatic use as of February 2016.15
At this time there is no evidence on
the safety and efficacy of combining
bedaquiline with delamanid, andcurrently there is no recommendation
regarding their combination. Drugdrug interaction studies are due tocommence in early 2016 to look at the
cardiac safety of combining these two
drugs with QT prolongation potential.88
Number of quality sources
Janssen is currently responsible for all
global manufacturing of bedaquiline.

When greater numbers of patients arereached worldwide in the future, Janssen
may look into engaging with other global
partners for production and/or marketing.
Bedaquiline has received approvals
in 9 out of the 27 high MDR-TB
burden countries – where 60% of
total patients from the high burdencountries live – Russia, India, South
Africa, Philippines, Peru, South Korea,
Turkmenistan, and Armenia, and has
ongoing submissions in 9 of 27 high
MDR-TB burden countries (covering
a further 20% of total patients fromhigh burden countries). Bedaquiline
has recently been registered by
the Indian Central Drugs Standard
Control Organisation for use in thetreatment of multidrug-resistant TB
under the strict supervision of the
Revised National Tuberculosis Control
Program. Sale or supply of bedaquilinein the private sector is not allowed.
The file to register bedaquiline has been
rejected in Kyrgyzstan due to a lack ofphase III clinical studies. In addition,
Janssen entered into a licensing
agreement with Pharmstandard toPrices
Janssen officially announced a donation
programme for bedaquiline on 11
December 201489, where over the next
four years, they will donate 30,000
treatment courses of bedaquiline. From
1 April 2015, bedaquiline orderedthrough the Global Drug Facility is free
if procured for countries eligible for
the Janssen donation (eligible countries
are Global Fund-eligible countries for
TB grants), with South Africa being
excluded from the donation.
Janssen communicated for the
purposes of this report that it will be
implementing a three-tiered pricing‘framework’, in an attempt ‘to balancea country’s ability to pay with theburden of disease’ for countries that are
not eligible for Global Fund grants.90
Countries will be classified into threegroups, which initial communication
with the company suggests will belabelled ‘high-income’, ‘upper middleincome’, and ‘least-developed/resourcelimited’. For a six-month treatment
course, a country in the high-income
bracket would pay US$30,000, acountry in the upper middle-income
bracket would pay $3,000, and acountry in the least-developed/resourcelimited bracket would pay $900. Janssen
points to the fact that its proposed
pricing for the middle and lower pricing
tiers is aligned with a WHO-sponsored
cost effectiveness assessment of
bedaquiline.91
Janssen have indicated that countries
will be classified in the ‘framework’
both according to World Bank grossnational income per capita definitions
and according to disease burden as
per the WHO’s MDR- and XDR-TB
2010 Global Report on Surveillance
and Response. However, the company
was unwilling to divulge placementof individual countries in the threerespective groups until regulatory
efforts had concluded (and, whereapplicable, ‘following completionof reimbursement processes’). It
remains to be seen what pricing will
be offered to countries like China
which is simultaneously a high-burden
TB country and in the upper middleincome bracket.
Patents
Bedaquiline is a newly approved drugand UNITAID has published a patent

DR-TB Drugs Under the Microscopelandscape report of its patent status inmajor developing countries.92
The base compound patent on
bedaquiline has been granted inIndia, China and South Africa, which
will expire between 2023-2025.93
The patent application on the basecompound remains pending in Brazil.94
The basic patent has also been
granted in several countries including
Armenia, Azerbaijan, Kazakhstan,
Russia, Tajikistan, Ukraine and anumber of African Intellectual Property
Organisation (ARIPO) and Organisation
Africaine de la Propriété Intellectuelle(OAPI) countries.94
In India, the patent office has granted
the compound patent on bedaquiline– IN236811 – to Janssen which will expire
in 2023. Generic manufacturers are notkeen to develop the drug unless they
are provided a licence to market andsupply developing countries. Janssen has
filed several other types of evergreening
patent applications for bedaquiline that,
if granted, would further extend Janssen’smonopoly and restrict the timely entry ofaffordable generic versions in India andmany developing countries. The patenton the use of bedaquiline in treating DRTB (6315/DELNP/2006) has been granted(IN264718) and this patent expires onlyin May 2025.95 This patent has also been
granted in South Africa, but remains
pending in China and Brazil.94
The Indian application on the salt form
(1220/MUMNP/2009) was opposed
in March 2013 by the Network of
Maharashtra People Living with HIV(NMP+), and the decision is awaited.96
This patent remains pending in China
and Brazil, but has been granted inSouth Africa.94
Another patent application covering theprocess of preparation of bedaquiline,
including its API, is pending, and if
granted will expire in 2026.97 This patent
has also been granted in South Africa andChina, but remains pending in Brazil.94
It is also important to note that
bedaquiline is included in patents fortuberculosis combination therapies.
These patents, such as WO2010026526,
can potentially block the development of
new treatment regimens.98 This patentis pending in several countries and if
granted it would not lapse before 2029.
Given the patent barriers on bedaquiline
both as a standalone treatment andas a part of combination therapies, aproactive strategy will be needed tomitigate access challenges.
Secondary and follow-on patents
are a typical problem in the area ofpharmaceuticals and such patents often
extend monopolies even after the expiry

of compound patents. This problem canpartially be addressed by applying strict
patentability criteria and by proactively
challenging secondary patents. In Indiaand in other countries where suchstrategies can be employed, pre-grant
oppositions of patent applications by
third parties on secondary patents
for bedaquiline will therefore be an
important strategy to avoid patent term
extensions beyond the expiry of thebasic patent in 2023.
In addition, some governments – andparticularly India, where the productpatent blocks the manufacture ofgenerics even for export to countries
where there is no applicable patent –will have to decide whether to employ
compulsory licensing to enable theproduction, use and export of more
affordable generic versions.

BEDAQUILINE (Bdq) NEW DRUG/GROUP 5

register and commercialise
bedaquiline in the Commonwealthof Independent States as well as inGeorgia, Turkmenistan and Ukraine.
By the end of 2015 Janssen announced
it was phasing out its compassionate
use programmes, which had been the
major access channel of bedaquiline
until its donation came into effect.

As of November 2015, the Medicines
Patent Pool (MPP) has been given
a mandate to negotiate voluntary
licences for TB drugs.99 There is no
indication yet whether Janssen will
negotiate a voluntary licence with
the MPP that will include a broad
geographic scope that includes all
low- and middle-income countries.
Paediatrics
The safety and effectiveness of
bedaquiline in children has notbeen established.
There is an urgent need for further
research (pharmacokinetics,
pharmacodynamics, safety data) into theuse of this drug in younger populations,in particular in children aged under five
years. Paediatric studies are planned aspart of the paediatric development planrequired for the company to complete
the regulatory approval process.100,101
There is no paediatric formulation
currently available.
HIV co-infection
Early research shows that efavirenz
interacts with bedaquiline by reducing
its blood concentration, while
lopinavir/ritonavir slightly increases theconcentration of the drug.
More detailed studies are required.
Special caution
Bedaquiline can affect cardiac
conduction (QT prolongation). QT
prolongation can infrequently resultin a serious (rarely fatal) fast/irregularheartbeat, known as torsades de point.
This is an important consideration
as several other drugs (such as
moxifloxacin and delamanid) andrepurposed TB drugs (clofazimine) havea similar risk and it is unclear if this will
be an additive effect.

37

DELAMANID (Dlm) NEW DRUG/GROUP 5

DELAMANID (Dlm)
NEW DRUG/GROUP 5
GENERAL INFORMATION• Therapeutic Class: nitroimidazole (Nitrodihydro-imidazo-oxazole derivative).
•A TC Code: J04AK06.82•W HO issued interim guidelines on
the use of delamanid to treat MDRTB in October 2014. Delamanid wasallocated to Group 5 drugs.102• Approved indication in EMA:
“as part of an appropriate
combination regimen for pulmonary
multidrug-resistant tuberculosis in
adult patients when an effective
treatment regimen cannot otherwise
be composed for reasons ofresistance or tolerability.”32• Delamanid was included for the firsttime in the 19th edition of the WHO
Model List of Essential Medicines.23• Presentations available: 50mg film
coated tablets.
• Approved in April 2014 by theEuropean Medicines Agency (EMA).32

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

Quality status

SRA approved*

GDF Quality Assurance policy

50mg film
coated tablet

Manufacturer has not made pricing strategy public
for non Global Fund-eligible countries

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

SPOTLIGHT ON ACCESS ISSUES
Delamanid received approval fromthe European Medicines Agency(EMA) and Japan’s Pharmaceuticals
Medical Devices Agency (PMDA)
in 2014. Delamanid, previously
OPC-67863, is a drug of thedihydro-nitroimidazole class andis thought to primarily inhibit
synthesis of methoxy-mycolic andketo-mycolic acid, components ofthe mycobacterial cell wall.
Clinical trial data come fromthree related Phase IIb studies
on the same cohort of MDR-TB
patients (Trial 204, Trial 208 andObservational Study 116). Thesestudies showed promising results
amongst patients who received
6-8 months of treatment withdelamanid, compared to those who
received 0-2 months of delamanid,
with significantly higher proportion

38

Médecins Sans Frontières | March 2016

The Phase III trial to assess efficacy
against MDR-TB using six monthsof delamanid added to a WHOrecommended Optimal Background
Regimen has recently completed
recruitment and results are
expected late 2017/early 2018.

In February 2016, Otsuka andthe GDF announced a price of $1,700
per treatment course, available
to Global Fund-eligible countries
through the GDF.31 However, withdelamanid currently registered in justJapan, South Korea and the European
Union, programmatic access in themedium term will remain extremely
difficult, while in the short term,
most countries will have to issue
import waivers.

WHO issued interim guidelines
on the use of delamanid to treat
MDR-TB in November 2014. The
scale up of the use of delamanid has
been slow, with just 180 patients on
delamanid outside of clinical trials
as of February 2016. The majorityof patients who have accessed
delamanid have done so throughcompassionate use programmes.

At this time there is no evidence
on the safety and efficacy of
combining delamanid withbedaquiline, and there is norecommendation regarding their
combination. Drug-drug interaction
studies are due to commence inearly 2016 to look at the cardiac
safety of combining these two drugs
with QT prolongation potential.103

of favourable outcomes (cure ortreatment completed) (75.5%
versus 55%) and lower mortality(1% versus 8.3%).

The working statement (Form 27)
related to the patents on the drug,
as submitted to the Indian patentoffice, reveals a startling fact - thatthe patented invention is not being
worked in India. The working
statement also shows that neither
is it being imported from anyother country, nor there are any
applicable licences or sub-licenceson the invention.

Number of quality sources
Delamanid has received approval
only from the EMA, Japan andSouth Korea. Registration has been
submitted in China and Hong Kong.

The patent on the base compoundof delamanid has also been granted
in China, South Africa and the US,
and will expire between 2023-2025.94
The patent application remains
pending in Brazil.94 In addition, there
is one patent on the compositionof delamanid and its derivative
forms104, and another patent on the
combination of delamanid and othercompounds105, have been granted inIndia, China and South Africa, andremain pending in Brazil.60 These
patents will remain valid until 2026.94

Patents
The originator company Otsuka
has applied multiple patents
upon delamanid.
India - a key producer of TB drugs has granted the compound patenton delamanid (IN250365) to Otsuka
Pharmaceutical Ltd, which is set to
expire in 2023. By granting the salt
form patent (9790/DELNP/2009)of the drug (an obvious form), thepatent office has already extended
the monopoly an additional three
years, from 2023 to 2026. Anotherapplication (1255/KOLNP/2008) on
its use in combination with otherdrugs has been also granted.
Further, Otsuka, which holds
multiple Indian patents (DELcompound IN250365, DEL salt form
IN253642 and DEL combination
IN268015) for this drug, has also
not exerted itself to work the patentin India by filing for registration,
doing necessary local trials or
making the drug available to thenational TB programme, eventhough over three years have lapsed
since the grant of the patents.

DR-TB Drugs Under the Microscope

A number of other secondary
patents on delamanid may also
add to the obstacles in introducing
generic products into the market.
In particular, two patents covering
the process of producing delamanidintermediates have been granted
in India and China, and will remain
valid until 2023-2025.106,107 A
separate patent on the process of
preparation of delamanid has also
been granted in India and China,
and will expire in 2025.108 In China,
an additional patent on delamanidintermediate has also been granted
and will expire in 2031.109
As of November 2015, the Medicines
Patent Pool (MPP) has been given
with a mandate to negotiate
voluntary licences for TB drugs.

There is no indication yet whether
Otsuka will negotiate a voluntary
licence with the MPP that will
include a broad geographic scopethat includes all low- and middleincome countries.
Paediatrics
The safety and effectiveness ofdelamanid in children has notbeen established.
Paediatric studies are currently
underway. Bioequivalence studies
have been completed. Patient
cohorts have commenced enrolment
with data submitted for 6 to 15
years old age group, commencing
enrolment for the 3 to 5 years oldcohort and 0 to 3 years old groups.

DELAMANID (Dlm) NEW DRUG/GROUP 5

PricesThe GDF price for Global Fund-eligible
countries is $1,700 per treatment
course.31 Given that delamanid is justone drug combined with multiple
other drugs needed to form a DR-TB
regimen, this price is prohibitively
expensive for most high-burdencountries. The manufacturer has notdisclosed the pricing strategy for non
Global Fund-eligible countries.

There is a paediatric formulation
under development.
HIV co-infection
Early research shows delamanid
does not have a significant effecton concentrations of tenofovir,
lopinavir–ritonavir, or efavirenz.
Lopinavir plus ritonavir however,
was associated with a 20% increasein delamanid exposure and a 30%
increase in delamanid’s metabolite
DM-6705.110
More detailed studies are required.
Special caution
Delamanid can affect cardiac
conduction (QT prolongation).
QT prolongation can infrequently
result in a serious (rarely fatal)
fast/irregular heartbeat, known
as torsades de point. This is an
important consideration as several
other drugs (such as moxifloxacin
and bedaquiline) and repurposed
TB drugs (clofazimine) have asimilar risk and it is unclear if thiswill be an additive effect.

39

ANNEX 1: SUMMARY TABLE OF PRICES PROVIDED BY PHARMACEUTICAL COMPANIESANNEX 1: SUMMARY TABLE OF PRICES PROVIDED BY PHARMACEUTICAL COMPANIESThe price corresponds to the price of one unit (tablet, capsule, etc.).
Please refer to Annex 2 for the conditions of eligibility set by individual companies, and for the incoterms associated with these prices.
Drug

GDF pooled
procurement

AMIKACIN

GDF

CadilaCipla

Pharmatex

Vianex

500mg/2ml solution
for injection

0.678-0.805

0.980

1.600

0.678

2.500

Macleods

Meiji

Panpharma

KANAMYCIN

Companies

1g powder for injection

1.000-1.721

1.000

xx

Manufacturer did not agree
to publish prices

1g/4ml solution for
injection

2.560

xx

Manufacturer did notagree to publish prices

xx

Akorn

Aspen

Hisun

Macleods

Vianex

8.000

8.100

Manufacturer did not agree
to publish prices

4.150

6.000

Cipla

HeteroMacleods

Microlabs

Sunpharma
0.510

CAPREOMYCIN
1g powder for injection

3.800-4.700

MOXIFLOXACIN
400mg tablet

0.437-0.540

LEVOFLOXACIN

0.600

0.660

0.580

Manufacturer did notagree to publish prices

Apotex*

Cipla

HeteroLabatec

Macleods

Microlabs

250mg tablet

0.033-0.055

0.090

0.061

0.059

1.538

0.043

0.057

500mg tablet

0.059-0.097

0.130

0.110

0.105

2.315

0.078

0.092

750mg tablet

0.100

0.150

xx

0.240

xx

0.128

xx

Macleods

Cipla

Lupin

Macleods

Microlabs

0.112

xx

xx

xx

xx

0.098

Manufacturer did not agree
to publish prices

0.066

0.082

ETHIONAMIDE
125mg tablet

xx
0.062-0.080

xx

PROTHIONAMIDE

Fatol

Lupin

Microlabs

Olainfarm

250mg tablet

0.130-0.178

Manufacturer did not agree topublish prices

Manufacturer did notagree to publish prices

0.120

0.100

Cipla

Dong-A

Macleods

Microlabs

Strides0.187-0.330

Price was not available at timeof data collection

0.216

0.390

Manufacturer did notagree to publish prices

0.600

TERIZIDONE

Fatol

Macleods

250mg capsule1.588-1.666

Manufacturer did not agree topublish prices

0.850

250mg tabletCYCLOSERINE
250mg capPAS
4g sachet

Jacobus

1.333

PAS-SODIUM

1.500
Macleods

Olainfarm

1.690

1.690

xx

60% w/w granules –100g jar

18.36018.360xx

Powder for oral solution –5.52g sachet

1.370

xx

1.400

60% w/w granules –9.2g sachet

CLOFAZIMINE

Novartis

50mg soft-gel capsule0.547-0.713

Manufacturer did not agree topublish prices

100mg soft-gel capsule

1.095-1.267

Manufacturer did not agree topublish prices

LINEZOLID

HeteroMacleods

Pfizer600mg tablet

5.350-5.480

5.800

5.500

Manufacturer has not madepricing strategy public

100mg/ml powder
for suspension

xx

xx

xx

Manufacturer has not madepricing strategy public

BEDAQUILINE

Janssen

100mg tablet

0.00(donation)

Tiered pricing based on disease
burden and affordability. Pleaserefer to both GDF and/or USAID
donation program

DELAMANID
50mg film coated tab

Otsuka2.530

Manufacturer has not madepricing strategy public for non
Global Fund-eligible countries* Incoterm CIF
40

Médecins Sans Frontières | March 2016

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

Eligibility(countries)

Eligibility(bodies)

Additional comments

Deliveryof goods

AKORN

Price is eligible outside US andCanada only

No restriction

Min. purchase: one batch

Ex-works

APOTEX

No restriction

No restriction

CIF by air to airportof destination

ASPEN

South Africa only

No restriction

Ex-works

CADILAAll countries except European
countries & USA

No restriction

CIPLA

Generic accessible countries

Public sector

Price is valid until
November 2016

Ex-works
Ex-works

DONG-A

Ex-works

FATOL

No restriction

No restriction

Ex-works

HETERONo restriction

No restriction

Ex-works

JACOBUSNo restriction

No restriction

Ex-works

JANSSEN

All countries

In low- and middle-income
countries, bedaquiline is madeavailable through the Global Drug
Facility. Alternatively, for selected
middle- and high-income countries
bedaquiline is also supplied
through the local Janssen affiliate
directly to the MoH/NTP (ordesignated purchasing entities).

LUPIN

All countries where GDF, MSF,
UNDP, PAHO or Damien aresupplying TB medicines to MoH
and/or specific projects.

All institutional buyers,
including GDF, MSF, PAHO,UNDP and Damien.

Ex-works

MACLEODS

Prices are subject to volumes andregistrations. Macleods will not ship
to countries where products areunder patent. Macleods will not ship
to countries where products are notregistered, without a registration waiver.

Prices are subject to volumes.
Macleods has no restrictions inselling products to any customer.

Ex-works

MICROLABS

No restriction

No restriction

Ex-works

OLAINFARM

No restriction

No restriction

Ex-worksOTSUKANo price communicatedNo restriction

Ex-works

PHARMATEXNo restriction

No restriction

Ex-works

SUNPHARMANo restrictions as long as goods areimported against an import permit
or a valid registration in that country.

No restriction

Ex-works

VIANEX

No restriction except USA

No restriction

Ex-works

As of 1st April 2015, USAID
and Janssen have jointly
announced a four-year
bedaquiline donation
program. For further
details on eligibility pleaserefer to http://www.stoptb.
org/gdf/drugsupply/
bedaquiline.asp

ANNEX 2: CONDITIONS OF OFFER, AS QUOTED BY COMPANIESANNEX 2: CONDITIONS OF OFFER, AS QUOTED BY COMPANIESDelivery of goods isdone in a majorityof cases via the
Global Drug Facility.
Please refer directly
to the GDF for full
information.

LABATEC

PANPHARMA

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

DR-TB Drugs Under the Microscope

41

ANNEX 3: COMPANY CONTACTS

ANNEX 3: COMPANY CONTACTS
This section reports the contact details of companies that have been contributing with price information to this publication.
Akorn
Lana Vostrova
Associate Director, Global Business Development
1925 West Field Court, Suite 300,
Lake Forest, Illinois 60045 USA
Tel: +1 631 789 8228 (ext. 4185)
E-mail: lana.vostrova@akorn.com
Apotex
Patti BlackManager, International Tenders
150 Signet Drive, Toronto,
Ontario Canada M9L 1T9
Tel: +1 416 401 7345
E-mail: pblack@apotex.com
Aspen
Stavros Nicolaou
Senior Executive, Strategic Trade Development
Building 7, Healthcare Park, Woodlands
Drive, Woodmead, Sandton, 2196 South Africa
Tel: +2 711 239 6798
E-mail: SNicolaou@aspenpharma.com
CadilaSupreet Sharma
Manager, International Business
Cadila Pharmaceuticals Ltd, Sarkhej Dholka Road,
Bhat, Ahmedabad - 382210, Gujarat, India
Tel: +91 27 18225001
E-mail: supreet.sharma@cadilapharma.co.in
Cipla
Mr. Sharadd Jain, Mr. Rahul Lande
Global Institutional Business
Cipla Ltd, 289, Belasis Road,
Mumbai Central, Mumbai-08, India
Tel: +91 22 2302 5387, 5686
E-mail: sharadd.jain@cipla.com
rahul.lande@cipla.com
Dong-APatch Lee
Regional Manager
64, Cheonho-daero, Dongdaemun-gu,
Seoul, South Korea
Tel: +82 2 920 8683
E-mail: ljs@donga.co.kr
Fatol
Ulrike Wandt
International Business
RIEMSER Pharma GmbH, Site Fatol
Arzneimittel, Robert-Koch-Strasse,
66578 Schiffweiler, Germany
Tel: +49 30 33 84 27 411
E-mail: wandt@riemser.com

42

Médecins Sans Frontières | March 2016

HeteroPrashant Sisodia
Vice President, International Marketing
Hetero Labs Ltd, Hetero Corporate, 7-2-A2,
Industrial Estates, Sanath Nagar,
Hyderabad-500 013, Telangana, India
Tel: +91 40 23704923/24/25
E-mail: prashant.s@heterodrugs.com

Microlabs
N.K.Kothari
President, International Operations
Microlabs Ltd, No.11 Bank Street,
Kilpauk, Chennai 600010, India
Tel: +91 44 26450789, 26471205
E-mail: nkkothari@microlabs.in,nkkothari@hotmail.com

JacobusLaura Jacobus
Vice President
Jacobus Pharmaceutical Co. Inc.,
37 Cleveland Lane, Princeton,
New Jersey 08540 USA
Tel: +1 609 921 7447 (Ext. 208)
E-mail: lrjacobus@aol.com

Olainfarm
Mrs. Elena Vasilevskaya
Senior Manager, Business Development Division
5 Rupnicu Street, Olaine LV-2114, Latvia
Tel: +371 67013745
E-mail: evasilevskaja@olainfarm.lv,
olainfarm@olainfarm.lv

JanssenRoss Underwood
Global Access Commercial Leader
Janssen Pharmaceuticals Inc,
1000 U.S. Route 202 South, Raritan,
New Jersey 08869 USA
Tel: +1 908 722 5393
E-mail: runderw@its.jnj.com
Labatec
Faisal Darwazeh
General Manager
31 Rue du Cardinal Jounet,
1217 Meyrin, Switzerland
Tel: +41 5937825
E-mail: faisal.darwazeh@labatec.ch
Lupin
Srikant Kulkarni/Mukul Jerath
Senior Vice President-Exports/
General Manager-Global Institutional Business
Lupin Limited, Laxmi Towers, B Wing,
4th Floor, Bandra Kurla Complex,
Bandra (East), Mumbai, India 400086
Tel: +91 22 66402242
E-mail: shrikantkulkarni@lupinpharma.com
mukuljerath@lupin.com
Macleods
Vijay Agarwal
Business Development Director
Macleods Pharmaceuticals Lts,
304 Atlanta Arcade, Andheri Kurla Road,
Andheri East, Mumbai, 400099 India
Tel: +91 22 61132900
E-mail: vijay@macleodspharma.com

OtsukaMarc Desito
Communications Director
7 Rue du Mont-Blanc, 1201 Geneva,
Switzerland
Tel: +41 22 5607960
E-mail: communication@otsuka.ch
PanPharma
Gildas Blonsard
Sales Manager
ZI du Clairay 35133 Luitré, France
Tel: +33 299979212
E-mail: panpharma@panpharma.fr
Pharmatex
Antonio Sergio Tripodi
CEO
Pharmatex Italia Srl, Via Appiani,
22-20121 Milan, Italy
Tel: +39 02 29000410
E-mail: info@pharmatex.it
Sunpharma
Ravi Mehta
Head of Global ARV Business
Sun Pharmaceutical Industries Ltd, 201 B/1,
Western Express Highway, Georegaon [E],
Mumbai 400063, India
Tel: +91 22 43244324
E-mail: ravi.mehta@sunpharma.com
VianexMrs. Lemonia Xenitos
Export Director
Tatoiou Street, 18th km National Road
Athens-Lamia, 146 71 Athens, Greece
Tel: +30 210 800 9634
E-mail: xenitoul@vianex.gr

1. World Health Organization. Global
tuberculosis report 2015 [Online]. Geneva;
WHO: 2015 [cited 2016 Jan 19]. Available
from: http://www.who.int/tb/publications/
global_report/en/
2. MSF. First new TB drugs in half a century
reach just 2% of people who need them.
Press Release. 3 December 2015. [Cited
2016 Jan 27]. Available from: http://www.
msfaccess.org/about-us/media-room/pressreleases/first-new-tb-drugs-half-centuryreach-just-2-people-who-need-them
3. MSF. Out of Step 2015: TB policies in 24
countries [Online]. Geneva; MSF: 2015 Nov[cited 2016 Jan 27]. Available from: http://
www.msfaccess.org/content/report-out-step2015-tb-policies-24-countries
4. MSF. DR-TB Drugs Under the Microscope.
March 2011 [cited 2016 Jan 27]. Available
from: https://www.msfaccess.org/our-work/overcoming-barriers-access/article/888
5. Dooley KE, Obuku EA, Durakovic N,
Belitsky V, Mitnick C, Nuer¬mberger EL.
World Health Organization group 5 drugs forthe treatment of drug-resistant tuberculosis:
unclear efficacy or untapped potential?
J Infect Dis. 2013;207(9):1352–1358.
doi:10.1093/infdis/jis460.
6. Cox H, Ford N. Linezolid for thetreatment of complicated drug-resistanttuberculosis: a systematic review andmeta-analysis. Int J Tuberc Lung Dis.
2012;16(4):447–454. doi:10.5588/
ijtld.11.0451.
7. Hill, J. South Africa is coughing up
too much money for DR-TB treatment[Online]. MSF 2016 [cited 2016 Jan 19].
Available from: http://www.nspreview.
org/2015/11/30/south-africa-is-coughingup-too-much-money-for-dr-tb-treatment/
8. Knoetze, D. The need for medicines for
drug-resistant [Online]. Ground Up: 2014
Nov 26 [cited 2016 Jan 19]. Available
from: http://www.groundup.org.za/article/
the_need_for_medicines_for_drug_resistant_
tb_2475/
9. Gotham D et al. Target generic prices
for novel treatments for drug-resistanttuberculosis.15th European AIDS
Conference, Barcelona, abstract PS2/4,
2015 [cited 2015 Oct 30].
10. Nunn A, Rusen I, Van Deun A, Torrea G,
Phillips P, Chiang C, S Bertel Squire, Madan J
and Meredith K. Evaluation of a standardized
treatment regimen of anti-tuberculosis drugs forpatients with multi-drug-resistant tuberculosis(STREAM): study protocol for a randomized
controlled trial. Trials 2014, 15:353
11. Lessem, E. Tuberculosis drug
development hobbles forward. I-base: 2014
Jul 19 [cited 2016 Jan 19]. Available from:http://i-base.info/htb/26985

12. RESIST-TB. DR-TB Clinical Trials Progress
Report [Online]. Updated 2015 October 19[cited 2015 Nov 9]. Available from: http://
www.resisttb.org/?page_id=1602
13. Brigden G, Hewison C, Varaine H. New
developments in the treatment of drugresistant tuberculosis: clinical utility of
bedaquiline and delamanid. Infection andDrug Resistance [Online]. 2015 October
30 [cited 2015 November 2]. Available
from: https://www.dovepress.com/newdevelopments-in-the-treatment-of-drugresistant-tuberculosis-clini-peer-reviewedarticle-IDR (p. 372)
14. Ndjeka N, Conradie F, Schnippel K, et al.
Treatment of drug-resistant tuberculosis withbedaquiline in a high HIV prevalence setting:an interim cohort analysis. Int J Tuberc Lung
Dis 19(8):979-985. 2015 [cited 2015 Nov 4]
15. DR-TB STAT Update, January 2016.
For more information on DR-TB STAT, see:
http://www.stoptb.org/wg/mdrtb/taskforces.
asp?tf=4
16. Sampson S. What needs to be added
to South Africa’s anti-TB toolbox. The
Conversation [Online] 2015 May 15[Cited 2015 Nov 2]. Available from:http://theconversation.com/what-needsto-be-added-to-south-africas-anti-tbtoolbox-40538; Department of Health,Republic of South Africa. Invitation to Bid
HP02-2015AI/01: Supply and Deliveryof Anti-infective Medicines (Antibiotics,
Antifungal, Antiprotozoal and Antiviral
Agents) to the Department of Health for the
Period Up to 30 September 2017 [Online].
2015 August 28 [cited 2015 Nov 2].
Available from: http://www.health.gov.za/
tender/docs/tenders/HP022015AI01Bid.pdf
17. Médecins Sans Frontières. Letter tothe Department of Health of South Africa.
2 March 201518. Mukadi YD. Bedaquiline Donation
Program & USAID’s Perspectives on
Introduction and Access to New Drugs[Online]. 2015 April 27 [cited 2015 Oct 30].
Available from: http://www.stoptb.org/wg/
gli/assets/documents/M7/2.%20MUKADI_
bdg%20donation%20programme%20
USAID.pdf
19. USAID. USAID To Reach Patients In MoreThan 100 Countries With Life-saving Medicine
for Drug-resistant Tuberculosis [Online]. 2015
October 19 [cited 2015 Oct 30]. Available
from: https://www.usaid.gov/what-we-do/
global-health/tuberculosis/resources/newsand-updates/usaid-reach-patients-more-100
20. World Health Organization Global TB
Programme. NewsFlash: An initiative toextend access to a new TB drug [Online].
2015 April 28 [cited 2015 Oct 29]. Available
from: http://us8.campaign-archive1.com/?u=f093a7c38a3780cd9504f8d9d&id=e5f466b
b8a&e=f946a4a378

21. Médecins Sans Frontières. MSF responseto announcement of Otsuka’s donation
programme for the TB drug delamanid[Online]. 2015 April 29 [cited 2015 Oct 29].
Available from: http://www.msfaccess.org/
about-us/media-room/press-releases/msfresponse-announcement-otsukas-donationprogramme-tb-drug

REFERENCESREFERENCES

22. World Health Organization. 8th Invitation
to manufacturers of Active Pharmaceutical
Ingredients (API) to submit an Expression ofInterest (EOI) for API evaluation to the WHO
Prequalification Team—Medicines [Online]
2015 August. [cited 2015 Oct 30]. Available
from: http://apps.who.int/prequal/info_
applicants/eoi/2015/API-EOI_V8_1.pdf
23. World Health Organization. WHO Model
List of Essential Medicines (19th Edition).
[Online] 2015 August [cited 2015 Oct29]. Available from: http://www.who.int/
selection_medicines/committees/expert/20/
EML_2015_FINAL_amended_AUG2015.
pdf?ua=1
24. National Center for Biotechnology
Information. PubChem Compound
Database; CID=2761171. [cited 2015 Oct29]. Available from: https://pubchem.ncbi.
nlm.nih.gov/compound/thioamide
25. International Union Against Tuberculosisand Lung Disease. STREAM clinical trial totest first all-oral MDR-TB treatment regimen[Online]. [cited 2015 Oct 29]. Available
from: http://www.theunion.org/what-we-do/
research/clinical-trials
26. ClinicalTrials.gov. A Phase 2 OpenLabel Partially Randomized Trial to Evaluate
the Efficacy, Safety and Tolerability ofCombinations of Bedaquiline, Moxifloxacin,
PA-824 and Pyrazinamide in Adult Subjects
With Drug-Sensitive or Multi Drug-ResistantPulmonary Tuberculosis. (NC-005) [Online].
Global Alliance for TB Development: 2016
January [cited 2016 Jan 19]. Available
from: https://clinicaltrials.gov/ct2/show/
NCT02193776
27. ClinicalTrials.gov. Shortening
Treatment by Advancing Novel Drugs(STAND) [Online]. Global Alliance for TB
Development: 2016 January [cited 2016 Jan
19]. Available from: https://clinicaltrials.gov/
ct2/show/NCT02342886
28. MSF. TB Practecal: innovating MDR-TB
treatment [Online]. [cited 2016 Jan 19].
Available from: www.msf.org.uk/tb-practecal
29. Partners in Health, Médecins
Sans Frontières, Interactive Research& Development. The endTB Project:
Expanding New Drugs for TB [Online].
2015 April 29 [cited 2015 October 29].
Available from: http://www.stoptb.org/
wg/gli/assets/documents/M7/3.%20RICH_
endTB%20Project.pdf (of the 16 countries,
MSF will be the implementing partner in
7: Armenia, Belarus, Georgia, India, Kenya,
Kyrgyzstan, Myanmar)

Continued overleaf
DR-TB Drugs Under the Microscope

43

REFERENCES

References continued

30. Médecins Sans Frontières. The 3P Project.
[cited 2016 Jan 19]. Available from: http://www.
msfaccess.org/spotlight-on/3p-project-newapproach-developing-better-treatments-tb
31. Stop TB Partnership. Stop-TB
Partnership’s Global Drug Facility jumpstarts
access to new drugs for multidrug-resistanttuberculosis with innovative publicprivate partnerships. 2016, February 24.
[Online] cited 2016 February 24. Available
from: http://www.eurekalert.org/pub_releases/2016-02/stpu-spg022416.php
32. European Medicines Agency.
Deltyba - Opinion. 2013, November
22. [Online]. Cited 2016 February
25. Available from: http://www.ema.
europa.eu/ema/index.jsp?curl=pages/
medicines/human/medicines/002552/
smops/Positive/human_smop_000572.
jsp&mid=WC0b01ac058001d127
33. World Health Organization.
Prequalification of Medicines Programme[Online]. 2016 [cited 2016 Jan 19]. Available
from: http://apps.who.int/prequal/
36. World Health Organization/NorwegianInstitute for Public Health. ATC/DDD Index
2013 [Online]. World Health Organization
Collaborating Centre for Drug Statistics
Methodology; Geneva, 2012, December 20[cited 2016 Jan 19]. Available from: http://
www.whocc.no/atc_ddd_index/
37. World Health Organization. Guidelines
for the programmatic management of drugresistant tuberculosis - 2011 update [Online].
WHO; Geneva, 2011 [cited 2016 Jan 19].
Available from: http://whqlibdoc.who.int/
publications/2011/9789241501583_eng.pdf
38. World Health Organization. WHO Model
List of Essential Medicines for Children,
5th edition, Revised April 2013 [Online].
WHO; Geneva, April 2015 (Revised August2015) [cited 2016 Jan 19]. Available from:http://who.int/medicines/publications/
essentialmedicines/en/index.html
39. US FDA. Amikacin overview. [Online].
United States Food and Drug Administration.
[cited 2016 Jan 19] Available from: http://
www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
Overview&DrugName=AMIKACIN%20
SULFATE
40. Drugs.com. Amikacin official FDA
information, side effects and uses. [Online]
2007, December [cited 2016 Jan 19].
Available from: http://www.drugs.com/pro/amikacin.html
41. Drugs.com. Kantrex official FDA
information, side effects and uses [Online].
2006, March [cited 2016 Jan 19]. Available
from: http://www.drugs.com/pro/kantrex.html
42. World Health Organization. Guidance
for national tuberculosis programmes on
the management of tuberculosis in children.
2nd Edition [Online]. WHO; Geneva, 2014[cited 2016 Jan 19]. Available from: http://
apps.who.int/medicinedocs/documents/
s21535en/s21535en.pdf

44

Médecins Sans Frontières | March 201643. Sentinel Project on Pediatric DrugResistant Tuberculosis. Management ofmultidrug-resistant tuberculosis in children:a field guide. 2nd Edition [Online]. Boston,
2015 [cited 2016 Jan 19]. Available from:http://sentinel-project.org/wp-content/
uploads/2015/11/Field_Handbook_2nd_Ed_
revised-no-logos_07Jul15.pdf
44. US FDA. Approved product label: USFDA
Capastat [Online]. United States Food andDrug Administration. 2008, January 14 [cited
2016 Jan 19]. Available from: http://www.
accessdata.fda.gov/scripts/cder/drugsatfda/
index.cfm?fuseaction=Search.DrugDetails
45. US FDA. Cycloserine drug product details[Online]. United States Food and Drug
Administration [cited 2016 Jan 19]. Available
from: http://www.accessdata.fda.govscripts/
cder/drugsatfda/index.cfm
46. US FDA. Highlights of prescribing
information: Avelox [Online]. United States
Food and Drug Administration. 2011, January[cited 2016 Jan 19]. Available from: http://
www.accessdata.fda.gov/drugsatfda_docs/lab
el/2011/021085s047,021277s041lbl.pdf
47. Espacenet. Crystal modification of
CDCH a process for its preparation andpharmaceutical formulations comprising
this modification [Online]. Munich:European Patent Office; 2012 September
24 [cited 16 Oct 2015]. Available from:http://worldwide.espacenet.com/
publicationDetails/biblio?DB=worldwide.
espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19981215&C
C=US&NR=5849752A&KC=A
48. Espacenet. Pharmaceutical moxifloxacin
preparation [Online]. European Patent Office,2012 September 24 [cited 16 Oct 2015]
Available from: http://worldwide.espacenet.
com/publicationDetails/biblio?DB=worldwide.
espacenet.com&II=0&ND=3&adjacent=true&
locale=en_EP&FT=D&date=20030826&CC=U
S&NR=6610327B1&KC=B1
49. United States Food and Drug
Administration. Orange Book: Approved
Drug Products with Therapeutic Equivalence
Evaluations [Online]. US FDA [cited 16
Oct 2015]. Available from: http://www.
accessdata.fda.gov/scripts/cder/ob/docs/
queryai.cfm
50. Thee S, Garcia-Prats A, Donald P,
Hesseling A, Schaaf H. Fluoroquinolones forthe treatment of tuberculosis in children.
Tuberculosis. 2015;95(3):229-245.
51. US FDA. Levofloxacin drug details.
[Online]. United States Food and Drug
Administration [cited 2016 Jan 19]. Available
from: http://www.accessdata.fda.gov/scripts/
cder/drugsatfda/index.cfm
52. US FDA. Trecator (ethiomanide tablets,
USP) [Online] United States Food and Drug
Administration. 2005, December (revised)[cited 2016 Jan 19]. Available from: http://
www.accessdata.fda.gov/drugsatfda_docs/
label/2006/013026s024lbl.pdf

53. Axel A, Dr. Personal Communication with
Karen Day. [E-mail]. 2011, March 11.
54. Terizidone product specifications
provided to MSF by RIEMSER Arzneimittel
AG, Germany, 2011, June 6.
55. US FDA. Cycloserine drug productdetails. [Online]. United States Food andDrug Administration [cited 2016 Jan 19].
Available from: http://www.accessdata.fda.
govscripts/cder/drugsatfda/index.cfm
56. US FDA. Paser drug details. [Online].
United States Food and Drug Administration[cited 2016 Jan 19]. Available from: http://
www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
DrugDetails
57. US FDA. Linezolid drug details [Online].
United States Food and Drug Administration[cited 2016 Jan 19]. Available from: http://
www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
Overview&DrugName=LINEZOLID
58. Gopal M, Padayatchi N, Metcalfe
JZ, O’Donnell MR. Systematic review ofclofazimine for the treatment of drugresistant tuberculosis. Int J Tuberc Lung
Dis [Online]. 2013 [cited 2013 Oct04];17(8):1001-1007. Available from: http://
www.ncbi.nlm.nih.gov/pubmed/23541151
doi: 10.5588/ijtld.12.0144
59. World Health Organization. Use ofclofazimine for treating ENL reactions inleprosy [Online]. Geneva: World HealthOrganization; [cited 2016 Jan 19]. Available
from: http://www.who.int/lep/mdt/
clofazimine/en/index.html
60. Direct communication from Novartis;
no public source available
61. World Health Organization. 2nd
Global Green Light Committee Meeting
Report [Online]. Geneva: World HealthOrganization; 2012 Feb [cited 2016 Jan
19]. Available from: http://www.who.int/
tb/challenges/mdr/greenlightcommittee/
Meetingreport2ndgGLCmeeting.pdf
62. Global Drug Facility/Global Fund. Global
Fund (GF) and Global Drug facility (GDF)
Invitation to manufacturers of first, second
and third-line anti-tuberculosis medicines
to submit an Expression of Interest (EoI) for
product evaluation by Expert Review Panel(ERP) [Online]. Geneva: Global Drug Facility/
Global Fund; 2013 Jul 10 [cited 2016 Jan
19]. Available from: www.theglobalfund.org/
documents/psm/psm_eoiantitberp_rfp_en/
63. Global Drug Facility. GDF ProductCatalogue [Online]. Geneva: Global Drug
Facility; [cited 2016 Jan 19]. Available from:http://www.stoptb.org/gdf/drugsupply/
drugs_available.asp
64. Pharmaworld. Clofazimine [Online].
Pharmaworld; [cited 2016 Jan 19]. Available
from: https://www.pharmaworld.com/en/
products/product-news.html

66. Sotgiu G, Centis R, D’Ambrosio L,
Alffenaar J, Anger H, Caminero J et al.
Efficacy, safety and tolerability of linezolid
containing regimens in treating MDR-TB
and XDR-TB: systematic review and metaanalysis. European Respiratory Journal.
2012;40(6):1430-1442.
67. Myungsun Lee, M.D., Jongseok Lee,
Ph.D., Matthew W. Carroll, M.D., et al.
Linezolid for Treatment of Chronic Extensively
Drug-Resistant Tuberculosis. New England
Journal of Medicine. 2012; 367:1508-1518
68. Lee M, Song T, Kim Y, Jeong I, Cho
S, Barry C. Linezolid for XDR-TB — Final
Study Outcomes. New England Journal of
Medicine. 2015;373(3):290-291.
69. Mylan. Mylan Launches Generic Zyvox®
Tablets - Dec 29, 2015 [Online]. 2016[cited 2016 Jan 19]. Available from: http://
newsroom.mylan.com/2015-12-29-MylanLaunches-Generic-Zyvox-Tablets
70. Espacenet. Substituted oxazine andthiazine oxazolidinone antimicrobials. [Online]
European Patent Office [cited 2012 Jul 31]
Available from: http://v3.espacenet.com/
publicationDetails/biblio?DB=EPODOC&adjac
ent=true&locale=en_EP&FT=D&date=199503
16&CC=WO&NR=9507271A1&KC=A1
71. South African Companies and Intellectual
Property Commission. Online Patent
Search Facility, Official publication number
1994/05894. Available from:http://patentsearch.cipc.co.za
72. WO/2001/057035, PCT/
US2001/000657, Linezolid-Crystal Form II,
expiring in approximately January 2021.
Wipo Patentscope, available from: https://patentscope.wipo.int/search/en/detail.jsf?do
cId=WO2001057035&redirectedID=true
73. India patent number IN/
PCT/2002/00871/MUM. Available fromhttp://ipindiaservices.gov.in/publicsearch/
74. WO/2001/070225, PCT/
US2001/005812, Oxazolidinone Tablet
Formulation. Wipo PatentScope. Available
from: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001070225&recNu
m=1&maxRec=&office=&prevFilter=&sortO
ption=&queryString=&tab=PCT+Biblio. The
equivalent US Patent is 6514529.
75. India patent number IN/
PCT/2002/01181/MUM. Available
from: http://ipindiaservices.gov.in/
publicsearch/, China patent number:
CN1208058C(CN01806469.8), available tosearch from: http://www.pss-system.gov.cn/
sipopublicsearch/enportal/index.shtml
76. South Africa patent number
ZA2002/0707. Available from: http://patentsearch.cipc.co.za/patents/
patentresult.aspx

77. EP1265608, European Patent Register.
Available from: https://register.epo.org/app
lication?number=EP01916186&lng=en&ta
b=legal[cited 2016 Jan 2016]; 56(6):3271–6.
Available from: http://www.ncbi.nlm.nih.
gov/pubmed/22391540 doi: 10.1128/
AAC.06126-11

78. Espacenet. BR0108846 (A) ― 2003-05-06,
Oxazolidinone Tablet Formulation. Available
from: http://worldwide.espacenet.com/
publicationDetails/inpadoc?CC=BR&NR=010
8846A&KC=A&FT=D&ND=3&date=200305
06&DB=&locale=en_EP

88. Verbal presentation from the 46th Union
Conference on Lung Health, Cape Town, 2-6
December 2015

79. India patent number IN/
PCT/2002/00871/MUM and IN/
PCT/2002/01181/MUM. Available fromhttp://ipindiaservices.gov.in/publicsearch/
80. Glenmark Pharmaceuticals Limited &Anr V Symed Labs Limited. 17 July, 2015.
Available from: http://delhihighcourt.nic.in/
dhcqrydisp_o.asp?pn=140133&yr=2015
81. Matteelli A, Carvalho AC, Dooley KE,
Kritski A. TMC207: the first compound of a
new class of potent anti-tuberculosis drugs.
Future Microbiol [Online]. 2010 [cited 2016
Jan 19]; 5(6):849-58. Available from: http://
www.ncbi.nlm.nih.gov/pubmed/20521931
doi: 10.2217/fmb.10.50
82. WHO Collaborating Centre for Drug
Statistics Methodology. New ATC [Online].
Geneva: World Health Organization [updated
2013 Jul 16, cited 2016 Jan 19]. Available
from: http://www.whocc.no/atc/ lists_of_
new_atc_ddds_and_altera/new_ atc/?order_
by=1lastconsulted15.8.2013
83. World Health Organization. WHO interim
guidance on the use of bedaquiline to treat
MDR-TB [Online]. Geneva: World HealthOrganization; 2013 Jun 13 [cited 2016 Jan
19]. Available from: http://www.who.int/
mediacentre/news/notes/2013/bedaquiline_
mdr_tb_20130613/en/
84. USFDA Center for Drug Evaluation
and Research. Application Number:
204384Orig1s000 Summary Review[Online]. USFDA; [cited 2016 Jan
19]. Available from: http://www.
accessdata.fda.gov/drugsatfda_docs/
nda/2012/204384Orig1s000SumR.pdf
85. US FDA. FDA news release – bedaquiline.
[Online]. USFDA; 2012 Dec 31 [cited
2016 Jan 19] Available from: http://
www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm333695.htm
86. US Food and Drug Administration.
Antimicrobial Drugs Advisory Committee(formerly known as the Anti-Infective Drugs
Advisory Committee) [Online]. USFDA,
2015 [cited 2016 Jan 2016]. Available from:http://www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/AntiInfectiveDrugsAdvisoryCommittee/default.htm
87. Diacon AH, Donald PR, Pym A,
Grobusch M, Patientia RF, Mahanyele R, etal. Randomized pilot trial of eight weeks
of bedaquiline (TMC207) treatment for
multidrug-resistant tuberculosis: longterm
outcome, tolerability, and effect on
emergence of drug resistance. Antimicrob
Agents Chemother [Online]. 2012 Jun

REFERENCES

65. US FDA. Zyvox drug details. [Online]
United States Food and Drug Administration.
2010, June (revised) [cited 2016 Jan 19]
Available from: http://www.accessdata.fda.
gov/scripts/cder/drugsatfda/index.cfm

89. Market Watch. Johnson & Johnson
Announces Collaboration between
Janssen and USAID to Expand Access to
Anti-Multidrug-Resistant Tuberculosis(MDR-TB) Compound [Online]. Johnson& Johnson 2014 [2016 Jan 20]. Available
from http://www.marketwatch.com/story/johnson-johnson-announces-collaborationbetween-janssen-and-usaid-to-expandaccess-to-anti-multidrug-resistanttuberculosis-mdr-tb-compound-201412-11?reflink=MW_news_stmp
90. Personal communication from Janssen,
September 2015
91. World Health Organization. Cost –effectiveness of introducing bedaquiline in
mdr‐tb regimens – an exploratory analysis[Online]. WHO; London, 2013. [cited 2016
January 20]. Available from: http://www.
who.int/tb/challenges/mdr/CEA_bdqreport_
final.pdf
92. UNITAID. A review of the bedaquiline
patent landscape, 2014 [Online]. Available
from: http://www.nitaid.eu/images/
marketdynamics/publications/TMC_207_
Patent_Landscape.pdf
93. Espacenet. Quinoline Derivatives andTheir Use as Mycobacterial Inhibitors[Online]. European Patent Office; [cited 2013
August 12] Available from: http://worldwide.
espacenet.com/publicationDetails/biblio?CC=WO&NR=2004011436&KC=&FT=E&local
e=en_EP
94. Information based on MSF’s own patent
searches and patent landscape prepared by
I-MAK for UNITAID (forthcoming); on filewith MSF
95. WO/2005/117875, PCT/EP2005/052371,
India patent number: 6315/DELNP/2006.
India patent database InPass. Available from:http://ipindiaservices.gov.in/publicsearch/
96. India patent number: 1220/
MUMNP/2009. India patent database InPass.
Available from: http://ipindiaservices.gov.in/
publicsearch/
97. WO/2006/125769, PCT/EP2006/062502,
India patent number: 9746/DELNP/2007.
India patent database InPass. Available from:http://ipindiaservices.gov.in/publicsearch/
98. Espacenet. Combination therapy fortuberculosis. [Online] European Patent
Office. [cited 2013 August 12] Available
from: http://worldwide.espacenet.com/
publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true&locale=en_EP&FT=
D&date=20100311&CC=WO&NR=2010026
526A1&KC=A1

Continued overleaf
DR-TB Drugs Under the Microscope

45

REFERENCES / ABBREVIATIONS

References continued

99. Medicines Patent Pool. The medicines
patent pool expands mandate to hepatitis
c and tuberculosis treatment [Online].
Geneva; MPP: 2015 November 6 [cited
2016 Jan 19]. Available from: http://www.
medicinespatentpool.org/the-medicinespatent-pool-expands-mandate-to-hepatitis-cand-tuberculosis-treatment/
100. Dooley K, Park J, Swindells S,
Allen R, Haas D, Cramer Y et al. Safety,
Tolerability, and Pharmacokinetic
Interactions of the Antituberculous Agent
TMC207 (Bedaquiline) With Efavirenz
in Healthy Volunteers. JAIDS Journal of
Acquired Immune Deficiency Syndromes.
2012;59(5):455-462.
101. Dooley K, Kim P, Williams S, Hafner
R. TB and HIV Therapeutics: Pharmacology
Research Priorities. AIDS Research andTreatment. 2012;2012:1-9.
102. World Health Organization. WHOinterim guidance on the use of delamanidin the treatment of MDR-TB. [Online] WHO;
Geneva, 2014. [cited 2016 January 22].
Available from: http://www.who.int/tb/
features_archive/delamanid/en/

103. Personal communication at the 46th
Union Conference on Lung Health, CapeTown, 2-6 December 2015
104. WO/2007/013477, PCT/JP2006/314708,
pharmaceutical composition comprising
2,3-dihydro-6-nitroimidazo [2,1-b] oxazole
derivatives. Wipo PatentScope. Available from:https://patentscope.wipo.int/search/en/detail.
jsf?docId=WO2007013477&recNum=1&max
Rec=&office=&prevFilter=&sortOption=&quer
yString=&tab=PCT+Biblio
105. WO/2007/043542, PCT/JP2006/320239,
antituberculous composition comprisingoxazole compounds. Wipo PatentScope:
https://patentscope.wipo.int/search/en/detail.
jsf?docId=WO2007043542&recNum=2&offic
e=&queryString=ALL%3A%28PCT%2FJP2006%2F320239%29&prevFilter=&sortOption=Pu
b+Date+Desc&maxRec=2
106. WO/2004/035547, PCT/
JP2003/013134, 1-substituted
4-nitroimidazole compound and process
for producing the same. Wipo PatentScope:
https://patentscope.wipo.int/search/en/
detail.jsf?docId=WO2004035547&recNum=
2&office=&queryString=ALL%3A%28PCT%2
FJP2003%2F013134%29&prevFilter=&sortO
ption=Pub+Date+Desc&maxRec=2

107. WO/2005/077913, PCT/
JP2005/002668, method for producing
4-nitroimidazole compound. Wipo
PatentScope: Available from: https://patentscope.wipo.int/search/en/detail.jsf?do
cId=WO2005077913&redirectedID=true
108. WO/2005/092832, PCT/
JP2005/006408, method of producing
aminophenol compounds. Wipo
PatentScope. Available from: https://patentscope.wipo.int/search/en/detail.jsf?do
cId=WO2005092832&redirectedID=true
109. WO/2011/093529, PCT/
JP2011/052307, Chinese Patent Number:
CN102725269, synthetic intermediateof oxazole compound and method for
producing the same. Wipo PatentScope:
https://patentscope.wipo.int/search/en/
detail.jsf?docId=WO2011093529&recNum=
2&office=&queryString=ALL%3A%28PCT%2
FJP2011%2F052307%29&prevFilter=&sortO
ption=Pub+Date+Desc&maxRec=2
110. Lynch J, Szumowski J. Profile ofdelamanid for the treatment of multidrugresistant tuberculosis. DDDT. 2015;:677.

ABBREVIATIONSANDA – Abbreviated New Drug
Application
API – Active pharmaceutical ingredient
API PQ – Active Pharmaceutical
Ingredient-Prequalification
CEWG – Consultative Expert
Working GroupCIS – Commonwealth of
Independent States
DR-TB – Drug-resistant tuberculosis
DS-TB – Drug-sensitive tuberculosis
EMA – European Medicines Agency
EML – Essential Medicines List
EoI – WHO Prequalification
Expression of Interest
ERP – Expert Review Panel
EU – European Union

46

GDF – Global Drug Facility

PAS – Para-aminosalicylic acid

GFATM – Global Fund to Fight AIDS,
Tuberculosis and Malaria

PIH – Partners In Health

GLC – Green Light Committee

R&D – Research and development

HIV – Human immunodeficiency virus

SRA – Stringent regulatory authority

IDR – Interactive Research& Development

TB – Tuberculosis

IP – Intellectual property
LIC – Low-income countries
MDR-TB – Multidrug-resistanttuberculosis
MCC - Medicines Control Council(South Africa)
MIC – Middle-income countries
MRC – Medical Research Council (UK)MSF – Médecins Sans Frontières

FDC – Fixed-dose combination

NMRA – National Medicine
Regulatory Authority

GLI – Global Laboratory Initiative

NGO – Non-governmental organisation

Médecins Sans Frontières | March 2016

PQ – Prequalification

TDR-TB – Totally drug-resistanttuberculosis
TRIPS – (Agreement on) Trade-Related
Aspects of Intellectual Property Rights
USAID – US Agency forInternational Development
US FDA – US Food and Drug
Administration
w/w – weight for weight
WHO – World Health Organization
WHO PQ – World Health Organization
Prequalification Programme
XDR-TB – Extensively drug-resistanttuberculosisAbbreviated New Drug
Application (ANDA)
An Abbreviated New Drug Application(ANDA) contains data that, whensubmitted to the US FDA, 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 efficacy. Instead,a generic applicant must scientificallydemonstrate that its product isbioequivalent (i.e. performs in thesame manner as the innovator drug).
Once approved, an applicant may
manufacture and market the genericdrug product to provide a safe,
effective, low-cost alternative in the US.
Bangladesh trial/regimen
A non-randomised observational study
in Bangladesh which looked at a ninemonth combination of existing TBdrugs for the treatment of MDR-TB. The
study regimen included ethambutol,
pyrazinamide, gatifloxacin andclofazimine throughout, supplemented
by kanamycin, prothionamide and highdose isoniazid in the first four months.
Active pharmaceutical ingredient (API)Any substance or mixture of substances
intended to be used in the manufactureof a pharmaceutical dosage form andthat, when so used, becomes an active
ingredient of that pharmaceutical
dosage form.
CIF: Cost, Insurance and Freight(named port of destination)
A commercial term (incoterm 2010),
meaning that the seller must pay
the costs and freight to bring thegoods to the port of destination.
Risk is transferred to the buyer once
the goods are loaded on the vessel.
Insurance for the goods is included
and paid by the seller; only maritime
transports are covered.
CIS: Commonwealth of
Independent States
The Commonwealth of Independent
States is a regional organisation formed
during the breakup of the Soviet Union,
whose participating countries are someformer Soviet Republics.
Clinical trials
Sets of tests in medical research anddrug development that generate safety
and efficacy data (including information
about adverse drug reactions andadverse effects of other treatments)
for health interventions (e.g., drugs,
diagnostics, devices, therapy protocols).
Compassionate Use
The terms “compassionate use,”“expanded access” or “special access”
programmes have essentially the same
meaning. They refer to programmesthat are intended to provide potentiallylifesaving experimental treatments
to patients suffering from a disease
for which no satisfactory authorised
therapy exists and/or who cannot entera clinical trial. It refers to programmesthat make medicinal products available
either on a named-patient basis or tocohorts of patients. Compassionate
use needs to be framed within national
legislation that establishes underwhat conditions the drug is madeavailable. Refer to Annex 5 (Use ofexperimental drugs outside of clinical
trials “compassionate use”) of the
WHO Guidelines for the programmaticmanagement of drug-resistanttuberculosis: Emergency update 2008.
CultureBacterial culture is a laboratory method
to multiply bacteria in order to assess
their presence or not in a patient’s
sample. This is done by letting thebacteria grow in predetermined culture
media under controlled laboratory
conditions, outside the naturalenvironment 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, the bacteria is said tobe resistant to the drug (as opposed todrug-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 multiplication ofbacteria in the body and can therefore
clear the infection. The strains of TB
which are sensitive to all first-line drugs
are called drug-susceptible.
Ex-works
A commercial term (incoterm 2010)
meaning that the seller delivers when
the goods are placed at the disposalof the buyer at the seller’s premises
or another 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 technical experts,
hosted by the WHO Department ofEssential Medicines and Pharmaceutical
Policies. Their purpose is to review thepotential risks and benefits associatedwith the use of antiretroviral, anti-TB andantimalarial products which are not yet
WHO-prequalified or authorised by astringent regulatory authority. The ERP
makes recommendations to the Global
Fund and the Global Drug Facility on
whether procurement of such products
can be authorised. The recommendation
is valid for a period of no more than 12
months or until the product is either
WHO-prequalified or SRA-authorised.
(http://www.theglobalfund.org/en/
procurement/quality/pharmaceutical/).

GLOSSARYGLOSSARY

Extensively drug-resistant TB
see XDR-TB
Extra-pulmonary TB
Form of TB where M. tuberculosis
infects parts of the body other thanthe lungs. This occurs most commonlyin the lymph 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 four drugs are usually chosen:
isoniazid (H), rifampicin (R), ethambutol(E), pyrazinamide (Z). These drugs arehighly effective in drug-susceptible TB
and patients usually tolerate them well.
Streptomycin (S) injectable is used infirst-line treatment of TB meningitis.
Global Drug Facility (GDF)
A mechanism hosted by UNOPS toexpand access to, and availabilityof, quality-assured anti-TB drugs
and diagnostics through pooled
procurement. Products procured comply
with the GDF’s Quality Assurance
policy, which deems eligible for GDF
procurement all products that areincluded on the WHO List of Prequalified
Medicinal Products, that are approvedby a stringent regulatory authority, orthat are temporarily approved by theExpert Review Panel.
Global FundThe Global Fund to Fight AIDS,
Tuberculosis and Malaria is aninternational financing institution thatinvests in 150 countries to support largescale prevention, treatment and careprograms against the three diseases.
Continued overleaf

DR-TB Drugs Under the Microscope

47

GLOSSARY

Glossary continued

Green Light Committee (GLC)
The GLC Initiative was created in2001 to help countries gain accessto quality-assured second-line antiTB drugs so they could provide
treatment for people with multidrugresistant tuberculosis in line with the
WHO guidelines, the latest scientificevidence and country experiences.
The Initiative originally consistedof a secretariat, the GLC (an expert
review and WHO advisory body) and
the Global Drug Facility (the drug
procurement arm of the Initiative). As
of 2011, GLC approval is no longer
needed to procure quality-assured
second-line TB drugs through GDF.
GLC was restructured in June 2011
into a Global GLC (gGLC) and regional
GLC (rGLC) to focus on monitoring
and technical assistance to National TB
programmes in countries and WHO.
Microscopy
Microscopy is currently the mostcommonly used technique to diagnose
TB. Two to three sputum samples aretaken from the patient and the sample
is stained and later read under the
microscope. If TB bacilli are present,
they occur in the form of small red rods,
while the rest of 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 andisoniazid, are said to have multidrugresistant TB, or MDR-TB.
Mycobacteria
Types of bacteria, of the genus
Mycobacterium, that cause diseases
such as TB and leprosy.
M. Tuberculosis
Mycobacterium tuberculosis
A pathogenic bacterial species of
the genus Mycobacterium andthe causative agent of most casesof TB. First discovered in 1882 byRobert Koch.
New Drug Application (NDA)
When the sponsor of a new drug
believes that enough evidence on the
drug’s safety and efficacy has beenobtained to meet US FDA requirements
for marketing approval, the sponsor
submits to US FDA a new drug
application (NDA). The application must
contain data from specific technicalviewpoints for review, including
chemistry, pharmacology, medical,
biopharmaceutics, and statistics. If the
NDA is approved, the product may bemarketed in the United States.

48

Médecins Sans Frontières | March 2016

Pharmacokinetic (PK)
Branch of pharmacology that studies
the mechanisms of absorption anddistribution of an administered drug,
the rate at which a drug action begins
and the duration of the effect, thechemical changes of the substance inthe body (e.g. by metabolic enzymes)
and the effects and routes of excretionof the metabolites of the drug.
Pharmacovigilance
The science and activities relating to thedetection, evaluation, understanding
and prevention of adverse drug reactions
or any other drug-related problems.
Pharmacodynamic (PD)
Branch of pharmacology that studies
the biochemical and physiologicaleffects of drugs on the body or on
microorganisms or parasites withinor on the body and the mechanismsof drug action and the relationshipbetween drug concentration and effect.
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-of-care
testing is having a test as convenientto the patient as possible and giving
immediate results that can lead toprompt initiation of treatment.
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 the startof the Q wave and the end of the
T wave in the heart’s electrical cycle.
This represents the total duration ofelectrical activity of the ventricles. A
prolonged QT interval is a biomarker
of life-threatening ventriculartachyarrhythmias - including torsdes
de pointes.
Second-line drugs
Second-line drugs are used when firstline drugs are no longer effective incuring a patient. Second-line TB drugs
are less effective and have many moreside effects than first-line TB drugs.
Staircase pricing
Global Drug Facility prices occasionallydepend on volume, with lower prices
per unit if larger quantities are ordered.
The GDF refers to this pricing structureas ‘staircase pricing’.
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 WHO; or (c) aregulatory authority associated withan ICH member through a legallybinding mutual recognition agreement
including Australia, Norway, Icelandand Liechtenstein.” Please consult
http://www.ich.org.
TB Alliance
The TB Alliance is a not-for-profit,
product development partnershipaccelerating the discovery anddevelopment of new TB drugs that will
shorten treatment, be effective against
susceptible and resistant strains, becompatible with antiretroviral therapies
for those HIV-TB patients currently onsuch therapies, and improve treatmentof latent 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 approvalAwarded by the US 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 US
President’s Emergency Plan for AIDS
Relief (PEPFAR) programme.
Totally drug-resistant (see XDR-TB).
The term “totally drug-resistant TB” wasused in 2011 for a group of patients in
India presenting resistance to all drugs
that they were tested for. The term,
while widely used by the media, is notrecognised by WHO, which defines
those cases as extensively drug-resistanttuberculosis (XDR-TB).
WHO Prequalification (PQ) Programme
The Prequalification Programme,
set up in 2001, is a service provided
by WHO to make priority medicines
available for HIV/AIDS, malaria,
tuberculosis and reproductive healththat meet unified standards of quality,
safety and efficacy. Please consult
http://apps.who.int/prequal/
XDR-TB (Extensively drug-resistant TB)
Patients, who have MDR-TB and also
show resistance to second-line drugs,
including at least one from the classknown as fluoroquinolones and one of theinjectable drugs, are described as having
extensively drug-resistant TB or XDR-TB.

ACKNOWLEDGEMENTS:
Médecins Sans Frontières wishes to thankmanufacturers and the Global Drug Facility forsharing price information for this publication.

Front cover photo:© Helmut Wachter
Back cover photo:© Helmut Wachter

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

DISCLAIMER:
DR-TB Drugs Under the Microscope - The Sources and Prices of Medicines for
Drug-Resistant Tuberculosis is a pricing guide and cannot be regarded as acompany price list nor as a clinical guideline. It is crucial that any purchaser
verify prices and availability as well as quality status directly with the supplier
before procurement. Médecins Sans Frontières (MSF) has made every effort
to ensure the accuracy of prices and other information presented in thisreport, but MSF makes 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
purchases or uses the product. Information in this guide is indicative only
and not exhaustive, and should be verified with relevant offices when used
for purposes other than providing general information. Clinical decisions
should not be made based on this document.

DR-TB Drugs Under the Microscope

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