The Global Alliance for Tuberculosis Drug Development by blindlove200


									                                           Clin Chest Med 26 (2005) 341 – 347

        The Global Alliance for Tuberculosis Drug
   Development—Accomplishments and Future Directions
                Charles A. Gardner, PhDa,*, Tara Acharya, PhD, MPHa,
                           Ariel Pablos-Mendez, MD, MPHb
                        The Rockefeller Foundation, 420 Fifth Avenue, New York, NY 10018, USA
                      The World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland

    Nearly 2 billion people, one third of the world’s            of isoniazid, rifampin, pyrazinamide, and ethambutol.
population, are infected with tuberculosis (TB). Eight           Patients find it difficult to adhere to this complicated
million of these people develop active TB every year,            regimen, leading to an increase in drug-resistant
leading to 2 million deaths annually [1]. Although               strains [3]. Second-line drugs for multidrug-resistant
an effective vaccine against active disease would be             tuberculosis (MDR-TB) are expensive and more toxic
key in ultimately eradicating TB as a public health              than the standard treatment.
problem, there is, as yet, no satisfactory vaccine for               It has been more than 30 years since a novel TB
the disease. The commonly used bacille Calmette-                 drug has been introduced into clinical practice. The
Guerin vaccine is reasonably effective when admin-               estimated costs of discovery and development of a
istered to infants but is much less effective against            new TB drug (including the costs of failure) are
the pulmonary form of TB in adults. Despite a re-                between $115 million and $240 million [4]. Adopting
cent increase in vaccine research, ongoing efforts               a portfolio approach, the Global Alliance for TB
to develop a new, more effective vaccine are not                 Drug Development (TB Alliance) expects to pursue
expected to yield results for at least a decade, and an          multiple candidate drugs. The global TB market
effective vaccine would not substantially diminish the           could reach $700 million by 2010 but is concentrated
TB epidemic for several decades after that. Both                 in developing countries, and the pharmaceutical in-
effective drugs and an effective vaccine will probably           dustry, guided by the perception that the TB market
be needed for many decades to come, until the pool               remains too small and diverse to guarantee return on
of current TB patients and latently infected individu-           investment, has not driven a comprehensive devel-
als is eliminated. Drugs that improve or shorten                 opment program for new TB drugs.
therapy, in contrast, would affect treatment of current
patients almost immediately upon their adoption.
    The World Health Organization’s directly ob-                 The Global Alliance for Tuberculosis Drug
served treatment, short course (DOTS) strategy is an             Development
effective TB control strategy but reaches only one
third of the people who need it [2]. Moreover, it is                 In response to these challenges, and with initial
expensive, labor-intensive, and usually involves a 6- to         support from the Rockefeller Foundation and other
12-month, four-drug combination regimen consisting               international organizations, the TB Alliance [5] was
                                                                 established in 2000 with a mission to accelerate the
                                                                 discovery and development of new drugs to fight TB
    The views expressed by the authors do not necessarily        and to ensure their affordability and accessibility. The
reflect the views of their institutions.                         initiative was born at a pivotal meeting in Cape
    * Corresponding author.                                      Town, South Africa [6], and soon gained substantial
    E-mail address: (C.A. Gardner).       support from the Bill and Melinda Gates Foundation.

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
342                                                gardner et al

   As one of a new breed of nonprofit product-              fined and measurable milestones, and clear go/no-go
development public – private partnerships (PD PPPs),        decision points. So far, the TB Alliance has as-
the TB Alliance draws on strengths of the public and        sembled a portfolio of projects that are in various
private sector to achieve its objectives—new and            phases—lead identification, lead optimization, and
better TB treatments that                                   preclinical development (Fig. 1).
                                                                Since 2000, the TB Alliance has catalyzed the
       Shorten or significantly simplify the treatment     expansion of the TB drug pipeline. In 2005, up to
       of active tuberculosis                               seven compounds are expected to be in or to enter
       Provide effective treatment of MDR-TB               clinical trials, many of them with novel modes of
       Improve the treatment of latent tuberculosis        action. For comparison, in 2000 only two TB candi-
                                                            date drugs were in development, and these products
    The TB Alliance operates like a nonprofit com-          represented only slight modifications to existing
pany based on an innovative partnership designed to         molecules. The sequencing of the genome of
share risks and incentives. The range of organizations      Mycobacterium tuberculosis is expected to yield
that partner with the TB Alliance includes academic         useful results for drug discovery, although not before
institutions, government research laboratories and          substantial investment by the global research com-
public health institutions, nongovernmental organi-         munity. Examples of compound families reviewed
zations, the pharmaceutical industry, and contract          by the TB Alliance for drug candidacy over the last
research organizations worldwide. Its headquarters          several years include
are in New York, but it also maintains offices in Cape
Town, South Africa, and Brussels, Belgium.                      Nitroimidazoles, with potentially sterilizing ac-
                                                                   tivity and effectiveness against MDR-TB
                                                                Fluoroquinolones and quinolizine derivatives
                                                                   that may hold the key to significantly shorter
The strategy of the Global Alliance for                            treatment regimens
Tuberculosis Drug Development                                     Longer-acting rifamycins for more widely
                                                                   spaced intermittent treatment that have a poten-
      The TB Alliance has five strategic objectives:               tial for avoiding cross-resistance to other rifa-
                                                                   mycins and antiretroviral drug interactions
      1. Identify and access promising compounds                  Macrolides, an excellent antibiotic class with
      2. Oversee the preclinical development of candi-             significant potential to yield a tuberculosis drug
         date drugs                                                because of its excellent pharmacologic features
      3. Spearhead clinical trials and drive regula-               and its promising antibacterial activity against
         tory approval                                             M. tuberculosis
      4. Ensure affordability, adoption, and access               Oxazolidinones, broad-spectrum antimicrobials,
         (AAA strategy)                                            which may have substantial antimycobacte-
      5. Mobilize expertise and resources for tuber-               rial activity;
         culosis drug development                                 Pleuromutilins, a novel class of antibiotics of a
                                                                   natural product origin, which have tuberculosis
    These objectives and selected accomplishments                  efficacy in early tests, do not have cross-
for each objective are outlined below [5].                         resistance with other antibiotics, and seem to
                                                                   produce resistance very slowly
Objective 1: identify and access promising                        Pyrroles, a previously largely unexplored class
compounds                                                          of compounds with antimycobacterial activity in
                                                                   vitro and in preclinical animal models, with a
   Through proactive business development and                      novel mechanism of action.
periodic requests for proposals from public, private,
and academic institutions, the TB Alliance selects,         Selected lead compounds in the Global Alliance for
assembles, and manages a portfolio of promising             Tuberculosis Drug Development portfolio
candidate drugs. The TB Alliance collaborates with              A lead compound in the portfolio, the nitro-
or outsources (and provides funding for) the devel-         imidazopyran PA-824, has successfully passed estab-
opment of these candidates to public and private            lished milestones and is expected to be in clinical
partners but retains overall responsibility for these       trials by the first half of 2005. PA-824 was the first
projects, with dedicated project management, prede-         compound acquired by the TB Alliance, in June
                                                                 global alliance for tuberculosis drug development                                                                343

                                                         Discovery                                              Preclinical                          Clinical Testing

                                         Nitroimidazole Analogs
                                                                                                  Nitroimidazole PA-824                    Moxifloxacin
                                        (TB Alliance, Novartis Institute for Tropical Diseases,
                                                                                                  (TB Alliance, Chiron)                    (TB Alliance, Bayer Pharmaceuticals)
   Compounds, Analogs and Derivatives

                                        Carboxylates                                              Pyrrole LL-3858                          Diarylquinoline R207910
                                        (TB Alliance, Wellesley College)                          (LupinLimited)                           (Johnson & Johnson)
                                        Quinolones                                                Diamine SQ-109                           Proprietary Compound
                                        (TB Alliance, KRICT/Yonsei University)                    (Sequella, Inc.)                         (PrivateSector Company)
                                        Macrolides                                                                                         Gatifloxacin
                                        (TB Alliance, University of Illinois at Chicago)                                                   (OFLOTUB – TDR)
                                        (TB Alliance, GlaxoSmithKline)
                                        Isocitrate Lyase (ICL)
                                        (TB Alliance, GlaxoSmithKline)
                                        (TB Alliance, GlaxoSmithKline)
                                        Focused Screening
                                        (TB Alliance, GlaxoSmithKline)
                                        Methyltransferase inhibitors
                                        Screening and Target Identification

Fig. 1. Global tuberculosis drug pipeline, March 2005. (Courtesy of the Global Alliance for TB Drug Development, New York,
NY; with permission.)

2002, through an exclusive license agreement with                                                                    of rifampicin. Developed by Bayer AG (Leverkusen,
Chiron Corporation (Emeryville, California). The                                                                     Germany), the drug currently has been approved by
compound has bactericidal activity similar to isonia-                                                                the Food and Drug Administration (FDA) for treat-
zid and sterilizing activity that rivals that of rifam-                                                              ment of skin and upper respiratory tract infections
picin. During the discovery stage, PA-824 and its                                                                    and pneumonia. In vivo experiments using a murine
analogues demonstrated activity against both drug-                                                                   model at the Center for Tuberculosis Research at
sensitive and MDR strains of TB. Preclinical develop-                                                                Johns Hopkins University and funded by the TB
ment results so far have demonstrated the feasibility                                                                Alliance have affirmed moxifloxacin’s early promise
of increasing synthesis for animal and clinical trials.                                                              for shortening therapy. Support from the TB Alliance
In preliminary toxicology testing, PA-824 did not                                                                    helps ensure that this murine model, one of the TB
demonstrate teratogenic or toxic effects on normal                                                                   Alliance’s platform technologies, will continue to be
metabolic or hormonal systems. Additional animal                                                                     available for the development of other TB drugs. The
studies to assess the safety and efficacy of PA-824                                                                  Johns Hopkins team substituted moxifloxacin in
have also yielded encouraging results. As a result,                                                                  various combinations to replace or enhance aspects
PA-824 will be entering phase I clinical trials in the                                                               of existing treatment. Substitution of moxifloxacin
first half of 2005. The TB Alliance is also working to                                                               for isoniazid significantly increases efficacy, and
optimize the synthesis of PA-824 to reduce production                                                                studies have suggested that inclusion of moxifloxacin
costs. To ensure further development of this promising                                                               in a combination regimen can shorten the time of TB
class of drug candidates, the TB Alliance is pursuing                                                                treatment [7].
research into analogues of PA-824. To this end, the                                                                      The next step is to confirm these results in clinical
Alliance has also launched a partnership with Novartis                                                               trials. To that end, the TB Alliance is working with
Institute of Tropical Diseases in Singapore to explore                                                               Bayer and several partners, including the Centers for
new avenues within the nitroimidazole class, working                                                                 Disease Control and Prevention (CDC), Johns Hop-
closely with the National Institutes of Allergy and                                                                  kins University, and University College, London
Infectious Diseases (NIAID), among others.                                                                           (with funding from the European and Developing
    Moxifloxacin is a quinolone that has shown high                                                                  Countries Clinical Trials Program), to formulate and
levels of activity against M. tuberculosis in vitro and                                                              support a global clinical development plan for
has generated significant interest from the TB                                                                       moxifloxacin in the treatment of TB. This under-
community for its potential to become the first major                                                                taking would build on an existing Cooperative
advance in TB therapy since the 1965 introduction                                                                    Research and Development Agreement between
344                                                 gardner et al

Bayer AG and the CDC that the TB Alliance                    a diverse portfolio and working with countries to
facilitated in 2002. As part of this plan, the CDC           build capacity for drug development. For instance,
TB Trials Consortium is conducting phase II clinical         the TB Alliance is working with the International
trials in Spain, North America, and Africa to evalu-         Union Against Tuberculosis and Lung Disease to
ate the safety and efficacy of a regimen in which            build clinical trials capabilities at international loca-
moxifloxacin is substituted for ethambutol in the            tions in Africa, South America, and Asia. The TB
treatment of patients who have newly diagnosed TB.           Alliance is exploring multiple approaches to stream-
                                                             lining clinical development, including simultaneous
Objective 2: oversee the preclinical development of          rather than sequential testing of new compounds and
drug candidates                                              validation of novel surrogate markers.

    The TB Alliance has established an effective             Objective 4: ensure affordability, adoption, and
process and enabling technologies to develop can-            access
didate drugs. It has developed a comprehensive
management plan, created a diverse network of                    In developing countries, the TB Alliance is
outsourced, global expertise, and established go/no-         working to ensure the AAA strategy for the products
go decision gates to advance candidates along the            it develops. Affordability of the final product depends
development pipeline.                                        on both technical and business factors. The costs of
    A research plan and development timeline is              production and development of potential compounds
established for each compound or project selected            are evaluated, and all agreements are structured to
for the portfolio. The development plan requires a           limit royalties in countries where TB is endemic and
series of tests, each designed to provide a go/no-go         to include licensing provisions and manufacturing
decision point for continued development. At pre-            rights to keep prices low. The TB Alliance is also
clinical stages, a comprehensive program of safety           working with the World Health Organization and
and toxicology pharmacologic investigations is per-          national TB control programs to ensure early adop-
formed. Because TB drugs must be designed to                 tion of a new product in existing programs and thera-
optimize combination therapy, the cornerstone of             peutic regimens. Access ensures that medicines reach
resistance control, these safety considerations must         all patients, particularly the poorest of the poor. As
include drug – drug interactions with companion anti-        part of the AAA strategy, the TB Alliance is ex-
TB medications. Furthermore, because an increas-             ploring innovative intellectual-property strategies to
ing percentage of TB patients are also infected with         balance access and incentives. The TB Alliance
HIV, it is critical to determine the compatibility with      hopes to retain the ability to deliver new anti-TB
antiretroviral treatments and in particular to ensure        drugs equitably to those areas most in need while
the lack of induction or metabolism by cytochrome            helping to maintain incentives for the pharmaceutical
P450 enzymes.                                                industry to develop new TB medicines. The costs of
                                                             production and development of potential compounds
Objective 3: spearhead clinical trials and drive             are evaluated, and all agreements are structured to
regulatory approval                                          limit royalties in endemic countries and to include
                                                             licensing provisions and manufacturing rights to keep
    The TB Alliance is working to ensure that there          prices low.
is adequate capacity for clinical trials to test the com-        The TB Alliance is also working with the World
pounds that successfully pass preclinical milestones.        Health Organization, the Stop TB Partnership, and
These facilities must meet the highest regulatory            national TB control programs to ensure early adop-
standards, including those of the FDA and European           tion of a new product in existing programs and
Medicines Agency. The aim is to reduce unnecessary           therapeutic regimens. Unlike PD PPPs developing
regulatory hurdles to ensure that new drugs are made         novel prevention tools lacking any existing distribu-
available to patients as soon as possible. Therefore,        tion mechanisms, the TB Alliance will be able to rely
the TB Alliance is also working to harmonize regu-           on a decade of investments in DOTS programs and
latory approval processes to expedite the inclusion of       their drug procurement and distribution mechanisms
new products in standardized treatment.                      such as the Global Drug Facility. Although further
    As in any drug discovery and development                 improvements in access to DOTS are imperative,
program, general delays or setbacks are expected in          these mechanisms are in place, and the TB Alliance
the process of TB drug development. The TB                   can rely on them for the distribution of the new drugs
Alliance hopes to reduce these risks by maintaining          in combination therapy.
                           global alliance for tuberculosis drug development                                     345

Objective 5: mobilize expertise and resources for          portfolio and could offer their laboratories’ preclinical
tuberculosis drug development                              capacity to develop the portfolio. For instance, in April
                                                           2003 the TB Alliance signed a 2-year agreement with
    Following initial funding by the Rockefeller and       the Korea Research Institute of Chemical Technology,
The Bill and Melinda Gates Foundations, the TB             where scientists will synthesize more than 400 com-
Alliance has secured further public funding from the       pounds, including novel quinolones, pyridones, and
United States Agency for International Development         quinolizines. This project aims to yield up to three
and the Dutch Ministry of Development Coopera-             lead candidates for the TB Alliance portfolio and is
tion and in-kind support from the NIAID. The TB            the TB Alliance’s first research and development
Alliance has leveraged this funding to position itself     partnership in Asia as well as the first in a country that
as the catalyst in developing new TB drugs. The TB         has a significant TB burden. Patient enrollment plays
Alliance has mobilized worldwide expertise and             a central role in the clinical development stage.
resources by establishing solid relationships with         Because of TB’s global impact, most patients reside
pharmaceutical and biotechnology companies, proac-         in developing countries, where clinical trial infra-
tively seeking new sources of support, and actively        structure is limited but where reasonable cost struc-
participating in global forums to promote its mission.     tures help fulfill the ultimate goal of affordability.
For example, the TB Alliance is the lead agency of         Furthermore, DOTS infrastructure, expanded during
the Stop TB Partnership Working Group on TB Drug           the last 10 years, offers an excellent starting point for
Development, which coordinates a forum to facilitate       clinical trial capacity building.
research and development collaborations worldwide              The TB Alliance is also working closely with
for new TB drugs. While building its own portfolio         other PD PPPs with similar goals, such as Medicines
through the partnerships described previously, the TB      for Malaria Venture, the Malaria Vaccine Initiative,
Alliance has helped catalyze the global TB drug            the International AIDS Vaccine Initiative, the Interna-
pipeline by engaging all relevant industry entities and    tional Partnership for Microbicides, and others, to
by enhancing technologies to support drug develop-         coordinate overall activities and to strengthen the
ment in general. The TB Alliance has taken both            incentive for investment in new tools to solve global
advisory and advocacy roles to support corporate           health problems. The TB Alliance has welcomed the
efforts for TB, such as those currently underway           creation of a new research effort, the Foundation for
at Novartis, Anacor, AstraZeneca, Lupin, Glaxo-            Innovative New Diagnostics (FIND) to develop bet-
SmithKline, and other companies. For example,              ter diagnostic tests for infectious diseases, with an
AstraZeneca has committed $25 million over 5 years         initial emphasis on TB [10]. The TB Alliance and
at its newly established research facility in Bangalore,   FIND plan to work together to encourage the
India [8], and Novartis has established a $122 million     development of new tools for tuberculosis.
tropical disease research institute in Singapore to
focus on tuberculosis and dengue fever [9]. More-
over, the TB Alliance Scientific Advisory Committee        Global product development public – private
includes drug discovery and TB experts from                partnerships
GlaxoSmithKline, Pfizer, and Johnson & Johnson.
    Additionally, to enhance the scope and depth of           Globally based nonprofit PD PPPs emerged in the
the global pipeline, the TB Alliance has invested in       1990s as a way to
platform technologies that expedite, support, and
lower hurdles in TB drug development. One es-                 1. Link public-sector goals with private-sector
sential platform technology is the mouse model for               expertise as a means of accelerating drug and
preclinical testing, which has been instrumental in              vaccine development for neglected diseases
affirming preclinical efficacy of lead compounds.             2. Raise awareness of global health inequities and
Others include the establishment of a worldwide                  attract substantial new funding to the field
inventory of preclinical and clinical capacity/exper-         3. Promote culture change, incorporating methods
tise and clinical trial site standardization in selected         and models from the private sector into public-
countries to ensure the necessary clinical infra-                sector practice and encouraging more private
structure as portfolio compounds advance to clinical             entities to enter the field of neglected dis-
trials. In this context, the involvement of endemic              eases [11]
countries is central to the mission of the TB
Alliance. On the drug development front, these                 In many ways, PD PPDs can be seen as not-
countries may have compounds to expand the                 for-profit companies.
346                                                 gardner et al

     Building on its history, mission, and comparative           Together, these organizations provide a true, new,
advantages, The Rockefeller Foundation provided social       and coherent field of initiatives designed to bridge
venture capital toward the creation of the International     the gap between basic research and product develop-
AIDS Vaccine Initiative, Medicines for Malaria Ven-          ment, aligning public health goals with private-sector
ture, the TB Alliance, International Partnership             expertise to develop essential new products to pre-
for Microbicides, and Pediatric Dengue Vaccine Initia-       vent, control, and treat diseases of the poor. The field
tive [12]. At the same time, other organizations             is still young. Sufficient time has not yet passed to
established a Malaria Vaccine Initiative, Aeras Global       determine whether PD PPPs will achieve their
TB Vaccine Foundation, Foundation for Innovative             ultimate goals. A recent analysis of interim indicators
New Diagnostics, Drugs for Neglected Diseases Ini-           and organizational best-practice benchmarks gives
tiative, Institute for One World Health, and others. Most    room for hope, even enthusiasm [14]. Impressive
of these PD PPPs, including the TB Alliance, owe their       new public-sector support has arisen, and product-
continued financial well being to donors—principally         development pipelines have expanded significantly
the Bill and Melinda Gates Foundation—along with             both within and outside of PD PPP portfolios. To
other philanthropies, government development agencies,       build on this progress successfully, still more re-
and multilateral organizations.                              sources will be needed to carry the work forward
     The Rockefeller Foundation based its disease-           to the next stages including regulatory approvals,
product priorities (eg, in the creation of the TB            clinical trials, manufacturing, and distribution.
Alliance) on expert assessment of a combination of
high social demand and maturity of the science. The
Foundation pushed for pharmacoeconomic analy-                Future directions for the Global Alliance for
ses, business plans, and scientific blueprints for the       Tuberculosis Drug Development
organizations with which it was involved, and these
approaches have now become the norm.                             Among the TB Alliance’s achievements to date
     Like private for-profit companies, PD PPPs use          are the rapid scaling-up of their project portfolio,
business practices in staffing and in managing a             securing of endorsements at the highest national and
portfolio of candidate products. Most have explicit          international levels, and enlisting the assistance of
policies affecting portfolio turnover, including a guil-     leading global pharmaceutical and biotechnology
lotine strategy based on milestones in the project’s         companies. Most significantly, the TB Alliance is
business plan and criteria for acquiring new product         developing a growing, robust pipeline, a quantum
candidates. Go/no-go decisions are based on advice           leap from the situation 5 years ago when TB drug
from a scientific advisory board made up of experts          development was at a standstill.
in the field. Thus, for some donors, PD PPPs repre-              The ideal scenario in the next decade is one in
sent a way to delegate the tough decisions to profes-        which the TB Alliance successfully creates and
sional experts.                                              manages a portfolio of therapeutic alternatives and
     Each PD PPP seeks to deliver products that will         develops a novel anti-TB drug regimen that is as
be cheaper and easier to supply than existing in-            effective or more effective than the current treatment
terventions [13]. The quintessential example would           and that shortens the duration of treatment to less than
be a vaccine, just as the polio vaccine replaced the         2 months. The reduction in the duration of treat-
iron lung half a century ago. A shorter-course TB            ment would represent a significant reduction in the
treatment regimen to replace the existing 6- to              cost and complexity of DOTS. A drug that simplifies
12-month regimen represents a similar breakthrough           the regimen and shortens treatment by 3 months
goal. Such products will make access to better health        would also have a significant, positive impact
more attainable. In addition, PD PPPs focus directly         (although not as dramatic as the previous scenario).
on ensuring that their products will be affordable           In either case, the benefits of a new, faster-acting TB
and accessible to the poor. Criteria for acquisition of      regimen would go beyond the direct impact on TB
new candidate products include low manufacturing             incidence and prevalence and the indirect effect on
cost (often with manufacture in developing countries),       the global economy. The success of the TB Alliance
ease of delivery in tropical conditions, and advanta-        could encourage donors, mobilizing more funding
geous intellectual-property arrangements that entice         for additional projects. Demonstration of the success
private-sector participation and help ensure fulfill-        of the PD PPP model could spur support for other
ment of the AAA strategy in endemic countries. It is         PD PPPs. Other institutions might apply the TB
important that a series of strategic partnerships be         Alliance’s platform technologies and lessons learned
established to deliver products to the neediest.             during the process of TB drug development to
                              global alliance for tuberculosis drug development                                             347

their own objectives. Finally, a success from one of              [5] Global Alliance for TB Drug Development. Overview
the PD PPPs might energize the entire field of                        of the TB Alliance program. Available at: http//www.
global health.                                               Accessed March 4, 2005.
                                                                  [6] Pablos-Mendez A for the Working Alliance for TB
                                                                      Drug Development. The declaration of Cape Town. Int
                                                                      J Tuberc Lung Dis 2000;4(6):489 – 90.
                                                                  [7] Nuermberger EL, Yoshimatsu T, Tyagi S, et al.
Acknowledgments                                                       Moxifloxacin-containing regimen greatly reduces time
                                                                      to culture conversion in murine tuberculosis. Am J
   The authors thank Ann Ginsberg, Gwynne Ooster-                     Respir Crit Care Med 2004;169(3):421 – 6.
baan, Melvin Spigelman, and Joelle Tanguy at the                  [8] Astrazeneca. Astrazeneca opens multi-million dollar
TB Alliance for their valuable comments.                              Indian research facility to find new treatments for
                                                                      tuberculosis [press release, June 2, 2003]. Available at:
                                                                      Accessed March 4, 2005.
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                                                                      in Singapore’s state-of-the-art Biopolis research fa-
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