Addressing the Threat of Drug-Resistant Tuberculosis A Realistic Assessment of the Challenge: Workshop Summary (2009) / Chapter Skim
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7 Research on the Global Control of TB: Understanding the Role of Drugs, Vaccines, and Funding
7 Research on the Global Control of TB: Understanding the Role of Drugs, Vaccines, and Funding
Pages 81-96
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From page 81... ...
Harrington expressed his view that the number of drugs in the pipeline is inadequate to revolutionize treatment of TB, whether drug-sensitive or drug-resistant. He suggested further that "neither the background regimen nor how to use the new drugs with it is yet well defined, and there is no clinical trials infrastructure available to carry out the needed strategy trials, even as industry carries out its own
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From page 82... ...
The ideal is to find new drugs that simultaneously will be effective in drug-resistant TB using novel mechanisms of action and will shorten treatment. Current drugs that shorten treatment include rifampin, which combined with pyrazinamide is the most effective of the current drugs in shortening therapy and which inhibits RNA polymerase.
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From page 83... ...
First-line TB drugs (drug-sensitive TB) 1952 1961 1965 Isoniazid (H)
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From page 84... ...
Malate synthase inhibitors Peptide Streptomycin Energy metabolism inhibitors Kanamycin/Amikicin Isocitrate lyase inhibitors Capreomycin/Viomycin Menaquinone synthesis Riminophenoazines Pyrazinamide Others/Unknown tRNA Synthetase Pyrrole LL3858 ATP Synthase rRNA synthetase inhibitors Bifunctional molecules Diarylquinoline TMC-207 Protease inhibitors Peptide Deformylase Phenotypic screening PDF inhibitors Energy Metabolism Translation Compounds in preclinical: Green Current drugs: Black Compounds in clinical: Blue Discovery projects: Red FIGuRE 7-2 Distribution of TB drug targets. SOURCE: Ginsberg, 2008.
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From page 85... ...
Drugs for TB may take even longer than this average because the clinical trials for these agents can be very lengthy as a result of the efficacy end points that are currently required. The Phase III timelines could be shortened for MDR TB if regulators were to accept surrogate end points, such as sputum smear conversion rates at 4 or 6 months.
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From page 86... ...
OFLOTUB, gatifloxacin TDR Bayer, moxifloxacin TB Alliance Phase I Johnson & Johnson/ Tibotec TMC207 Phase II Otsuka Pharmaceutical Group OPC67683 Phase III TB Alliance PA-824 Sequella, Inc. SQ109 Lupin Limited LL-3858 FIGuRE 7-3 Global clinical portfolio of TB drugs in development.
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From page 87... ...
Clinical trials for these two indications involve very different patient populations and study designs, so the resources required to do both are essentially double those required to pursue either indication alone. Ray Woosley of The Critical Path Institute described recent discussions between the FDA and NIH, in association with the IOM, regarding formulation of a critical path for TB drug development.
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From page 88... ...
The extent of product development that took place in HIV/AIDS was possible because of a serious investment in biomedical research, partnerships with industry, and the pharmaceutical industry's realization that the development of antiretroviral drugs promises a large return on investment and significantly impacts the lives of patients in the United States and globally. In addition to a significant pharmaceutical industry investment in the development of antiretroviral drugs, there has been a profusion of governmental and privately funded global programs directed at the prevention of
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From page 89... ...
Since 2002, the number of HIV/AIDS patients in the developing world receiving antiretroviral drugs has grown from about 200,000 to more than 3 million. Fauci noted that many of the challenges faced in combating HIV are similar to those for TB, and that lessons learned from biomedical, clinical, and operational research in HIV/AIDS may apply to TB.
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From page 90... ...
. Fauci highlighted five areas of the research agenda that, in NIAID's view, require major consideration: • Development of rapid and reliable diagnostic methods that can be used at the point of care; • Investment in the pipeline of new drugs, as well as proper use of existing first- and second-line therapies; • Investment in research to understand the epidemiology that con tributes to the spread of drug-resistant and drug-sensitive strains of TB; • Understanding of the relationship between and comorbidities of HIV/AIDS and TB; and • Development of effective vaccine and chemotherapy prevention strategies for all forms of TB (see Table 7-1 for a list of the most advanced international vaccine development efforts)
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From page 91... ...
Multidisciplinary research must also include robust partnerships with various product developers and sustainable investment in the development and retention of human capital. Cassell asked Fauci to share his experience with advances in accelerated review and licensure of new antiretroviral drugs and whether they offer any lessons applicable to product development for TB.
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From page 92... ...
As for moving forward without animal models, Fauci noted that there is a much better possibility of gaining important research and preliminary efficacy data from current and emerging models of TB infection and disease than was the case with HIV since HIV/AIDS is a uniquely human disease. Woosley asked whether a national clinical research infrastructure comparable to the AIDS Clinical Trial Group (ACTG)
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From page 93... ...
Some examples of each are listed in Box 7-1. Push mechanisms stimulate the supply or production side of the market, while pull mechanisms stimulate the demand side.
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From page 94... ...
A third pull mechanism is patent extension for an existing medicine as a reward for developing a drug to treat a disease of the developing world or a bioterrorism agent. The benefit to a company is clear: Extended patent life and therefore increased profitability of a drug constitute a highly tangible reward, which if applied to a blockbuster drug would be worth billions to a manufacturer.
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From page 95... ...
Moe argued that, if the incentive is to be effective, the application of these five criteria is critical to motivate private industry to direct R&D monies toward highly risky development efforts for neglected diseases, including TB. 5 The FDA issued its guidance on the administration of the PRV incentive in October 2008 and is receiving public comments.
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