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Chapter 6.8: Tuberculosis




6.8
-
1

Priority Medicines for Europe and the World

"A Public Health Approach to Innovation"





Background Paper








Tuberculosis








By Dr Mary Moran



7

October

2004






Chapter 6.8: Tuberculosis




6.8
-
2


Table of Contents


Summary

................................
................................
................................
................................
...............

3

Introduction


What is the Size and Nature of the TB buRden?
................................
................................
................

4

What is the TB Control Strategy?

................................
................................
................................
.........

6

Why Does the Disease Burden Persist?
................................
................................
...............................

8

Research into Pharmaceutical Interventions Past and Present: What Can be Learnt?

........

10

Diagnostics

................................
................................
................................
................................
............

10

Drugs

................................
................................
................................
................................
.....................

11

Vaccines

................................
................................
................................
................................
.................

18

Existing Res
ource Flows for TB R&D
................................
................................
............................

20

Basic research

................................
................................
................................
................................
.......

20

Diagnostics

................................
................................
................................
................................
............

20

Drugs

................................
................................
................................
................................
.....................

20

The Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF)

....................

22

Vaccines

................................
................................
................................
................................
.................

24

Resource flow lessons

................................
................................
................................
..........................

25

What is the Current Pipeline?

................................
................................
................................
.........

25

TB Diagnostics

................................
................................
................................
................................
......

25

TB Drugs

................................
................................
................................
................................
...............

26

TB Vaccines

................................
................................
................................
................................
...........

26

Opportunities for Research into New Pharmaceutical Interventions

................................
.....

27

Are there research gaps that could be filled affordably, have a significant impact and be
achieved in a) 5 years or b) the longer term? Which of these are pharmaceutical research
gaps?

................................
................................
................................
................................
.....................

30

Basic research

................................
................................
................................
................................
.......

30

Diagnostics

................................
................................
................................
................................
............

31

Drugs

................................
................................
................................
................................
.....................

32

Vaccines

................................
................................
................................
................................
.................

37

Conclusion

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................................
................................
................................
..........

38

References

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................................
................................
................................
...........

40



Annexes


Appendices



Chapter 6.8: Tuberculosis




6.8
-
3

Summary

Tuberculosis is a major and growing threat. The expanded European Union now has a
substantial and increasing TB burden of more than 50,000 cases per year, around 10% of
whom have T
B which is already resistant to one or more of our existing drugs. And globally,
TB control is now threatened by the upsurge in HIV
-
TB co
-
infected patients, who are
straining current TB tools and DOTS approaches to the limit.


Controlling TB with our exis
ting tools is a cumbersome, expensive and sometimes
unsuccessful task. There are no cheap, rapid, reliable diagnostics for TB screening or MDR
-
TB diagnosis, and our first
-
line TB diagnostic test picks up only around 50% of patients with
active TB. Drug t
herapies are resource
-
intensive and expensive, particularly in European
settings, requiring 6
-
8 months of therapy with up to one
-
hundred observed doses. Therapies
for MDR
-
TB are even longer, up to 2 years, and have high failure rates. And there is no
rel
iable vaccine to prevent TB in adults.


Although new tools and approaches are being developed in all areas


including basic
research, drugs, diagnostics and vaccines
-

progress is being delayed by lack of targeted
funding and support, in particular from

the EU which now provides less than 5% of global
funding for development of new TB tools. The U.S. is driving the TB R&D agenda,
particularly for new drugs, with the preponderance of research and development now being
funded by the U.S. government and U.
S. philanthropists, and with U.S.
-
based industry and
academic groups being the main collaborators (and beneficiaries of R&D contracts).


The landscape of R&D for these new tools has also changed dramatically, with the major
pharmaceutical industry no longe
r playing a lead role. Development of new TB drugs,
diagnostics and vaccines is now almost entirely driven by public
-
private partnerships,
funded by philanthropists; while industry participation tends to be from smaller companies,
such as biotech firms an
d contract research organisations, rather than large multinational
companies. Those large companies who are involved


for instance in developing vaccine
adjuvants or working on the discovery stage of TB drugs


are almost all EU
-
based.


Current EU fund
ing for R&D of new TB tools does not always reflect these new
epidemiological and pharmaceutical realities. EU funding is insufficient (around $8.5
million per year under the Fifth Framework Programme) and is not well targeted at the PPPs
and smaller indu
stry and academic groups who are now most active in TB research and
development.


This paper suggests a new EU funding model which would support European industry and
academic research while ensuring it is closely focussed on optimal health outcomes for
TB
patients and the governments who provide their care.

Chapter 6.8: Tuberculosis




6.8
-
4

Introduction

TB is an infectious disease, caused by
M. tuberculosis.
Although it most commonly presents
as pulmonary TB (80% of patients), up to 1 in 5 patients present with extra
-
pulmonary
manifest
ations, including miliary TB, bone and joint TB and TB meningitis.
1

TB normally
progresses slowly from the latent stage (infection without active disease) to active TB
disease, except in HIV co
-
infected patients where progression can be rapid and fatal.


What is the Size and Nature of the TB burden?


One in three people globally is infected with TB (latent TB), although only a small proportion
of these progress to clinical disease (active TB).
2

In 2001, an estimated 8.5 million cases of TB
disease occur
red globally, with just under half of these being diagnosed (3.8 million cases)
and around three
-
quarters of diagnosed cases being cured.

a
3

The bulk of TB is concentrated
in 22 high
-
burden countries, all in the developing world, while multi
-
drug resistan
t TB
(MDR
-
TB) is focussed in “hot spots” such as Latvia, Estonia, parts of the Former Soviet
Union and several Chinese provinces.
4


TB now ranks as the ninth most significant burden of disease globally, representing 2.4% of
all DALYs lost


as a comparison
, HIV/AIDS is responsible for 5.8% of lost DALYs and
malaria for 3.0%.
5

However, although the extensive burden of TB is a concern, a greater
cause of disquiet is the rapid growth of TB in some regions, leading to an overall increase in
TB notifications of

around 0.4% per year (see Fig 1).


Fig.1: Global trends in TB case notification
6












This overall trend hides important disparities in TB control. Within Western Europe there are
several countries with increasing TB rates (including the UK, Denma
rk and Norway) and TB
burdens in Eastern Europe and Africa are growing rapidly.
7

However, many regions,
including the Eastern Mediterranean; South East Asia; Western Europe; and India and China
(which together make up 40% of the global TB burden) have sta
ble or declining TB
notification rates, consistent with improved socio
-
economic conditions and more rigorous
implementation of TB treatment programmes.





a

Global cure rates are 49% (non
-
DOTS programmes) and 74% (DOTS programmes). If cure plus completion of
treatment are measured, these figures are 67% and 82% respectively. (The same refer
ence applies.)

Global trends in case notifications
90
100
110
120
130
140
150
160
170
1980
1985
1990
1995
2000
Standardized case
notification rate
Chapter 6.8: Tuberculosis




6.8
-
5

Fig. 2







Fig. 3
8


The rise of TB in Eastern European countries is linked to declining social cond
itions and the
breakdown of health
-
care systems (including TB programmes) during the transition to
market
-
based economies. The impact of this socio
-
economic decline was compounded by a
lack of political commitment to DOTS, with many Former Soviet Union (F
SU) countries
continuing to use inappropriate TB control strategies, such as non
-
DOTS protocols and
unproven revaccination programmes.
9

As a result, these countries


including many EU
accession countries


have high and rapidly increasing rates of both T
B and MDR
-
TB. (See
Annex
6.8.
1a
-
c
)


Globally, the rise of TB, particularly in Africa, is largely due to the unchecked HIV/AIDS
pandemic. This is due to the direct role played

by HIV immunosuppression in activation of
latent TB; the sheer number of new TB patients spreading the disease; the poorer
performance of TB tools in HIV+ immunosuppressed patients; and the impact of HIV on
health systems, health workers and the general e
conomy.


Three factors are likely to impact on the future TB burden in Europe.




The accession of Central European and Former Soviet Union countries means the
expanded EU will soon face a substantially increased burden of TB and MDR
-
TB.
Although much of
this will remain within the borders of the accession countries,
migration means that the relatively TB
-
naïve health systems of Western Europe will also
be exposed to increased TB, including potentially untreatable drug
-
resistant strains of
TB (at least one
-
third of MDR
-
TB patients do not respond to existing drugs).

10

Around
20,000 TB cases were notified in the first
-
rank accession countries in 2001, with TB
incidence rates as high as 75
-
85 per 100,000 in Latvia and Lithuania
-

by comparison,
France and Germ
any have incidence rates around 10 per 100,000. (See
Annex
6.8.
2
)
Latvia and Estonia also had the dubious honour of being in the Top 5 for both MDR
-
TB
and poly
-
drug resistant

TB (MDR was a disturbing 18% in Estonia and 12% in Latvia).
11




Central and Eastern Europe and the Former Soviet Union (CEE/FSU) currently combine
some of the world’s highest MDR
-
TB rates with the world’s fastest growing HIV
infection rates. In 1995, the
number of HIV infections in the region was estimated at
below 30,000. By end 1999, this had climbed to 420,000, reaching 700,000 in 2000.
12

The
course of the TB
-
HIV epidemic in Sub
-
Saharan Africa (where MDR
-
TB rates are low) is a
salutary lesson for the
CEE/FSU region, but one which is not being adequately
addressed.

The epidemiology of TB
in Europe
0
50
100
150
200
250
300
1980
1985
1990
1995
2000
Sta
nd
ard
ize
d
ca
se
notificat
ion rate
Former Soviet
Central Europe
Established Markets
The rise and rise of TB in
Africa, linked to HIV
0
50
100
150
200
250
300
350
400
1980
1985
1990
1995
2000
Standardized case
notificaiton rate
Chapter 6.8: Tuberculosis




6.8
-
6



In the longer term, economic growth in the accession countries is highly likely to reduce
their burden of both TB and MDR
-
TB.

Globally, the two factors most likely to influence the TB burden

are:




DOTS expansion, which delivers increased TB detection and cure rates in areas of DOTS
coverage. There has been a renewed push for DOTS expansion, with rapidly increased
coverage in four of the top five high
-
incidence countries (India 45%; China 68
%;
Indonesia 98% and Bangladesh 95%).
13

Results from Vietnam, Peru and early results
from China show that DOTS can reduce the TB burden, however we will need to
substantially improve case
-
finding tools and strategies, which currently find a minority
of TB

patients even with 100% DOTS coverage.



The HIV/AIDS pandemic, particularly in Sub
-
Saharan Africa, but increasingly in South
-
East Asia, India and China. Country data show that HIV
-
TB has grown from 4% of the
global TB burden in 1995 to 12% in 2000, wit
h Africa now representing 20% of all TB
cases.
14

Without new TB tools and
additional
approaches, new AIDS epidemics in other
areas of the world will be catastrophic for TB control.

Scaling up of joint TB/HIV
activities will be required.


What is the TB Co
ntrol Strategy?


The fundamental TB control strategy, recommended for all epidemiological settings, is DOTS
(Directly Observed Treatment, Short
-
course). Its five key elements are:
15



Political commitment and resources to address TB



Uninterrupted supply of t
he four to six most effective anti
-
TB drugs



A standardised recording and reporting system to enable outcome assessment of
patients and TB programmes



Access to sputum microscopy to detect patients with smear
-
positive pulmonary TB



Standardised 6
-
8 month drug

therapy, with directly observed treatment for at least
the first 2 months.

In high HIV
-
TB settings,

DOTS is supplemented by scaling up of 12 collaborative TB/HIV
activities defined in the interim Policy on Collaborative TB/HIV Activities (ref:
WHO/HTM/TB/
2004.330; WHO/HTM/HIV/2004.1
. DOTS
-
Plus for the treatment of MDR
-
TB
(including access to cheaper drugs) is now also being piloted by WHO in a limited number
of settings.
16

Finally, wider use of anti
-
retroviral therapy in developing countries is see
n as
an

important adjunct to TB treatment
.


The effectiveness of DOTS and its supplementary programmes varies depending on the
epidemiological setting. Epidemiological modelling suggest that, in normal settings, DOTS
can deliver a 6
-
7% annual TB decrease if cov
erage is 100% and if TB programmes can detect
70% of smear
-
positive patients and cure 85% of these


the so
-
called 70/85 targets. These
figures are premised on passive case
-
finding, rather than active TB screening or contact
-
tracing, as is used in most We
stern countries. The passive case
-
finding approach has been
partly dictated by the absence of cheap, reliable screening tests to detect either latent or
smear
-
negative TB, with most developing countries unable to afford the more sophisticated
Chapter 6.8: Tuberculosis




6.8
-
7

diagnostics
available in the West. Modelling also suggests that achieving DOTS targets
would have averted 3.4 million additional TB deaths between 2001 and 2005, and allowed a
total of 12.8 million people to be treated for TB.
17



However, real
-
life results of DOTS
are more mixed. DOTS clearly delivers higher detection
and cure rates of smear positive new pulmonary cases than non
-
DOTS approaches.
b

But
DOTS implementation has been slow and, even when implemented, most developing
countries are struggling to reach the

global 70/85 targets, in particular the 70% case
-
finding
target.
c

Only two of the 22 high
-
burden countries (Vietnam and Peru) have achieved the
70/85 targets; and case
-
finding rates in the major
-
burden TB countries (India, China,
Indonesia, Nigeria, Bang
ladesh) are still below 35
%.
18


Importantly, there are two settings where the DOTS strategy alone does not appear to be
adequate

without additional activities
. The first is high
-
prevalence HIV settings, where
DOTS can slow the increase in TB but “on its own

... is unlikely to reverse the upward
trend”.

19

This view is confirmed by epidemiological modelling for Sub
-
Saharan Africa
which suggests that, even if full DOTS implementation to the 70/85 targets could be achieved
(in itself problematic), growth in TB
will only be slowed from 10% to 7% per
year.
20

Collaborative TB/HIV activities will be required in these circumstances.


The second area is MDR
-
TB. DOTS reduces generation of new MDR
-
TB cases, but
management of existing MDR
-
TB patients is beyond the capaci
ty and finances of most
developing country DOTS programmes. In the absence of suitable tests, most MDR
-
TB
patients are diagnosed on the basis of two failed courses of DOTS (15 months therapy)


during which time they remain infective with drug
-
resistant TB

strains. Once diagnosed, the
vast majority receive no further treatment, since MDR
-
TB treatment is around 1,400 times
more expensive than TB treatment, with the drugs alone costing up to $8,000
-
13,000 per
patient. DOTS
-
Plus, which offers subsidised drugs
, currently covers only around 2,500 of the
estimated 300,000
-
400,000 patients with MDR
-
TB, although additional patients are treated
outside DOTS
-
Plus in wealthier countries such as South Africa or Latvia.
21

Delays in
diagnosis, lack of treatment, and relat
ively low cure rates in patients who are treated, all
mean that MDR incidence is not being reduced as quickly as possible.

The DOTS Plus
strategy is required in these circumstances.





b

DOTS averages 60% detection rates compared to 36% under non
-
DOTS programmes, and 77% cure
-
rates
compared to 52% for non
-
DOTS. (WHO Global TB Control Report 2003, pp19
-
23)

c

After a decade of DOTS, 71% of TB patients globally are still tr
eated outside DOTS programmes and slightly less
than half of the 22 high
-
burden TB countries have achieved country
-
wide DOTS coverage of 95% or greater, while
all top five high
-
incidence TB countries continue to have case
-
finding rates of around 35% or les
s.

Chapter 6.8: Tuberculosis




6.8
-
8

Why Does the Disease Burden Persist?


Obstacles to improved TB control f
all into two main categories. The first are obstacles
related to DOTS itself; while the second are factors relating to developing country health care
more generally. The main DOTS
-
related obstacles are:


1.

Technical limitations of existing DOTS tools.

W
HO and CDC staff noted in 2001
that “as DOTS coverage has expanded, it has become apparent that the performance of
existing tools for TB diagnosis and treatment limits more efficient implementation of the
strategy”.

22

Key limitations are:




Lack of cheap,

quick and reliable tests for:

-

Screening for latent TB (which would allow preventative therapy to be given before
infectious or active TB supervene);

-

TB diagnosis. Our fundamental TB diagnostic test, AFB microscopy, has an overall
detection rate of only 5
0% (up to 75% in pulmonary cases) and is cumbersome,
requiring trained microscopists and repeat patient visits. There is no suitable test for
detection of TB in paediatric, extra
-
pulmonary or smear
-
negative patients in poor
settings, many of whom are HIV
-
positive;

-

MDR
-
TB diagnosis. Current diagnosis relies on manual culture, which is cheap but
extremely time
-
consuming (results take 6
-
9 weeks), and must be performed in a
National Reference Laboratory or its equivalent. The scarcity of such laboratories
me
ans culture and drug
-
sensitivity testing (DST) are barely used in most developing
countries, who instead rely on lengthy treatment trials. (See
Annex
6.8.
3
)



Lack of short
-
cour
se drugs in long
-
acting formulations. Current TB drugs are cheap and
can deliver cure rates of 85% or more. However they must be given daily or three
-
times
weekly for 6
-
8 months (with observation of each dose for the first 2 months; and for all
doses in
rifampicin
-
containing regimens)



Lack of an effective adult TB vaccine



Lack of effective drugs for MDR
-
TB. Current drugs are described by WHO as
“inherently more toxic and less effective than first
-
line drugs”
23
; they require treatment
courses of 20
-
24 mo
nths; are prohibitively priced at up to US$8,000
-
13,000 per patient;
and typically cure only around half to two
-
thirds of patients.
24



2.

DOTS “cumbersome, labour intensive and expensive” system of administration

(as it was described by staff at WHO and the

CDC) makes it difficult for developing
countries to implement DOTS or to reach the global 70/85 targets.

25

The programme
measures needed to overcome the technical weaknesses of existing TB tools (for example,
repeat testing, lengthy treatment courses a
nd frequent direct observation of patient therapy)
now significantly outweigh the cost of the drugs themselves


indeed, they commonly
represent around 90% of the cost of DOTS.

Chapter 6.8: Tuberculosis




6.8
-
9

Table 1: Estimated public sector health system costs per treated case of infe
ctious TB,
excluding MDR
-
TB (US$)
26


Country

Total

Drugs

United Kingdom

$9,029

$200

India

$57
-
$201

$7

China

$61
-
$75

$18

Uganda

$430
-
$541

$32

Thailand

$219
-
$280

$43

Russia

$1,115
-
$1,395

$83


The costs of MDR
-
TB treatment are even more prohibitive,
reaching as high as US $250,000
per patient in Western settings. Although the drugs are very expensive, the chief costs are
incurred by hospitalisation, direct observation and monitoring during the 2
-
year treatment
course needed with these old second
-
line

drugs. We note that Latvia alone needs to spend
Euro 6.3 million to manage 600 MDR
-
TB patients.
27

This is more than twice the sum of
money dedicated annually by the EC to development of shorter, more effective treatments
for TB and MDR
-
TB.


3.

The 70% case de
tection target may not be realistic

using current diagnostic tools and
passive case
-
finding approaches, with recent WHO research suggesting TB case
-
finding may
plateau at 40
-
50% of smear
-
positive (infectious) patients.
28



The second group of obstacles ar
e factors relating to developing country health care more
generally, and which apply to other diseases as well as TB:


1.

The 22 high
-
burden TB countries identified five main country
-
level constraints
to

reaching the DOTS targets, including:



lack of human res
ources;



impact of health system restructuring, in particular decentralisation;



poor health system infrastructure, organisation and management;



private sector non
-
compliance with DOTS recommendations;



lack of political commitment in some developing coun
tries.

Additional factors included poor drug supply

systems; and poor physical access to
treatment centres, especially for remote patients.
29


2.

A funding gap. In 2003, the WHO reported the known country
-
level gap in TB
funding at $219 million; the probabl
e additional country
-
level gap at $838 million;
and the gap in international technical assistance at $115 million (all figures for the 22
high
-
burden countries only).
30

These gaps are likely to widen, particularly in Sub
-
Saharan Africa, as increased number
s of HIV patients are detected (many co
-
infected
with TB) in response to current international initiatives. These include the WHO 3 x 5
initiative; the US $15 billion Bush grant; the work of the GFATM and Clinton
Foundation; and WHO’s

policy on TB/HIV col
laborative activities
.


3.

Patient factors, including TB stigma and reliance on alternative healthcare providers.

Chapter 6.8: Tuberculosis




6.8
-
10

Research into Pharmaceutical Interventions Past and Present: What
Can be Learnt?

Diagnostics

Research into new TB diagnostics has been increasi
ng in the past 10
-
15 years, with research
and development toward new tests for smear
-
negative TB, TB screening, and rapid detection
of MDR
-
TB; as well as tests to improve or replace sputum
-
based AFB for smear
-
positive
patients.


Much of the commercial R&D
for TB has been undertaken by small and medium sized
biotechnology companies taking advantage of the advanced state of diagnostics science, the
lower development costs than for pharmaceuticals, and the presence of a modest Western
market. Over 50 groups i
n 18 countries are developing or already marketing new TB tests,
though of the largest 10 diagnostic companies, only 3 have any products for this disease.
Academic research supporting these TB diagnostics development activities is carried out by
a wide ran
ge of institutions, with support coming primarily from national research institutes
or other public funds.


Although multiple new tests have been developed for all patient categories, review of these
reveals a number of weaknesses. The lack of regulato
ry oversight for diagnostics in
developing countries means that clinical evaluations are often poor and advertised test
specifications often overstate their efficacy. Smaller companies often lack the skills, financing
or depth to make improvements needed t
o improve performance. A wider problem is that
almost all the tests developed by the larger, more capable companies have been developed
with the Western market in mind and are therefore unsuitable for wide use in TB
-
endemic
countries due to their cost and
high
-
tech nature. Nevertheless,
promising new technologies
do exist and, with adaptation, could be widely implemented in low
-
income settings.


In an attempt to address this, the Tuberculosis Diagnostic Initiative (TBDI) was set up within
WHO/TDR in 1996 t
o support industry and academic research into tests for resource
-
poor
settings by providing an enabling infrastructure and a modest budget to fund development
or evaluation projects. Despite offering substantial support to industry


including a 12,000
sa
mple specimen bank for diagnostic testing; a database of all diagnostics in development;
test performance guidelines; and support for field trials
-

this enabling approach was unable
to drive the development process forcefully enough to deliver new tools a
nd was
supplemented in May 2003 by a new public
-
private
-
partnership, the Foundation for
Innovative New Diagnostics (FIND).


FIND is reviewing existing technologies, prioritising them from a health perspective and
funding co
-
development of promising techno
logies with industry, in order to deliver new
diagnostic tests for latent, active and MDR
-
TB. In conjunction with TDR, they will also trial
existing (and eventually new) diagnostics to independently validate their performance.


Diagnostic lessons

This
history of TB diagnostics research holds a number of lessons. The first is that it is not
enough to support R&D indirectly: companies have little incentive to invest the estimated
additional $5
-
20 million needed to conduct adaptation or development work a
nd, in the
Chapter 6.8: Tuberculosis




6.8
-
11

continued absence of such incentives, will not do so. Secondly, diagnostic development is
increasingly the province of smaller companies and biotechs. Incentives targeted towards
these companies will need to differ in size and scope from the i
ncentives needed to stimulate
multinational pharmaceutical companies. And, finally, the plethora of small companies,
each promoting their own technology, can make it difficult for funders (or indeed
purchasers) to determine where best to invest their fund
s. (For suggested solutions, see
R&D
Gaps
, below.)


Drugs


A review of TB drug development needs to look at both industry and public/not
-
for
-
profit
groups, since the balance of activity between these has changed dramatically.


Industry


All our current
TB drugs were developed between 1940 and 1970, but there has since been a
marked downturn in industry interest. Only three of the world’s Top 20 drug companies
conduct any TB drug research or screen new compounds for anti
-
TB activity. And only one
of the
se companies conducts TB research as part of its mainstream R&D activities, rather
than as free
-
standing, smaller
-
scale research which tends to fall under the “corporate social
responsibility” umbrella.

d
31

These three companies (all European) are GSK, Nov
artis and
Astra
-
Zeneca. The chief disincentive to TB drug research by the multinational
pharmaceutical industry is the lack of a sufficiently large commercial market for the final
product. While global sales of TB drugs are potentially large (estimated a
t $450 million in
2000, expanding to $640 million in 2010), the key driver of commercial R&D investment is the
private sector market in developed economies: for TB, this is estimated at only $113 million
globally per year.

32


Although the major pharmaceut
ical industry has not developed any novel TB drugs in the
past 30 years, they have produced two groups of drugs relevant to TB. The first consists of
four drugs based on the rifamycins (discovered in the 1960s) and developed specifically to
treat mycobacte
rial infections (
M. tuberculosis

and
M. avium
). All four of these were
supported with US Orphan Drug funding although none are suitable for routine use in TB
-
endemic settings for the reasons noted in Table 2.
e

Nevertheless, further development of one
of t
hese new drugs, rifapentin, may allow the frequency of drug administration, and
therefore observation, to be reduced from daily to weekly or even fortnightly.





d

In 2001, this was reported as five companies, however mergers have since reduced this to three companies.

e

Orphan legislation has existed in the U.S. since 1982 and in the E.U. since 2000. Neither the US nor EU
legislation mention neglected deve
loping country diseases as a target, although the US later specifically noted
these in the Pharmaceutical Exports Amendment Act (1986) to their Orphan Drug legislation. It is worth noting
that, while neglected diseases are theoretically covered by the EU l
egislation, since even a few cases in the EC
would qualify as a disease with prevalence less than 5 per 10,000, the original suggestion to explicitly include
neglected developing country diseases in the legislation was blocked by EC Commissioner Bangemann.


Chapter 6.8: Tuberculosis




6.8
-
12

Table 2: TB drugs developed by pharmaceutical industry 1980
-
2000
33


Drug

Efficacy, safety, the
rapeutic benefit

US Orphan Drug
support

Rifater

(Rifampicin, INH
Pyrazinamide

(120/ 50/ 300)

Combination of 3 old drugs (1952, 1965, 1970)

Dosages do not comply with new WHO guidelines
(150/75/400)

WHO does not recommend use of 3
-
FDCs

Yes

1994

Hoechst Ma
rion
Roussel (EU)

Rifadin iv

(Rifampicin iv)

Intravenous form of old drug (1960’s)

Oral treatment preferential, but useful in some
circumstances

Yes

1989

Hoechst Marion
Roussel (EU)

Priftin

(Rifapentin)

Developed for AIDS opportunistic infection (
M.avium

complex)

Used for once
-
weekly continuation phase TB treatment in
some Western settings, where HIV can be excluded.

Not suitable for HIV
-
TB co
-
infected patients in current
dosage..

Yes

1998

Hoechst Marion
Roussel (EU)

Mycobutin

(Rifabutin)

Prevention an
d treatment of AIDS opportunistic infection
(
M. avium

complex)

Useful for TB treatment in HIV patients on ARV therapy

Very expensive

Yes

1992

Adria Laboratories

(US)


A second promising group of drugs are broad
-
spectrum antibiotics developed by industry
f
or Western infectious disease indications, but which incidentally have anti
-
TB activity. The
fluoroquinolone family are particularly promising (e.g. moxifloxacin, gatifloxacin, ofloxacin),
with public research from as early as the 1980s suggesting that th
e addition or substitution of
fluoroquinolones in TB therapy could dramatically shorten treatment, from 6
-
8 months to
around 3 months.
34

However, until recently, their potential for TB treatment was not further
explored nor were these patented drugs made a
vailable for large
-
scale public trials aimed at
a TB indication. Companies were apparently deterred from working on a TB indication for
these drugs (or assisting others to do so) because of the potential impact of a TB indication
on their sales as broad
-
sp
ectrum antibiotics in the West.
35

However o
ne major company,
Bayer, recently moved forward on this and is now collaborating in publicly
-
driven TB trials
of their existing broad
-
spectrum antibiotic (moxifloxacin).


A further interesting area of industry act
ivity is the foundation of specialised infectious
disease research institutes which include TB in their remit: the Novartis Institute for Tropical
Diseases in Singapore, launched in January 2003; GSK’s Tres Cantos research centre in Spain,
launched in 2003
; and Astra
-
Zeneca’s infectious disease research centre in Bangalore, India,
launched June, 2003 (and which appears to have a more commercial focus). These institutes
are currently focussed on the early pre
-
clinical stages of R&D. For instance, GSK and A
stra
-
Zeneca each has three projects in the early discovery stage; and Novartis has announced that
its Singapore Institute will cover pre
-
clinical stages only. Some of these groups have
intimated that they may seek public involvement, possibly through PPPs
, to deliver a
finished anti
-
TB drug but, whichever is the case, their work will play a critical role in
priming the drug pipeline.

Given their small market share, smaller biotech companies currently play a relatively more
active role in TB drug developme
nt (as opposed to drug discovery). For instance, a 2003
Chapter 6.8: Tuberculosis




6.8
-
13

review showed that 4 of the 5 companies currently collaborating on, providing or developing
TB lead compounds are biotechs: ActivBiotics, FasGen, Chiron and Sequella Inc., all US
-
based (See Table 3)
.

Small contract research organisations (CROs) are also the main supplier
of outsourced R&D services for the major drug development PPP, the TB Alliance.
36


Public and not
-
for
-
profit Private Sectors


The bulk of TB drug development is now being done in the
public sector and by the TB
Alliance. Collectively, this R&D ranges from basic research through to the development of
new TB drugs, including novel compounds and adapted existing antibiotics. (
See Current
Pipeline for full details
.)


Basic research

Basic
research led to the 1998 decoding of the TB genome by the Wellcome Sanger Institute;
while the TB Structural Genomics Consortium (over 70 laboratories in 12 countries)

(See
anne
x
6.8.
4
)

is now identifying and placing in the public domain, the genes involved in TB
persistence, virulence and reactivation; and the 3
-
D structure of their corresponding TB
proteins. This work has been a major breakthrough and is a first step towards
identifying
new TB drug and vaccine targets.


Novel drugs

Novel drugs offer the best hope for improved TB treatment, since they are likely to be potent
against MDR
-
TB as well as drug
-
sensitive strains and latent TB. A significant contributor to
novel TB d
rug development is the TB Alliance, the sole PPP working in this area. The TB
Alliance, launched in 2001, has a portfolio of 10 anti
-
TB compounds or groups, including PA
-
824, licenced from a US biotech and considered to be a promising TB compound because
of
its high bactericidal and sterilising activity.
37

Two of the TB Alliance’s drug development
projects are industry collaborations (rifalazil analogues with a US biotech firm, and pyrroles
with an Indian generic company); while the remaining nine are coll
aborations with academic
or public institutions (six of these are U.S. based). As of mid
-
2004, the TB Alliance had no
major industry partners, although we believe discussions are ongoing.
f


Three smaller groups are also working on TB drugs (these projects

include variations on
existing drugs in distinction to novel compounds), however their efforts are focussed on
development of a single drug or compound group held by an individual company, rather
than being a broad
-
ranging portfolio approach aimed at iden
tifying optimal drug leads.
Two of these projects involve US biotech companies (Sequella Inc and FasGen, supported by
the NIAID); while the third involves a major pharmaceutical company (development of
thiolactomycin analogues by GSK, NIAID and St Judes).



Adapted existing antibiotics

The second main area of drug development involves trialling antibiotics already on the
market, for a new TB indication. If successful, these drugs could be available relatively
quickly, since they already exist as finished

drugs; but, unlike novel TB drugs, they have the
drawback of being potentially unusable against MDR
-
TB due to cross
-
resistance engendered



f

Although not formal partners, GSH has seconded a senior scientist to the TB Alliance and BMS has donated
$150,000 to the Alliance’s work.

Chapter 6.8: Tuberculosis




6.8
-
14

through previous widespread use for non
-
TB indications.
38

The two most promising classes
of drugs are the fluoroquino
lones and longer
-
acting rifamycins (as noted above). If current
large
-
scale clinical trials of these drugs substantiate early promising results, we may be able
to reduce TB treatment in non
-
MDR settings to 3 months with 6
-
12 observations


as
opposed to t
he current regimen of 6
-
8 months treatment with up to 80
-
100 observed doses.


Despite evidence as early as the 1980s that these classes of antibiotics had potential for TB
therapy, there was little progress due to both public inertia, based on the expect
ation that
older TB drugs would suffice, and on the need for lengthy and sometimes unproductive
negotiations with patent holders for access to drugs for clinical trials.
g

Since 2003, however,
there has been an unprecedented increase in activity, with an
October 2003 review showing
13 trials (including 5 Phase III trials) to assess the potential of fluroquinolones and longer
-
acting rifamycins for first
-
line TB treatment. (See Table 3 Matrix.) The majority of these are
being conducted by U.S. public healt
h institutions, in particular the CDC and NIAID,
although the EC and WHO/TDR are involved in at least one larger
-
scale trial. Developing
country capacity to undertake these trials, including of novel drugs, is assisted by the pre
-
existence of good DOTS de
livery and recording systems. However, although trial capacity
in TB
-
endemic settings is being rapidly built up (see p.13), it is still below the standard
needed.






g

Lack of funds has also been cited as one reason for delays in trialling «

off the shelf

» drugs, even though s
uch
trials are relatively cheap and the savings for developing countries are potentially substantial (trials of new drugs
are estimated at $1.6
-
3 million for Phase II, and $8
-
22 million for phase III, depending on whether they are
conducted in developed or

developing countries.)

g


Chapter 6.8:

Tuberculosis



6.8
-
14

Table 3 TB DRUG DEVELOPMENT ACTIVITY MATRIX (Stop TB overview as of October 2003)


Basic
Research

Discovery

Lead
Identification

Lead Optimization

Preclinical

Clinical Trials

Regulatory

Inorganic Iron
Compounds as TB
Agents

UFRGS

Enoyl
-
ACP
-
Reductase
(InhA) Inhibitors

GSK(DDW)/TA
M

Pyridones and
Quinolizines

TB
Alliance/KRI
C
T/Yonsei

PA
-
647/PA
-
822

TB Alliance/NIAID

PA
-
824
-
Preclinical
Development

NIAID(DAIDS)/JHU/T
B Alliance and Others

Moxifloxacin
-
Phase 2
Randomized Moxi
-
Containing Regimen for
Smear+TB (II)


JHU/FURDJ/FDA


Ofloxacin
--
OFLOTUB
Comparative studies of

OFL, MXF, GFL 4 mo vs. 6
mo


St.
George's/EC/TDR/WHO

Shikimate Pathway
Enzymes As Targets
For Anti
-
TB Agents
Development


UFRGS

Isocitrate Lyase
(LCL) Inhibitors


GSK(DDW)

Ascididemin
Compounds

AUCKU/TB
Alliance

Thiolactomycin
Analogs
NIAID(TBRS)/GSK/St
.
Jude

PA
-
824
--
Confirmatory
Assessment of the Anti
-
TB Activity

of PA
-
824 in Mice

JHU/TB
Alliance/NJMRC

Rifapentine
(
INH/RIF/EMB/PZA)
-

4
mos vs. 6 mos in HIV
-
non
-
infected adults who
are sputum neg. after first
2 mos TB treatment
D
MID 01
-
009 (III)

DMID/NIAID/NIH
(TBRU)



Target Identification
and Validation

NHLS/WITS/GSK/
UW/UBC/

Harvard/LSHTM

Antimicrobials

GSK(DDW)

Third
Generation
Macrolides

UILL/TB
Alliance




KRQ
-
10018

TB
Alliance/KRICT/Yonsei

Moxiflo
xacin
--
Shortening
with

MXF II

JHU/CDC/NJMRC/Bay
er

Rifapentine
-
Randomized
Weekly RIF/INH for 3
Months vs. 2x Weekly
RIF/PZA for 2 Months
(III)
JHU/UCFF



Chapter 6.8: Tuberculosis




6.8
-
15

Basic
Research

Discovery

Lead
Identification

Lead Optimization

Preclinical

Clinical Trials

Regulatory

Mechanisms of DNA
Metabolism in
Mycobacteria
NHLS/WITS/NIAI
D/RVC

Sigma70
-
identifying
transcription

inhibitors
ASTRA


PA 20013

NIAID/JHU/FasGen,
Inc.

Moxifloxacin
--
Preventive
Therapy of LTBI with
MXF in the MDR Era
JHU/CDC/NJMRC/Bay
er

Rifapentine
-
RPT/INH
-
3,
INH/RIF
-
3, Continuous
INH,Novel TB
Prevention Regimens f
or
HIV+ Adults (III)

JHU/WITS/NIAID(DAI
DS)



Development of in
vitro test for
sterilizing activity

St. George's

Methyl
Erythritol
Pathway
inhibitors (end
product,
isprenoids)
ASTRA



Ethambutol Analogs
-
Second Generation

Ethambutol Antibiotics
NIAID(DMID)/Sequella
, Inc.

Gatifloxacin
-

Highly
Active Quinolones for
Treatment of MDRTB
(Gatifloxacin with
Ethionamide)

CNYRC/BMS

Rifapentine
(II) Dose
Escalation Study

CDC
-
TBTC



Studies on Drug
Tolerance

St. George's

DNA Synt
hesis
Inhibitors

ASTRA



MJH 98
-
I
-
81 & Analogs
(Isoniazid Compounds)

TB
Alliance/Wellesley/CN
YRC

LL
-
3858

(Pyrroles)

Lupin(TB Alliance)

Rifapentine
for Latent

TB Infection

CDC
-
TBTC



40 Grants in Target
Identification and
Assay Development

NIAID





Rifal
azil
Analogs

ActivBiotics(TB
Alliance)



Rifapentine

RIF/INH
efficacy of once weekly
(III)

CDC
-
TBTC



Chapter 6.8: Tuberculosis




6.8
-
16

Basic
Research

Discovery

Lead
Identification

Lead Optimization

Preclinical

Clinical Trials

Regulatory

The Regulation of
Dormancy in M.
Tuberculosis

NHLS/WITS/UPEN
N/NIAID/

PHRI/ROCK





Nitroimidazooxazines
Analogs

NIAID(TBRS)/TB
Alliance



Rifabuti
n
-
safety and
efficacy of short course in
HIV+ (II)

CDC
-
TBTC









Anti
-
Persister TB Drugs

St. George's



Capreomycin
-
Aerosol

Capreomycin (I)
TBRS/NIAID/Masan/Yo
nsei













EBA

of Moxifloxacin,
Gatifloxacin,
Levofloxacin,
Levofloxacin,

Lindezol
id (I)

NIAID(DMID)/TBRU













Isoniazid Resistance
-
Intermittent Short
-
Course Therapy

CDC
-
TBTC

















Chapter 6.8:

Tuberculosis



6.8
-
17








ACRONYMS







EMB
-
ethambutol FQ
-
flouroquinolone INH
-
isoniazid MXF
-
moxifloxacin OFL
-
ofloxacin PZA
-
pyrazinami
de RIF
-
rifapentine RMP
-
rifampicin



AUCKU
-
Auckland
University

ASTRA
--
AZIPL
AstraZeneca
R&D India

BMS
-
Bristol
-
Myers Squibb

BTRU
-
Brazilian
Tuberculosis
Research Unit

CWRU(TBRU)
-
Case Western
Reserve
University
Tuberculos
is
Research Unit

CDC
-
Centers for
Disease Control and
Prevention

CDC(TBRU)
-
Centers for
Disease Control
and Prevention
Tuberculosis
Research Unit

CDC
-
TBTC
-
Centers for
Disease Control
and Prevention
TB Trials
Consortium

CNYRC
-
Central New
York Research
Corpor
ation

CSU
-
Colorado
State University

CORU
-
Cornell
University

DHHS
-
U.S.
Department of
Health and
Human
Services

DMID
-
Division
of
Microbiology
and Infectious
Diseases

FUR
-
TD
-
TBRU
-
Federal
University of Rio de
Janeiro
-
Thorax
Institute
-
Tuberculosis
Research Unit

FDA
--
U.S.
Food and Drug
Administration

GSK
--
GlaxoSmithKline

IUATLD
-
International Union
Against Tuberculosis
and Lung Disease

JHU
-
Johns
Hopkins
University

KRICT
-
Korea
Research Institute
of Chemical
Technology

LSHT
-
London
School of
Hygiene and
Tropical
Med
icine

Masan
-
Masan
National TB
Hospital

NHDP
-
National
Hansen's Disease
Program

NHLS
-
National
Health
Laboratory
Service

NIAID
-
National
Institute of
Allergy and
Infectious
Diseases

NIH
-
National
Institutes of Health

NJMRC
-
National
Jewish Medical
and Research
Center

PHRI
-
Public
Health Research
Institute

RTI
-
Research
Triangle
Institute

ROCK
-
Rockefeller
University

RVC
-
Royal Veterinary
College

St. George's
-
St.George's
Medical School

St. Jude
-
St. Jude
Children's
Hospital

SKMOH
-
South
Korean Ministry of
Health

SRI
-
S
outhern
Research Institute

TAM
-
Texas
A&M University

TB Alliance
-
Global Alliance
for TB Drug
Development

TBRS
-
Tuberculosis
Research
Section

TDR/WHO
-
Special
Programme for
Research and Training
in Tropical Disease

UBC
-
University of
British
Columbia

UILL
-
Unive
rsity
of Illinois

UFRGS
-
Federal
University of the Rio
Grande Do Sul

UPENN
-
University of
Pennsylvania

Wellesley
-
Wellesley College

WITS
-
University of
Witwatersrand

Yonsei
-
Yonsei
University
Medical School





Chapter 6.8: Tuberculosis




6.8
-
18

Drug development lessons


The most striking les
son to be derived from this review of drug R&D is that the normal
mechanisms to supply new pharmaceutical tools simply do not apply. In particular, the
multinational pharmaceutical industry (with the notable exception of the three EU
-
based
companies noted

above) no longer plays a lead role in TB drug development. TB drug
development by most multinational companies was minimal during the 1980s and 1990s and
tended to focus on Western niche markets (e.g. drugs for HIV
-
TB co
-
infected patients on
antiretrovira
l therapies); large companies tend not to develop potential TB compounds in
their libraries; and they can be slow in providing access to existing antibiotics of potential TB
interest. The few multinational pharmaceutical companies who do show interest (all

European
-
based) are working in early pipeline areas


including the important discovery
area
-

and some have indicated that they will seek public partnership to move compounds
forward.


Instead, R&D of novel TB drugs, including for MDR
-
TB, is increasingly

the province of
publicly
-
driven groups. For instance, a Stop TB review of known TB drug development (as
opposed to discovery) projects underway at the end of 2003, showed that the majority (22)
were being conducted without any industry collaboration. Like
wise, just over half of the
compounds being developed into new TB drugs derived from the public and academic
sectors rather than from industry.
h



Commercial development of TB tools, where it exists, also tends to be within small biotech
companies rather
than large multinational pharmaceutical firms (MNPs), this holding true
for both drug and diagnostic development. The predominance of biotechs reflects two
factors that are not present for MNPs: biotechs do not systematically shy away from smaller
-
scale ma
rkets, with several companies continuing to work on these “niche” diseases; and
biotechs invariably need external funding partners, such as PPPs, to move their compounds
along the pipeline.


An unexpected but useful flow
-
on from this “new world” of TB d
rug development, is that
many compounds that had previously languished on the shelves of biotech companies and
academic research institutes


a significant waste of both public and private capital


are now
being developed into useful new TB drugs and diag
nostics. A less positive outcome is that
the substantial capacity of most multinational pharmaceutical companies is longer turned
towards TB drugs, which cannot compete with Western commercial sales.


Vaccines


The only TB vaccine, bacille Calmette
-
Guerin
(BCG), was developed over 80 years ago. Its
protective effect is limited and geographically variable, with studies showing a zero
protective effect in India, ranging up to a 77% protective effect in the U.K.
39






h

MNPs were active in only one of the fifteen novel TB drug development projects listed, compared to the biotech
industry which was providing lead compounds or participation in four projects.


Chapter 6.8: Tuberculosis




6.8
-
19

Research into new TB vaccines has increased
substantially since the early 1990’s


indeed,
more than 170 TB vaccine candidates have been screened in animal models since 1997. These
candidates fall into five main groups:



Sub
-
unit vaccines (nearly half of all vaccine candidates), which include one o
r more
mycobacterial components believed to induce protective immunity;



Naked DNA vaccines, consisting of DNA encoding protective antigens plus various
adjuvants;



Live attenuated mycobacteria vaccines (including recombinant BCGs, attenuated
strains of
M.tu
berculosis
, and non
-
pathogenic mycobacteria such as
M.smegmatis
);



Live attenuated non
-
mycobacterial vaccines, such as
Salmonella
or vaccinia virus;



Improved BCG (prime booster) vaccines, which combine BCG with a novel candidate
for improved efficacy.


How
ever, our incomplete scientific understanding of disease models of latency and
persistence, or of the human immune response to M. tuberculosis, means that development
of these new vaccines has been largely empirical, with current candidates representing
vi
rtually all known technological approaches to immunisation. The vast majority are also
still in the laboratory modelling stage, with only three candidates in Phase I trials (20
-
50
human subjects). Large clinical trials of these vaccines also pose major p
roblems given the
current state of scientific and technical knowledge (see “Opportunities” section below).


TB vaccine research is chiefly being conducted in the public sector and through Public
-
Private Partnerships (PPPs). The main players are:



The Aeras

Global TB Vaccine Foundation (formerly known as the Sequella Global
Tuberculosis Foundation), a PPP founded in 1997 (US
-
based);



The European Commission TB Vaccine Cluster (TBVac). TBVac is a consortium of
academic and industry TB vaccine researchers, coor
dinated from the Institut Pasteur,
and composed of 36 academic research groups from 12 EU countries, and two major
pharmaceutical companies (GSK and Aventis). (See
Annex
6.8.
6

for full list);



The Infectious Disease Research Institute, a PPP founded in 1993 (US
-
based);



Several mid
-
size biotech companies who are developing TB vaccine candidates or
technologies, often in conjunction with PPPs e.g. InterCell Corporation (Austria);

and
Corixa Corporation, Sequella Inc. and EpiVax Inc. (all US
-
based);



Several major pharmaceutical companies, including GSK
-
Biologicals, Aventis and
possibly Astra
-
Zeneca (all EU
-
based) who continue to work in the field of vaccines
generally. The NIAID n
otes that major industry research is “relatively low level but
steady”, although it can nevertheless play an important role.
40



A multitude of academic researchers funded through public research grants.


Vaccine lessons

The upsurge in R&D into TB vaccines ov
er the last decade has been made possible by recent
advances in basic TB science, in particular sequencing of the TB and related genomes;
development of new techniques for molecular manipulation of mycobacterial genomes; and
progress in our general underst
anding of TB and its biochemistry, biology and disease
mechanisms. These advances were, in turn, made possible through substantial increases in
public and not
-
for
-
profit funding for TB research since the early 1990s. For instance, the US
increased its TB

research funding from $3.6 million in 1991 to around $60 million in 2001,
Chapter 6.8: Tuberculosis




6.8
-
20

and the Wellcome Trust funded public discovery of the TB genome.
41

Progress in the more
general field of vaccinology, including by industry, has also been an important stimulus e.g.

the use of DNA immunisation and adjuvant technologies.


A second, and related, lesson is that our current state of scientific understanding and
technical tools, while improved, is still insufficient to support rational, targeted TB vaccine
development.

The current plethora of empirical vaccine candidates stems not from a
richness of proven opportunities, but rather from a lack of certainty as to where R&D efforts
are best focussed. Finally, the difficulty and expense of vaccine development suggests fut
ure
advances will continue to be through public
-
private collaborations, with no single group
having sufficient resources to bring a TB vaccine to completion alone.

Existing Resource Flows for TB R&D

Basic research

Most Western donors provide grants for T
B basic research to academic and public health
institutions. Total TB research funding (public and not
-
for
-
profit) is estimated by the
WHO/TDR at approximately $125 million per year in 2000.
42

As noted above, the US
National Institutes of Health (NIH) are
by far the largest investors, providing around half to
two
-
thirds of funding in most years. The US Centers for Disease Control, and Wellcome
Trust have also been major funders. The EC has been a more modest investor, providing
Euro 28 million over 4 years

for TB research under the Fifth Framework Programme
(approximately $8.5 million per year at March 2004 conversion rates). An unspecified
proportion of this goes to basic research (including structural and functional genomics,
molecular epidemiology of MD
R strains in Europe, and studies of the development of drug
resistance).
43

(See
A
nnex 6.8.8
)


Diagnostics

Development of new TB diagnostic tools was supported by a 2001 grant of

$10 million over 5
years from the Bill and Melinda Gates Foundation to the TB Diagnostic Initiative within
WHO/TDR. This was boosted in 2003 by a $30 million grant, also from the Gates Foundation,
to set up FIND. The EC’s Fifth Framework programme provide
d Euro 13 million for drug
and diagnostic R&D (the diagnostic proportion is not known), and the NIH also offers
relatively small amounts (for example, approximately 0.6 million through Small Business
Innovative Research Awards from 2002
-
2004). Expenditure
by companies is unknown.


Drugs

Resources for TB drug development come from 3 sources: industry investment, PPPs and
public investment. Although the three
industry TB research institutes

account for a relatively
small proportion of the pharmaceutical in
dustry’s current $40 billion annual spend on new
drug research, they nevertheless represent a substantial contribution to global TB drug R&D.
Astra
-
Zeneca invested $10 million to set up its 70
-
person Research Institute in India, with a
$5 million R&D budg
et for 2001; Novartis and the Singapore Government are jointly funding
the 70
-
person Novartis Singapore Institute with $25 million/year for 5 years (their respective
contributions are unknown); and TB
-
dedicated resources at GSK’s Tres Cantos centre are
unk
nown.
44


Chapter 6.8: Tuberculosis




6.8
-
21

Funding for
Public
-
Private Partnerships

is surprisingly small given their leading role in TB
drug development. The only PPP for TB drug development
-

the TB Alliance
-

has raised $42
million since 2001, the bulk of this from the Rockefeller Founda
tion ($15 million pledged)
and Gates Foundation ( $25 million grant). This sums are insufficient to finalise development
of the TB Alliance’s most promising lead compound, let alone other compounds in its
portfolio.


Public investment

in TB drug developmen
t takes a number of forms. Both EU governments
and the US offer a wide range of general R&D incentives to the pharmaceutical industry
including research subsidies, tax breaks and Orphan Drug market exclusivity. For instance,
the UK instituted a 150% tax

break for neglected disease research in 2002, and U.S. Orphan
Drug incentives (commenced in 1982) supported development of the industry TB drugs
noted above. The total costs of these financial incentives for industry are unknown, although
thought to be s
ubstantial, nor do we know the proportion devoted to TB. The U.S. also offers
in
-
kind support to industry (see the TAACF below).


However,
direct

public investment in novel TB drug development is far more limited. The
TB Alliance has received only one go
vernment grant (Euro 2 million from the Netherlands
Gov’t) to develop its current portfolio of ten compounds; and the GSK
-
NIH
-
St. Jude’s project
received a 3
-
year NIH Challenge Grant of $1.2 million with a matching contribution from
GSK to develop thiolact
omycin. Resources for the remaining two biotech projects are
unknown, although the NIAID provides support to both. The EC Fifth Framework
Programme provided Euro 13 million over 4 years for TB drug and diagnostic R&D,
including for basic research and epide
miology, with an unknown proportion going to drug
development.


The US also provides in
-
direct support in the form of in
-
kind contributions to TB drug
development. This is in the form of access to the NIH network of contract research
organisations and gr
antees (the TB Alliance estimates this contribution at equivalent to $1.5
million); as well as access to NIH in
-
house research capacity, in particular the important
services of the TB Antimicrobial Acquisition and Coordinating Facility (
see boxed text
).

Chapter 6.8: Tuberculosis




6.8
-
22


The Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF)

The TAACF was established by the NIAID in 1994 to encourage and support academic researchers
and pharmaceutical companies to re
-
enter the area of TB drug development. TAACF servic
es are free
to researchers anywhere in the world, including PPPs, industry and academic researchers; and data
are kept confidential in order to protect the user’s intellectual property (IP). The overall service is
managed by the Southern Research Institut
e (SRI), with individual services provided at five US
-
based
centres, as below:


High
-
throughput screening (HTS)

of large compound libraries


in particular industry compound
libraries
-

against validated TB targets. HTS has been provided by the SRI since
2001/2002. The SRI
and collaborating institutions (e.g. Texas A&M University) also develop, validate and optimise target
assays against which screening can be conducted.


In vitro

screening

of promising individual compounds or compound groups, performed
by the
National Hansen’s Disease Program in Baton Rouge, Louisiana. This step is readily available to public
researchers, who generally have the capacity to produce the small amounts of compound needed
(usually between 1
-
7mg).
In vitro

screening is, howev
er, slower and far more labour intensive than
HTS, although this can be improved by robotisation of some steps. Compounds that pass all screens
successfully are then referred for
in vivo

testing. TAACF data show that of more than 50,000
compounds screened
, over 500 were successful «

hits

» and approximately 200 had sufficient in vitro
potency and selectivity to warrant further testing as compounds with promising anti
-
TB activity.


In vivo

screening

of compounds that have shown
in vitro

activity is perfo
rmed by Colorado State
University. Promising compounds are tested for their capacity to inhibit the growth of TB in an
aerosol mouse model, using genetically modified mice that can deliver results in one month instead of
the usual three.


Medicinal chemi
stry

and structural analysis

services are also offered by the TAACF. These allow
promising groups of screened compounds to be narrowed down to the most active compound
structures within the group


the first step to identifying a drug lead.


Technology tr
ansfer

support is managed by the Research Triangle Institute (RTI). If the submitting
group is interested, the RTI can help find partners and funding opportunities.to further develop
promising anti
-
TB compounds identified by TAACF screening.


Chapter 6.8: Tuberculosis




6.8
-
23

Discussion

The TAACF is funded at around $2 million per year for all five facilities, and has now identified over
500 possible anti
-
TB compounds or «

hits

» from over 400 suppliers worldwide. This service has been
invaluable, however the TAACF still faces challenges
.

To date, no large companies have used the TAACF’s High
-
Throughput Screening service (although it
has also not been heavily marketed), apparently due to industry’s preference for keeping intellectual
property in
-
house. In response, the TAACF have sought

to purchase compound libraries, but note
that this is very expensive, costing around $100,000 for a 100,000 compound library, plus an estimated
additional $100,000 to put these through HTS. They are not currently budgeted to this level. An
alternative a
pproach suggested by TAACF staff might be to transfer TAACF
-
developed assays to
industry, who could then conduct in
-
house screening. This approach would protect their proprietary
knowledge


but industry would also have no obligation to divulge promising
results (or negative
results), or to conduct further drug development on any promising compounds discovered.

In vitro screening has been popular, as witnessed by the figures above. The majority of users are
academic groups (75%), with a further 10% of co
mpounds coming from small companies such as
biotechs. Only around 3% of compounds have been submitted by large drug companies, and often in
response to a specific request by the TAACF (for instance, due to the TAACF following up an
interesting literature
report on a company
-
held compound). Industry are apparently reluctant to
submit compounds since this would require them to reveal compound structures to the TAACF (the
TAACF in turn requires structure disclosure as a precaution against patent infringemen
t claims later
in the day). A possible approach would be for the TAACF to conduct screens blind, however they
would have no way of knowing which compounds were promising, or whether hits were being
pursued.

Many academic groups are unable to progress c
ompounds past the
in vitro

stage, since they lack the
capacity to scale
-
up production to the quantities needed for
in vivo

testing (up to 1gm of compound is
needed), and are unable to produce the large numbers of analogues used for secondary screening of a

promising compound or group. The TAACF has suggested that this could be overcome by providing
government
-
subsidised access to Contract Research Organisations (CROs) who could provide these
skills: these contracts could be extremely valuable to CROs. Fin
ally, the TAACF’s medicinal
chemistry services are warmly welcomed by non
-
industry groups but less relevant to industry which
has superior experience in this area.

The two most significant challenges identified by the TAACF were the inability to share in
formation
on promising «

hits

» with other researchers, since the TAACF is bound by confidentiality agreements;
and the lack of any follow
-
on mechanism to ensure that promising hits are followed up by either
academia or industry. Although some academic gr
oups will publish their results, most have neither
the incentives nor financial support to carry research forward into drug development. Likewise, our
current system actively incentivises industry to keep information (either positive or negative) in house

and, as noted above, does not highly reward investment in further TB drug development. Even if
participants were willing to follow up all promising «

hits

», there is a further obstacle: no one is
currently funded to do this work. While the TB Alliance

certainly has the scientific expertise to
identify the most promising «

hits

», its current under
-
resourcing means it lacks the capacity to
include many additional early stage compounds in its portfolio.

These latter obstacles are less easily overcome, si
nce they hinge on the management of intellectual
property. Solutions under consideration include a substantial incentive package for large
pharmaceutical companies who have little to gain from a TB drug, but fear the loss of IP. Likewise,
improved incent
ives to encourage academic researchers to relinquish or share IP would be valuable


and possibly less expensive.


Chapter 6.8: Tuberculosis




6.8
-
24

Finally, governments provide indirect assistance through supporting clinical trials and
building clinical trial capacity. This support is mo
re evenly balanced between the EU and
US, in particular since the launch of the European and Developing Countries Clinical Trials
Partnership (EDCTP). Major groups now supporting TB trials include the CDC and NIH
(e.g. through the NIAID, TBTC and TBRU);
the International Union Against TB and Lung
Disease; the EDCTP; and WHO/TDR, although the latter is constrained by resources. The
EDCTP budget is EUR 600 million over 5 years for AIDS, TB and malaria; while the TDR’s
budget is around $30 million/year for

both drug development and research capacity building
for all ten diseases in its portfolio.
45



Vaccines

Global investment in TB vaccine R&D was estimated at around $80 million per year in 2003,
a figure which was dramatically increased by a recent large

grant from the Bill and Melinda
Gates Foundation (see below).
46


The EC Fifth Framework programme allocated Euro 15 million (just under Euro 4 million per
year) to vaccine research, chiefly through the EC TB Vaccine Cluster (TBVac). In addition,
the EU is

funding research into alternative vaccine delivery mechanisms (2 projects), and
conducting early work to set up vaccine clinical trial sites in Africa (2 projects). The EDCTP
also offers funding support at the Phase II and Phase III stages of clinical tr
ials.


The largest public supporter of TB vaccine research is, however, the U.S., in particular the
NIAID, which provides:



Academic grants for TB vaccine research (basic research and vaccine candidates)



The TB Research Materials and Vaccine Testing contra
ct, which provides:

o


high quality TB research reagents to investigators throughout the world.
(One of the obstacles to TB vaccine research is the lack of quality reagents
from the contagious and technically difficult TB mycobacterium.);

o

screening of TB v
accine candidates (over 170 candidates already screened);



The TB Research Unit (TBRU) supports an international collaboration of scientists
working on immunological markers of infection; surrogate markers for vaccine trials;
and clinical trial capacity bui
lding;



Infrastructure for Phase 1 and 2 human trials is made available to industry and public
researchers (via the TBRU and the Vaccine and Treatment Evaluation Units; as well
as the CDC’s TB Trials Consortium).

Further U.S. support is provided through:



The CDC (as above);



The U.S. Food and Drug Administration, which will assist manufacturers in
developing and licencing any new TB vaccines.


Private not
-
for
-
profit groups are increasingly major funders of TB vaccine research,
including:



The Bill and Melind
a Gates Foundation, who donated just under $83 million to the
Aeras Global TB Vaccine Foundation in February 2004.



Infectious Disease Research Institute (budget unknown)


Chapter 6.8: Tuberculosis




6.8
-
25

Resource flow lessons

This review of resource flows holds a number of lessons. The f
irst is that government
funding at the basic and clinical trial stages is relatively well
-
developed, and increasingly
shared between the EU and U.S., but that funding for development of new TB tools


especially drugs and diagnostics
-

is, to be honest, a
bit of a mess.


Government financial incentives that do exist are largely aimed at and designed for the
wrong target i.e. in
-
house R&D by multinational pharmaceutical companies (MNPs).
However, the majority of MNPs no longer have scientific expertise in T
B and have expressed
a clear disinterest for working in this field; while those who are involved, have mostly
shown a preference for working through PPPs or in public collaborations rather than
developing drugs entirely in
-
house. Industry financial incen
tives are also poorly designed
for the smaller biotechs, medical technology firms and Contract Research Organisations
(CROs) who are now the main industry players in TB research: for instance, tax breaks are of
little or no interest to companies with nega
tive or small profits; and market exclusivity and
patent extensions are of limited relevance to one
-
product companies.


There is also a striking lack of public funding for the groups who driving development of
novel TB tools, in particular the TB Allianc
e, which dominates the field. Indeed, current TB
drug development


vital if we are to control TB and MDR
-
TB
-

is resting on the shaky
foundation of two philanthropic donations and a handful of in
-
kind support from the U.S.. .


A second major lesson is t
hat the EU does not appear to have positioned itself strategically in
terms of new TB tools, leaving the U.S. to play a dominant role. For instance, the EU
provides less than 5% of the funding dedicated to TB drug development projects and, unlike
the U.S.
, offers neither in
-
kind nor infrastructural support for most stages of drug
development. No EU academic groups, public health institutes or biotech companies
collaborate in TB Alliance projects, although a small number of EU institutions are members
of th
e TB Alliance’s expert advisory groups (See
Annex
6.8.
7

for list). The bulk of funding
for new TB tools comes from U.S. philanthropists; and drug development is dominated by
U
.S. research institutions (7 of 11 projects) and biotechs (all U.S. based). Trials to adapt
existing antibiotics for TB are also dominated by U.S. institutions, which were conducting 12
of the 13 projects identified by Stop TB as of end 2003. (See Table 3

for full details.)

What is the Current Pipeline?

TB Diagnostics


As noted above, there is a reasonably high level of activity in TB diagnostics, with new tests
at every stage of the R&D pipeline from proof of principle through to Phase III trials.
Alth
ough currently too expensive and technically difficult for resource
-
poor TB settings,
many tests have potential for such use, if adapted.

Diagnostics of particular interest include:

a) Rapid culture and DST systems (rapid detection of organisms and drug

resistance)



Oxygen quenching
MGIT (Becton Dickinson, USA)



Colorimetric liquid culture (Biotest, Germany)



Nitrase reduction assays (Sweden, Russia)



Colorimetric solid culture (TK medium, Turkey)

Chapter 6.8: Tuberculosis




6.8
-
26

b) Culture surrogates (for case detection and drug resistan
ce)



Phage amplification: FastPlaque (Biotec, UK)



Luciferase reporter
-
phages (Sequella Inc, USA)


c)

Molecular methods (nucleic acid amplification for the detection of TB organaisms or for
rapid detection of rifampin resistance)



Inno
-
LIPA (Innogenetics, B
elgium)



PCR (Roche, Switzerland)



SDA (Becton Dickinson, USA)



BioChip (Englehardt, Russia)



TMA (GenProbe, USA)

d)

Tests detecting antigen or volatile gases.
This work is at an earlier stage, just short of
proof of principle and, although technically chal
lenging, is considered promising.



Blood based tests to detect TB antigens (KIT, Netherlands; Univ. Bergen, Norway;
Lionex Diagnostics GBH, Germany; Pasteur, Madagascar)



“Electronic noses” to detect antigens in breath (KIT, Netherlands; Cranfield
University
, UK).

e)

Tests for latent TB infection, capable of distinguishing it from prior BCG vaccination or
infection with non
-
tuberculous species of mycobacteria.



Whole blood IFN
-



ELISPOT (Oxford Immunotec, UK)

f) L
aboratory free tests for active infection using transient cellular immunity



Skin patch test using MPT64 (Sequella Inc., US), now in Phase II trials


TB Drugs


As seen from the Matrix below, all stages of the TB drug pipeline are thin. The discovery
and le
ad identification stages, which provide new compounds to enter the TB pipeline, have
only a handful of projects; and the few compounds that are in development tend to be at the
earliest pre
-
clinical stages. This means we cannot expect a
novel

TB drug, act
ive against
both MDR
-
TB and drug
-
sensitive TB, until at least 2010.


From a first glance at this matrix, the late pipeline appears to be relatively full, however it
should be noted that these products are
existing antibiotics

in clinical trials for a new

TB
indication, rather than genuinely novel anti
-
TB drugs. The final products will therefore
probably be unsuitable for MDR
-
TB use, although they are promising in terms of simplifying
and shortening non
-
MDR TB treatment, and may be available as early as 2
007
-
2008.
See
Table 3 matrix.


TB Vaccines


Development of new TB vaccines has reached an important turning point, with a decade of
experimental laboratory modelling now leading to entry of the first vaccine candidates into
clinical trials. If successful,

delivery of a final vaccine will take at least 10 years (2014).


Chapter 6.8: Tuberculosis




6.8
-
27

Vaccine type

Developer

Clinical trial stage

Recombinant MVA (modified
vaccinia) Ag85A



Oxford University

Wellcome Trust (UK)

TBVac

Phase I, in UK and Gambia

(commenced 2001)


Live attenua
ted recombinant BCG
rBCG30

Aeras Global TB Vaccine
Foundation

UCLA, U.S.

NIAID

Phase I clinical trials (30
subjects)

Subunit vaccine/adjuvant (M72S)

(used as either a BCG booster or
an improved BCG)


NIAID

IDRI

Corixa Corporation

Licenced to GSK

(Possib
le EDCTP and Aeras
interest in trials)

Phase I clinical trials (20
subjects)

Subunit vaccine/adjuvant

-

ESAT
-
6 plus Ag85B

Staten Serum Institute
(Denmark)


Possibly Phase I in 2005

Multi
-
epitope subunit
vaccine/adjuvant

InterCell Corporation

Aeras Founda
tion

Uncertain progress: will
probably be abandoned

Opportunities for Research into New Pharmaceutical Interventions

a)

What is the state
-
of
-
the
-
art science for TB



what opportunities does it offer?


The greatest opportunity


and one which is realist
ic and achievable


is to apply our
existing scientific and technological skills to develop families or groups of compounds or
technologies already known to have anti
-
TB potential, but which have not progressed due to
lack of political will and funding.
47

(
See
A
ppendix 6.8.1
)
Seizing this opportunity alone
would deliver a broad range of new tools to address the growing threat of TB in Europe and
elsewhere.
Three opportunities stan
d out:



Completion of promising novel drugs already in the pipeline;



Adaptation of existing TB diagnostics for use in resource
-
poor settings, including
tests for screening, diagnosis and MDR
-
TB detection

;



Further investigation of compounds with promising a
nti
-
TB activity, and screening of
industry compound libraries to find remaining anti
-
TB compounds that have not
been examined and taken forward.


Scientific advances have also opened up a number of new opportunities, as listed below.
The most significant
breakthrough has been the decoding of the TB genome and other
mycobacterial genomes, and follow
-
on work by the TB Structural Genomics Consortium to
identify the TB genes and associated proteins responsible for latency, persistence and
activation of TB (the

first 40 proteins have already been elucidated).
48

This work, once
completed, will be the first step towards rational design of new TB tools, rather than the
resource
-
intensive empirical approach currently used to develop new drugs and vaccines.
The deve
lopment of TB fixed
-
dose combinations (FDCs), rather than single
-
drug
formulations, has also been a major therapeutic advance, in particular because of the role
FDCs play in reducing maladministration and consequent MDR
-
TB.


Key areas for further research
include:

Chapter 6.8: Tuberculosis




6.8
-
28

Basic science
49



Improved understanding of how TB “works” in the human host, in particular disease
models of latency, persistence and re
-
activation;



Improved understanding of the human immune response to
M. tuberculosis
,
including: the role of vario
us T
-
cell populations; the molecular signals that activate
the protective immune response; and the TB antigens that induce human protective
immunity.

Diagnostics



Increased discovery research into new diagnostic approaches



Increased research into new delive
ry methods, for example the “electronic nose”
concept noted earlier.

Drugs



Research to sift through TB target proteins (target validation), including those now
coming out of the TB Structural Genomics Consortium, in order to identify the most
promising tar
gets for drug and vaccine development.
50




Development of surrogate markers that can act as early end
-
points for success or
failure during clinical drug trials (we now have to follow patients for 2
-
years to rule
out treatment failure). Use of surrogate mar
kers would substantially reduce both the
cost and length of clinical trials, expediting the arrival of new drugs.
51




Aerosol drug delivery mechanisms that promise to rapidly debulk pulmonary TB
and to extend our range of treatments to drugs that cannot be
administered orally
because of poor pharmacokinetics or side
-
effects of high system exposure. However,
work in this area is early, and use may be limited by the expense of delivery
devices.
52



Depot formulations of existing TB drugs, which offer the promise
of once
-
monthly
administration instead of observed daily administration, delivering significant
benefits in terms of adherence, reduced creation of MDR
-
TB and lower TB
programme costs. Reports on depot preparations were published as early as 1966,
with fol
low
-
up studies by the University of Illinois showing that a
single
subcutaneous polymer depot implant of INH and pyrazinamide delivered the same
therapeutic activity as daily administration over 8 weeks.
53
54

Industrial technologies
for depot preparations al
ready exist (e.g. polymers or microspheres), as do the
component drugs, making this an interesting area for investigation.



Slow
-
release oral formulations of existing TB drugs, which maintain plasma levels for
around 3 days, theoretically allowing twice
-
wee
kly dosage. Research in this area has
been conducted
since 2001
by the

Postgraduate Institute of Medical Education and
Research, Chandigarh, India. As with depot preparations, the technologies and
component drugs already exist, again making this a promis
ing area for further
research.



Development of further fixed
-
dose combinations, in particular combinations that
include second
-
line drugs and new drugs that come out of the development pipeline.

Vaccines
55



Development of surrogate markers of vaccine
-
induced

immunity. In their absence,
clinical trials to establish immune status are likely to be very expensive, requiring
“long duration and/or enormous cohort sizes”, for instance patient follow
-
up would
need to be an estimated minimum 3
-
4 years post vaccinatio
n;
56

Chapter 6.8: Tuberculosis




6.8
-
29



Lack of cheap, simple diagnostics to distinguish BCG
-
vaccinated patients from those
with latent or active TB. In their absence, “identification of the appropriate patient
population remains a challenge”


a huge obstacle to clinical trials


with diag
nostics
being described as “essential tools for...clinical evaluation of candidate vaccines”;
57




Improved vaccine adjuvants;



Improved animal models to better mimic the action of TB in humans (eg. persistence,
reactivation and the cross
-
effect of non
-
pathoge
nic and environmental bacteria, and
of prior BCG vaccination);



Identification of the optimal route for vaccination (nasal, oral, intradermal etc.)
58


b)

What is the current status of institutions and human resources available to
address TB

?

Structural geno
mics



The TB Structural Genomics Consortium, set up in 2000. The TBSGC is composed of
70 member laboratories in 12 countries around the world, supported by central
facilities at three U.S. sites. Just under a third of member institutes are located in EU
M
ember states. (See
Annex
6.8.
5
for full list).

Basic research



Informal institutional support, funded through grants from national governments
and institutions, with the US be
ing the predominant funder;



The TB Alliance provides some assistance (e.g. through establishment of expert
working groups and seminars).
59

TB diagnostics



TDR (which plays a supportive role)



FIND (PPP): active review and prioritisation of technologies and
co
-
development of
new TB diagnostics with industry



Neither of these addresses discovery research, which is largely being supported
(under
-
supported) through ad
-
hoc national research grants



Limited NIH support



Within the EU, there are 28 biotech companies,

and at least 5 academic institutions
and 4 public institutes, working on TB diagnostics. (See
Annex
6.8.
6

for list.)

TB drugs



The TB Alliance (PPP): active review of promisi
ng compounds and development of
new TB drugs



Broad NIH support, including through the TAACF



A list of EU
-
based academic institutions and industry groups working in this area is
attached at
Annex
6.8.
7




There is limited institutional support for research into alternative drug delivery
mechanisms, which is largely conducted through ad
-
hoc national research grants,
including:

o

Animal studies of aerosol rifampicin (academic groups in

U.S., India and
UK);
60

and a later stage human trial of aerosol capreomycin for MDR
-
TB
(NIAID/TBRS/Masan/ Yonsei: see Table 3);

o

We are not aware of any formal institutional support for research into depot
or slow
-
release drug preparations, although

indust
ry (including small to mid
-
size firms) is very active in the high
-
growth area of alternative delivery
Chapter 6.8: Tuberculosis




6.8
-
30

technologies.
i

Two academic groups working in this area are the University
of Illinois (US) and the
Postgraduate Institute of Medical Education and
Resea
rch, Chandigarh, India.




Target identification and validation research:

o

Some institutional funding from NIAID (40 grants) See Table 3


Surrogate markers for drug and vaccine trials



The NIAID provides some funding (e.g.TBRU
-
Case Western Reserve University
-
Makerere University Uganda project);



GSK previously had a joint project with Stellenbosch University (South Africa) under
its Action TB initiative;



Informal support for academic research, funded through grants from national
governments and institutions.

Va
ccines



Aeras Global TB Vaccine Foundation (PPP)



The Infectious Disease Research Institute (PPP)



The European Commission TB Vaccine Cluster (see
Annex
6.8.
6

for member list);



B
road NIH support (see above)



Adjuvant development is moderately well supported, with significant industry
activity (biotechs and major companies) and some public grants (e.g. NIAID);



Alternative delivery models receive very little support, and mostly throu
gh ad
-
hoc
research grants (e.g. the EC funds 2 projects; NIH grant to Uni. North Carolina)

Are there research gaps that could be filled affordably, have a
significant impact and be achieved in a) 5 years or b) the longer term?
Which of these are pharmaceu
tical research gaps?

Investment into TB research offers two main opportunities: areas where relatively small
investments can deliver large returns; and areas where investment into a research gap or
bottleneck will deliver increased flows throughout the R&D

pipeline. These are outlined
below.


Basic research


A shortlist of validated molecular targets would revolutionise TB drug development by
allowing industry to move towards rational drug design in addition to current methods (e.g.
methodical examination
of compounds with known anti
-
TB activity). There have been
dramatic scientific steps in this direction, with the TB Structural Genomics Consortium now
examining the genetic basis of TB latency and persistence, and systematically publishing the
structure of

TB proteins (some of which will be valuable drug targets). However, we will



i

A 2004 conference noted that d
rug delivery systems and emerging technologies accounted for $38 billion in
revenues in 2002, with expected growth of 28% per annum over the next 5 years. Conference Ref

:
Drug Delivery
Systems, Europe 2004
-

Business Development, Emerging Technologies No
vel and Niche Delivery Methods; 25th
& 26th February 2004, London. Accessed March 2004 at
http://www.visiongain.com/b2b/Drug_delivery.htm




Chapter 6.8: Tuberculosis




6.8
-
31

not be able to capitalise on these advances unless we increase our input in two areas: target
identification and validation; and further research into disease models of latency
and
persistence.
61


Target identification and validation is the process of sifting through TB proteins to identify
those most likely to be useful for drug development (most relevant to the disease process
and most technically tractable). This work is in tu
rn facilitated by a better understanding of
the principles of latency, persistence and reactivation, and of the human immune response to
M.tuberculosis

infection.


The time is ripe for intervention in this area, since the TB Structural Genomics Consortium

(TBSCG) is already delivering TB protein structures, which will need to be prioritised in
terms of their relevance to TB disease mechanisms and many EU groups are already
involved in the TBSCG.


Diagnostics


Diagnosis is currently the rate
-
limiting step

in entry to TB treatment, with less than half of all
patients with active infection being diagnosed and treated. Within an expanded EU, there is
also an urgent need for cheap, rapid and reliable tests for TB screening (CXR is notoriously
unreliable) and
MDR
-
TB diagnosis (ideally within 3 days). The development and
implementation of such tests is well within reach.


There are promising TB diagnostics at all stages of the pipeline, and a plethora of low
-
hanging fruit in the form of existing tests that need
relatively cheap and minimal adaptation
before they could be used in TB and MDR
-
TB endemic settings. Diagnostic development is
far less resource
-
intensive than drug development, with an average new test costing between
$5
-
20 million to develop, compared to

the estimated $800 million needed for fully industrial
development of a new drug (adaptation of existing diagnostics is even cheaper).
Development times are also far shorter, at around 1
-
3 years compared to 10
-
15 years or more
for new drugs or vaccines. F
IND expects to produce the first new field
-
relevant diagnostics
in 2005
-
2008, with a stream of further trial results over the next 5 years.


EU support for new TB diagnostics has additional merits beyond the obvious need, and the
cost
-
effectiveness and fea
sibility of new tests. The EU already hosts a number of TB
diagnostic firms (28), as well as a network of Supranational Reference Laboratories (SRLs)
tasked with supervising MDR
-
TB diagnosis in laboratories in Eastern and Central Europe,
FSU and developing

countries.
j

Renewed TB diagnostic activity is now centred in Europe,
with both FIND and the TDR located in Geneva; and the mechanics of any EU intervention
would be significantly simplified by the presence of a single PPP in the diagnostic field
(FIND), w
hich has reliable start
-
up funding and well
-
established links with pharmaceutical
firms working in diagnostics. FIND offers the added advantage of having the scientific
expertise (including senior staff attracted from the CDC and TDR) to prioritise the co
nfusing
array of existing and new TB diagnostics, allowing R&D investments to be optimally
targeted. (See
Annex
6.8.
6

for a list of EU
-
based firms with interesting technologie
s.)




j

SRLs exist in the UK, Sweden, Germany, Italy, Bel
gium, amongst others.

Chapter 6.8: Tuberculosis




6.8
-
32


Finally, unlike R&D into TB drug development
-

which is already dominated by U.S.
funding, researchers and industry
-

the field of TB diagnostics is still “up for grabs”. The
NIH is currently looking at TB diagnostics to see whether it has a role to p
lay, but its activity
is still largely limited to blue skies research and field trials
-

in other words, it is an area
where the EU has room to make its mark.


Short
-
term, cost
-
effective results (< 5 years) could be achieved by:

1.

Funding FIND directly, in

conjunction with the Gates Foundation, to co
-
develop
tests with industry. Such an approach would support EU industry, while keeping
R&D firmly focussed on optimal public health outcomes;

2.

Providing industry incentives to encourage and reward EU
-
based diag
nostic
firms who work with FIND to develop new field
-
adapted tests, including new
tests for TB screening, and rapid (3
-
day) tests for MDR
-
TB. These incentives
should be designed with biotech companies in mind, since these dominate the
field;

3.

Ensuring ED
CTP support is allocated to trials of new and existing diagnostics,
including through FIND and TDR.


The EU could also fuel the longer
-
term diagnostic pipeline by funding the significantly
under
-
supported area of diagnostic discovery research. This would
in turn provide new
leads, which EU
-
based diagnostic firms could develop for Western markets and adapt, in
conjunction with FIND, for resource
-
poor countries. Possible approaches include:

4.

Funding FIND to either a) extend its scientific pipeline to the di
scovery stage; or
b) employing FIND as a technical advisory body to review existing approaches
and provide the EU with information on which are most promising

5.

Providing a formal funding stream for public research into TB diagnostic
discovery and encouragi
ng member states to do so.


Conversely, the EU may wish to directly support the biotech industry by providing
incentives for the industry to develop more sophisticated versions of any simple, new field
-
adapted tests that appear, for instance by developing
robotised assays for use in higher
-
income EU and Western markets.
k



Drugs


The biggest gap in TB drug development is primarily structural rather than technical. While
it is true that technical hurdles exist in identifying compounds, that the models of in
fection
are challenging and that clinical trials take years to undertake, nevertheless given adequate



k

A matter that is not related to R&D, but is nevertheless important to the EU. It would be extremely helpful if
EU
-
based Supranational Reference Labs could be funded to conduct their supervisory role with respect to
developing count
ry TB laboratories, in particular laboratories in high MDR
-
TB areas of Eastern and Central
Europe: this work is currently performed voluntarily. The lack of approved, high
-
quality national TB
laboratories in some countries (e.g. Russia) makes it extremel
y difficult to either map or control MDR
-
TB in these
settings and, by extension, the wider European forum. SRLs have repeatedly expressed willingness to increase
their contribution in this area, if funded.


Chapter 6.8: Tuberculosis




6.8
-
33

human and financial resources these problems can be addressed. What is lacking is the
commitment to overcome these problems.


As noted above, some large
pharmaceutical companies now play a significant role in TB
drug discovery, while TB drug development is dominated by publicly
-
driven groups, in
particular the TB Alliance, with the biotech sector playing a more minor role. The TB
Alliance has shown itself

willing and capable of developing new TB drugs, and the
pharmaceutical industry (in particular biotechs and CROs) are equally willing to provide the
necessary technical skills if paid or incentivised to do so. However, the EU currently has no
financial
tools to link these two groups together


neither direct funding for the TB Alliance,
to facilitate outsourcing of contracts; nor subsidised Alliance access to industry in
-
kind
services; nor incentives to encourage industry to offer in
-
kind services to the

Alliance.
Likewise, there is limited support for biotechs working in this sector, with many of current
industry incentives being poorly suited to smaller companies.


This lack of support for TB drug development, or for a role for EU industry in this
deve
lopment, is particularly surprising given the EU’s urgent need for more effective and
affordable drugs to manage TB and MDR
-
TB in an expanded EU. The EU accession
countries now report nearly 1,000 new cases of MDR
-
TB each year, and 4,721 cases of TB that
are resistant to at least one TB drug.
62

Differing costs between countries make the cost of
treating these cases difficult to estimate, however, at Latvian prices, treatment costs for all
new MDR
-
TB patients in the accession countries would be EUR 105 mill
ion in the next
decade, assuming no increase in patient numbers or in annual treatment costs.
63

We could
probably double or even triple this figure since, as noted above, TB numbers are trending
upwards at around 5
-
7% per year in the relevant countries; an
d costs will be far higher for
patients who enter Western European health systems (the US estimates $250,000 per patient,
compared to Latvia’s $12,500 per patient). In addition to MDR costs there are, of course, also
the costs of providing lengthy DOTS tr
eatment to the more than 50,000 cases of “normal” TB
reported in Europe and the accession countries each year (over 80,000 cases if the second
-
line
accession countries are included).
l

In the UK, “normal” TB treatment is estimated at $9,029
per patient, of

which only $200 is drug costs.
64


By contrast, the cost of developing a new drug that allows short, effective treatment of MDR
-
TB (and “normal” TB) is estimated at $76
-
115 million from lead compound up to registration,
including the cost of all failed proj
ects.
32

The final drug would be available not only for
MDR
-
TB patients in Europe but for all TB patients worldwide.
65


EU support for new TB drugs would not only cost
-
effectively address Europe’s substantial
and

growing TB problem but, if based on a well
-
thought out incentive or investment
structure, could also support the competitiveness of the EU
-
based pharmaceutical industry
(in particular biotechs and CROs) and their profitable involvement in TB drug developm
ent
activities that are currently dominated by US companies and institutions.





l

By “normal”, we mean TB uncomplicated by HIV/A
IDS or multi
-
drug resistance.

Chapter 6.8: Tuberculosis




6.8
-
34

There are three main areas where EU investment in TB drug R&D represents “value for
money”. These are:


1.

Discovery of promising TB lead compounds

2.

Lead optimisation and pre
-
cl
inical

3.

Clinical trials of existing drugs.


1.

Drug discovery research and lead identification
. These first steps in the drug
development process involve identifying the best approaches to a known target (eg.
inhibitors of DNA synthesis), and narrowing the
se down to a group of active compounds
(e.g. pyridones). These compounds can be discovered either by high throughput screening
of large industry compound libraries, or by targeted
in vitro

and
in vivo

screening of
compound families with known anti
-
TB acti
vity. Medicinal chemistry techniques are then
applied to screening results in order to determine which, among the many structures in a TB
-
active compound group, is most likely to be safe, effective and feasible i.e. a lead compound.


These R&D areas are

crucial, since relatively high numbers of lead compounds must enter
the pipeline in order to deliver a single successful TB drug


yet, as of end 2003, there were
only 6 discovery projects and 3 lead identification projects underway. (
See Table 3
) There

is
little direct public funding for discovery research, which is currently being conducted almost
entirely by EU
-
based industry (GSK, Astra
-
Zeneca and Novartis) and falls outside the remit
of the TB Alliance. The TB Alliance is more involved at the lead

identification stage, and
offers some support


for instance, it is developing a publicly
-
available database of the many
known compounds with anti
-
TB activity; while the NIH also provides a free screening and
medicinal chemistry service through the TAACF,

which could theoretically screen these
compounds (
see boxed text
). However, the TAACF’s services are ad
-
hoc rather than
systematic, being provided at the request of academic institutions, biotechs or industry who
are interested in and funded to do TB res
earch. There is no systematic method to review all
known promising compounds, nor is there systematic access to industry compound libraries,
most of which remain closed to public researchers.


Possible EU approaches could include:



Setting up a consor
tium of European academic institutions and industry groups
(perhaps similar to the successful TB Structural Genomics Consortium) who would
systematically prioritise, and submit for screening, those compounds with known or
suspected anti
-
TB activity, using
the TB Alliance database as a guide;



Supporting this consortium by providing a free EU
-
based facility for
in vitro

and
in
vivo

screening, taking into account the TAACF experience. (This approach is not
predicated on access to company
-
held intellectual pro
perty);



Sub
-
contracting CRO’s to produce analogues of promising compounds (“hits”)
identified by screening, with these hundreds of analogues then entering secondary
in
vitro

screening;



Sub
-
contracting CROs to conduct scale
-
up synthesis of promising “hits”
to produce
sufficient quantities for the next stage of testing (
in vivo

testing in mice);



Providing incentives to encourage researchers to relinquish or share IP with groups
who can conduct further drug development;

Chapter 6.8: Tuberculosis




6.8
-
35



Supporting development of the TB Allian
ce database of TB
-
active compounds, to
guide the work of the proposed consortium;



Providing a public medicinal chemistry service to optimise screening results, similar
to that provided by the TAACF. Or, given industry’s superior experience in this area,
a

better alternative might be to sub
-
contract this work to a loose network of EU
-
based
CROs, biotechs and industry groups who are willing to participate; or to offer
financial incentives to encourage firms to supply these in
-
kind services to not
-
for
-
profit
drug development groups;



Provision of a high throughput screening facility is less promising, given the
TAACF’s experience to date. However, the EU could fund purchase of compound
libraries by EU
-
based groups, for subsequent screening by the TAACF: this

approach
would allow costs to be shared 50:50 between the EU and U.S. and would facilitate
involvement of EU companies and academics in TB drug development.


There are several persuasive reasons for EU involvement in these areas. The structured
approach

suggested above would allow the EU to put in place a more productive model than
the less structured, individual enterprise approach being followed by the U.S.. At the same
time, it would provide financial and infrastructure support to EU
-
based academic
and
biotech institutions involved in the screening consortium; and would provide a range of
lucrative opportunities to European CROs, biotechs and industry by purchasing their private
sector skills for public use. Incentives or support at the discovery st
age would also benefit
EU
-
based multinationals who have a monopoly in this area. Finally, the paucity of discovery
and lead identification research is now choking off R&D further down the drug pipeline:
this alone is a major incentive for increased EU ac
tivity in this area.


Discovery research and lead identification of new anti
-
TB compounds require larger and
longer
-
term investments than pre
-
clinical research, with estimated costs, including costs of
failure, ranging from $40 million (using a PPP model)

to $125 million in a pure industry
model.

m

66

However, the EU would not have to bear the total cost since EU industry already
makes substantial investments through their infectious disease institutes; and the EU could
select the most cost
-
effective among

the suggested options
-

for example, a targeted
screening facility plus outsourced contracts for medicinal chemistry and scale
-
up production
of “hit” compounds. These initiatives would, in turn, provide substantial benefits to EU
academic networks and in
dustry.


2.

The lead optimisation and pre
-
clinical

stages of drug development offer a prime

opportunity for the EU to achieve these goals. Lead optimisation is the process of improving
a promising anti
-
TB compound to make it more potent, more selective an
d more “drug
-
like”.
The pre
-
clinical stage takes this optimised compound and conducts the toxicological and
ADME studies (pharmacokinetic and absorption, distribution, metabolism and elimination)
needed before clinical trialling in humans. These technolo
gies are well established and
readily available within industry, including contract research organisations (CROs). The
pre
-
clinical stage of drug development is also cost
-
competitive, being estimated at $4.9
-
5.3
million for a successful drug, including co
sts of failure (these costs are based on a survey of
CROs who provide these specialist services).
67

Results are deliverable within 5 years.




m

The wide range is explained by the difficulty of estimating discovery costs, since this information is generally
kept in
-
house by industry.

Chapter 6.8: Tuberculosis




6.8
-
36


Possible mechanisms to facilitate industry involvement at these stages of TB drug
development include:



Direct fun
ding of the TB Alliance, who would in turn outsource relevant activities to
industry. Again, this supports industry activity, while allowing it to be closely
targeted on tools of maximal public health utility;



Industry incentives designed to maximally re
ward contributions to gaps in the drug
development pipeline (ideally identified by the independent scientific experts e.g. the
TB Alliance’s scientific experts committee ) rather than the current scattergun
approach of broad
-
brush R&D subsidies;



Industry
incentives targeted to the needs of smaller European biotechs, CRO’s and
medical technology firms, as well as those more suited to multinational companies;



PPP access to industry groups who are already sub
-
contracted to EU public health
institutions (if th
ese exist).


Any or all of the above measures would be a win
-
win outcome, supporting EU industry
while using the scientific expertise of the TB Alliance or other public groups to ensure that
subsidised industry activity was tightly targeted on public healt
h outcomes of priority
interest for the EU.


3.

Clinical trials of existing industry antibiotics for a TB indication

(thirteen such trials (five
Phase III) have already commenced). Such trials are an extremely cost
-
effective use of
public funds, since
the cost of adapting existing drugs to a new indication is far lower than
developing new drugs from scratch. They also allow private innovation by EU companies
(Bayer, Aventis) to be extended to a broader public. Beyond supporting these trials
financial
ly, the EU could support the further industrial work needed to provide these drugs
in fixed
-
dose combinations with other TB drugs (FDCs) rather than single tablets. The cost
of Phase I to III clinical trials of a
novel

TB drug are estimated at $26.6 mill
ion in a developed
country setting and $9.9 million in a developing country setting, and would take an
estimated 7
-
10 years to complete (in the absence of surrogate markers).
68

The length and cost
of trials using
existing

antibiotics would be substantially

lower since many of these trials are
already well
-
advanced (in Phase II or Phase III) and partially funded, including by the EU.


Two further areas with investment potential are a) non
-
pharmaceutical gaps in the pipeline
and b) exploratory technologies n
oted above.


a)

Non
-
pharmaceutical gaps in the current pipeline e.g. developing country clinical trial capacity
and regulatory issues.


Clinical trial capacity building is not a clear area of comparative advantage for the EU.
Nevertheless, it represents a

“niche” opportunity due to the presence of a major new EU
initiative (the EDCTP); the relevance of the final outcome to EU industry (e.g. the potential
benefit of cheaper developing country trial sites); and the public health interests of EU
members. Su
pport should therefore continue, albeit with more resources applied more
quickly.


Chapter 6.8: Tuberculosis




6.8
-
37

Several gaps in the regulatory process for new TB drugs could also be usefully addressed by
changes in EU policy, including joint negotiation of a global standard for re
gulatory
approval of new TB drugs (with the WHO, FDA and others); institution of a formal fast
-
track
regulatory package for new TB drugs (similar to that provided for many orphan drugs); and
regulatory approval of surrogate markers (when available) as vali
d end
-
points to support
drug registration. Policy work on the first two issues will need to commence almost
immediately, in readiness for the first adapted TB drugs (some are already in Phase III
clinical trials, meaning possible registration as early as

2007
-
2008).


b)

Exploratory technologies


As discussed above, three areas of under
-
funded TB research are:



work on surrogate markers, to allow TB drug and vaccine trials to be completed more
cheaply and quickly;



research into depot drug preparations, to

allow reliable once
-
monthly administration;



research into new aerosol delivery mechanisms for TB drugs.


Of these, the first two are most relevant to the EU. The EU has a comparative advantage in
surrogate marker research, since studies have been conduct
ed by EU
-
based groups,
including GSK and St George’s Hospital Medical School (UK); and this work could be
brought to completion within a 5
-
year timeframe. Surrogate markers are also of great
interest to industry(and public researchers because of their ab
ility to dramatically cut clinical
trial times and hence costs; as well as expediting the arrival of novel drugs for TB and MDR
-
TB.


We are not aware of any work on depot or slow
-
release oral TB drugs being conducted in
Europe (there is also very little el
sewhere), however the clear advantages of this method of
administration in terms of reducing MDR
-
TB creation and cutting TB programme costs (both
financial and human) nevertheless mark it as a priority. If their early promise is
substantiated, depot or s
low
-
release preparations could be in the field more quickly than
novel drugs, since the component drugs already exist and there is already a substantial body
of industry experience in this area.


Vaccines


A TB vaccine is the holy grail of cheap, effective

TB control. However, the relatively early
nature of TB vaccine research and the lack of clear front
-
runners in this expensive and
lengthy process make investment in TB vaccines a difficult area for public funders. A useful
approach could be to target go
vernment support onto research that has a broad application
across TB tools and/or to selectively support specific platform technologies. Five key areas
stand out:




Basic research into the human immune response to TB infection, and into disease
models of
latency, persistence and re
-
activation, since these underpin both drug and
vaccine development (see above);



Improved TB diagnostics, without which clinical trials of new TB drugs and vaccines
will be extremely difficult and expensive (see above);

Chapter 6.8: Tuberculosis




6.8
-
38



R&D of su
rrogate markers of cure and protective immunity, vital if we are to reduce
the cost and length of clinical trials (see above);



Adjuvant development is a prime candidate for EU support, since much of this work
is conducted within the industry sector (major
and biotech) and the resulting
technologies can be applied by industry to other vaccines, including those for
Western markets. A useful EC intervention would be to incentivise and financially
support industry adjuvant research (methods of ensuring this re
search is applicable
to TB are discussed in the Drugs section above). Incentives could be rapidly put in
place, and results could be expected in less than 5 years.



Alternative vaccine delivery systems. Again, this is an area where EU academic
institution
s are already active; where under
-
funding is a problem; and where the
impact of oral or nasal vaccines, over injectables, is substantial.


In the mid
-
to
-
long term, funding will also be needed to manufacture vaccine lots for larger
-
scale clinical trials. M
anufacture will almost certainly need to be done by, or in collaboration
with industry, which has the technical know
-
how to scale up production and to handle high
volumes of potentially infectious biological material. At this stage, suitable incentives wi
ll be
needed to encourage and reward industry participation in this commercially less competitive
area.

Conclusion

The expanded European Union now has a substantial and increasing TB burden of more
than 50,000 cases per year, around 10% of whom have TB whi
ch is already resistant to one or
more of our existing drugs. Globally, TB control is also threatened by the upsurge in HIV
-
TB
co
-
infected patients, who are straining current TB tools and approaches to the limit.


Although new tools and approaches are bein
g developed in all areas


including basic
research, drugs, diagnostics and vaccines
-

progress is being delayed by lack of targeted
funding and support, in particular from the EU which now provides less than 5% of global
funding for new TB tools. The U.S
. is driving the TB R&D agenda, particularly for new
drugs, with the preponderance of research and development now being funded by the U.S.
government and U.S. philanthropists, and with U.S.
-
based industry and academic groups
being the main collaborators (
and beneficiaries of R&D contracts).


The EU could redress this situation by selecting optimal areas for investment, based on
current funding gaps, the potential impact of any intervention, the likelihood of rapid
results, and the opportunity for the chose
n approach to support EU industry and academic
institutions. Based on these criteria, the following areas are considered optimal:


1.

Adaptation of existing tools

:



Diagnostics (little support, including from US)



Clinical trials of existing antibiotics f
or a TB indication.



Depot and slow
-
release preparations of existing TB drugs (almost no support)


2.

Application of well
-
established technologies to further investigate and develop
known or suspected anti
-
TB compounds including:

Chapter 6.8: Tuberculosis




6.8
-
39



Establishing an EU consorti
um to prioritise and co
-
ordinate screening of known
compounds in order to discover new TB drug leads



Outsourcing relevant development work to industry (through public funding of
PPPs to cover outsourced work; or via industry incentives targetted to gaps
i
dentified by public R&D groups or PPPs). Outsourcing areas could include pre
-
clinical and lead optimisation work, medicinal chemistry, scale
-
up production of
screening compounds, analogue development etc, as discussed above



Providing a public facility for

compound screening, and possibly medicinal
chemistry, available at no cost to industry and academic groups.


3.

Support for technology research, particularly in areas where industry is the main
player or has a substantial interest:



Surrogate markers of tr
eatment (for drug trials) and protective immunity (vaccine
trials)



Adjuvant technologies for vaccines.


4.

Basic and discovery research that will feed into multiple R&D areas



Latency, persistence and reactivation of TB in the human host



The human immune res
ponse to
M.tuberculosis



Discovery research into new diagnostic and drug approaches.


In addition, the EU should continue its support for the work of the TB Structural Genomics
Consortium (which has provided breakthroughs in all R&D areas) and for clinical
trial
capacity
-
building in developing countries.


An EU decision to support research in these areas would deliver badly
-
needed new tools to
manage tuberculosis within its own borders and elsewhere. Importantly, it would also
establish a distinctive Europ
ean model for R&D funding. Features of this model would be:



A systematic, rather than ad
-
hoc, approach to promising R&D candidates;



Co
-
ordinated academic research in key areas;



Constructive use of PPPs as a conduit to identify gaps in the development pip
eline,
allowing R&D funding to be targeted to industry or academic groups who are active
in gap areas, rather than lower
-
priority activities;



Capacity to link support and rewards for industry, including biotechs and Contract
Research Organisations, to acti
vities that most closely match public health goals.



Chapter 6.8: Tuberculosis




6.8
-
40

References
69





1

What is DOTS?

WHO 1999; WHO/CDS/CPC/TB/99.270

2

Global Alliance for TB Drug Development website. Accessed Feb 2004 at
http://www.tballiance.org/2_0_TheNeedforNewDrugs.asp

3

Global TB Con
trol: Surveillance, Planning, Financing
; WHO; WHO/CDS/TB/2003.316

; p.10 & p.19

4

Anti
-
TB Drug Resistance in the World, Report No. 2, Prevalence and Trends
; 2000; WHO, Geneva
(WHO/CDS/TB/2000.278)

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The World Health Report 2003: Shaping the Future
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nex Table 3, p.160. Accessed online 21 Jan
2004 at
http://www.who.int/whr/2003/en/Annex3
-
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Dye C., Bleed D. & Hosseini M.,
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Survei
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; KNCV, Institut de veille
sanitaire, Saint
-
Maurice; Dec 2003; Fig. 5, p.57. Accessed Feb ’04 at
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Both figures from Dye C.

,
Progress in global TB control, with special reference to Europe
; Presentation
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TB deaths increasing in Eastern Europe
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Maksimov, January 15, 2004

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Task force on communicable disease control in the Baltic Sea Region, Council of the Baltic Sea States.
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11

Anti
-
TB Drug Resistance in the World, Report No. 2, Prevalence and Trends
; 2000; WHO, Geneva
(WHO/CDS/TB/2000.278)

12

Open Society Institute, Intern
ational Harm Reduction Development Programme. Accessed Feb 2004
at
http://www.soros.org/initiatives/ihrd/news/real_life


13

WHO Report 2003: Global TB Control
; WHO (WHO/CDS/TB/2003.316).
Respective country annexes.

14

Global Plan to Stop TB
. Stop TB Partnership (2001); WHO/CDS/STB/2001.16, p.53.

15

Global Plan to Stop TB
; op.cit; p.38

16

WHO website on DOTS
-
Plus and the Green Light Committee. Accessed at
http://www.who.int/gtb/policyrd/DOTSplus.htm

on 8 March 2004.

17

Global Plan to Stop

;
op.cit., p.22

18

Progress towards targets for global TB control
; Conference presentation by Chris Dye, Stop TB
Partnership, WHO; Slide 18. Accesse
d Feb 2004 at
http://www.who.int/gtb/policyrd/Dots_expansion/4dewg_hague_oct03/presentations/7_oct/
dye.ppt

19

Global Plan to Stop TB
; op.cit; p.62;

20

Dr Gi
js Elzinga, chair of the Stop TB Global TB/HIV Working Group; Presentation
at Global Alliance
Stakeholders’ Meeting, Paris, 30 Oct 2003

Chapter 6.8: Tuberculosis




6.8
-
41







21

Dye C, Williams B et al, Erasing the World's Slow Stain: Strategies to Beat Multidrug
-
Resistant
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,

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25

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28

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31

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32

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Chapter 6.8: Tuberculosis




6.8
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42







42

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45

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47
WHO/TDR The current anti
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56

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57

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58

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9 and many others (see PubMed)

Chapter 6.8: Tuberculosis




6.8
-
43







61

Duncan

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63

Task force on communicable disease control in the Baltic Sea Region, Council of the Baltic Sea States.
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64

Global Alliance for TB Drug Development (GATB);
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65

GATB; Oct 2001, op.cit., p.16

66

GATB; Oct 2001, op.cit., p.16

67

GATB; Oct 2001, op.cit., p.16

68

GATB; Oct 2001, op.cit., p.18