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9 The Development of New TB Diagnostics and Drugs1 Key Messages • he same principles that guided the successful response to the TB T epidemic in New York City in the 1990s can guide the global effort against TB. • egulatory authorities play an essential role in the response R against TB by assuring the quality of existing and new drugs and medical products. • egulatory science—the knowledge and tools needed to assess R a product’s safety, efficacy, quality, and performance—can serve as a link between biomedical research and safe and effective new medicines and therapies. • ombination therapies, biomarkers, stem cell therapy, and pediat- C ric TB therapies are examples of areas in which regulatory science will be critical to making rapid progress. • egulatory authorities need to work closely and continuously with R academia, industry, and government agencies to inform strate- gies for data collection, identify emerging concerns, and promote research needed for regulatory decisions. 1 This chapter and the key messages summarized at the beginning of the chapter are based on the presentation of Margaret Hamburg, U.S. Food and Drug Administration. 95

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96 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA Russia has been an epicenter of the TB epidemic, said Hamburg, but it is also a country with an extraordinary tradition of science and medicine. Therefore, holding a workshop on drug-resistant TB in Moscow is both symbolically and substantively important. In her presentation, Hamburg provided a global overview of the challenge of developing new TB diag- nostics and drugs. She then outlined the role of regulatory science and the need for collaboration in efforts to meet this challenge. THE GLOBAL CHALLENGE The numbers of TB cases during the New York City TB epidemic (see Box 2-3 in Chapter 2) appear small compared with the current numbers worldwide, Hamburg observed. Yet the same principles that guided the response in New York City apply globally. TB must be detected in all its forms as early as possible, which requires focused attention on at-risk popu- lations and on a host of social, economic, and clinical variables. Health systems must be strengthened through bold policies, and financial barriers need to be addressed and overcome. Success in controlling the epidemic will depend on the ability to develop and distribute better tools with which to prevent, diagnose, and cure TB, as well as to ensure the quality and safety of those products throughout the supply chain and their life cycle, said Hamburg. Regulatory authorities have an essential role to play in all these areas. First, regulatory authorities must assure the quality of existing and new drugs and medical products. This assurance is critical to achieving the benefits of treatment and avoiding the further development of resistance because of substandard medications. An example of efforts to that end is ongoing collaboration between the U.S. Food and Drug Administration (FDA) and regulatory colleagues in Russia.2 Hamburg said that on the morning of her presentation at the workshop, she had met with her Russian colleagues to begin developing a blueprint for working together to share information and best practices. They also identified good clinical practice as a key area for partnership. A series of training workshops in that area will harmonize standards and approaches, which is particularly important as a growing body of clinical data emerges from Russian studies. In addition, opportunities for harmonization and standardization through such entities as the International Conference on Harmonization and other international 2 The Statement of Intent on Collaboration between the U.S. Food and Drug Administration and the Federal Service on Surveillance in Health Care and Social Development of the Russian Federation (ROSZDRAVNADZOR) was agreed to on May 27, 2010. The agreement (Russian and English language versions) can be found at: http://www.fda.gov/InternationalPrograms/ Agreements/MemorandaofUnderstanding/ucm217539.htm (accessed May 19, 2011).

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97 DEVELOPMENT OF NEW TB DIAGNOSTICS AND DRUGS bodies can strengthen the quality of medical products overall. Hamburg emphasized that assuring the safety and effectiveness of new medical prod- ucts depends on having data from clinical trials that are conducted ethically and in accordance with internationally accepted practice. New tools to combat TB need to reflect the best, most up-to-date sci- ence and technology possible, and in that respect, Hamburg suggested, there is reason for optimism. Yet much remains to be done. TB, especially drug-resistant TB, is underdiagnosed. Contributing factors are the neglect of laboratory services (see Chapter 5) and the failure to translate advances in scientific capabilities into new diagnostic technologies. Although progress has been made—the number of new TB diagnostic methods is growing, and methods now in development are promising—Hamburg pointed out that rapid, cost-effective, and easy-to-use diagnostics for both analysis of drug resistance and point-of-care diagnosis are still lacking (see Chapter 5). Quite a few novel candidate TB drugs are in development, Hamburg observed. Five such drugs have entered clinical trials, with others in pre- clinical development (Global Alliance for TB Drug Development, 2010). Hamburg expressed the hope that two Phase III clinical trials, of 4-month drug regimens will be completed by 2012. In addition, almost 30 vaccine candidates are in preclinical develop- ment. Eight have entered clinical trials, three of which are in Phase II stud- ies. Thus, compared with a decade ago, there is “no shortage of innovation in the pipeline to prevent, diagnose, and cure TB,” said Hamburg. Still, continued investments of money and scientific expertise will be necessary to sustain and extend this progress, she noted. THE ROLE OF REGULATORY SCIENCE Hamburg pointed to the special responsibility of regulators in ensuring that regulatory pathways are in place for the evaluation and approval of new products. Regulators must help identify the types of studies and data needed for rapid review and approval. Fulfilling this responsibility will require applying better science and more innovative approaches to drug development and medical product review, Hamburg said. Regulatory science can serve as the link between cutting-edge science and technology and progress in the form of safe and effective new medi- cines and therapies. Regulatory science consists of the knowledge and tools needed to assess and evaluate a product’s safety, efficacy, quality, and per- formance. It comprises an array of disciplines and approaches, including bench research, clinical research, epidemiology, bioinformatics, statistics, and bioimaging. “Regulatory science is not really about the science that is brought to the table by any one company or innovator to support an indi- vidual product,” said Hamburg. “It’s really [about giving] us the knowledge

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98 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA and tools to address whole classes of important products. It requires the collaboration of government, industry, and academe to be effective.” Using this knowledge and these tools, regulators can develop new methods, stan- dards, and models that will speed the development, review, and approval of medical products and support optimal quality assurance. A key challenge is translating the explosion of new knowledge and capabilities from many domains of research into real-world products and programs. According to Hamburg, regulatory science is an important part of the answer, yet it has been “underappreciated and underdeveloped.” Continual developments in science and technology in fields as diverse as genomics, systems biology, stem cells, and nanotechnology hold prom- ise for major therapeutic advances. In the area of stem cell therapy, for example, characterizing stem cells and ensuring their stability and purity could make it possible to make those new products available to patients. But the scientific community currently lacks the ability to translate many of these developments into vital products for those who need them. Hamburg emphasized the importance of closing this gap, and suggested that one means to that end is to streamline and modernize regulatory pathways. To take advantage of the breakneck speed of scientific advances, inno- vation in regulatory science needs to be emphasized just as has innovation in biomedical research. An example is research into new treatments for drug-resistant TB. Curing drug-resistant TB requires multiple drugs over many months, and the development of resistance is a constant problem. Combination products could be much more effective, but the approval process for such products will be lengthy if each drug needs to be approved independently, followed by approval for their combination. As a result, the FDA has embarked on a new initiative to work with researchers and companies interested in developing combination products. This effort is scientifically complex for the agency, “but it is what patients need and what the public health demands,” said Hamburg. Another example involves the identification, characterization, and qualification of biomarkers. With serious or life-threatening diseases, sur- rogate endpoints based on epidemiologic, therapeutic, pathophysiologic, or other evidence can be used to predict clinical benefit. This approach has yielded great benefits in the case of HIV/AIDS. Appropriately selected and used, biomarkers can enhance the identification of candidates for drug discovery, support more efficient dose selection in early clinical research, and accelerate clinical trials. Hamburg emphasized the potential benefits of such approaches for TB. Last year, for example, an FDA advisory commit- tee recommended the accelerated approval of new drugs for MDR TB on the basis of sputum culture conversion, which could reduce by years the time required for the delivery of new, more effective treatments to patients. In addition, biomarkers have great potential value for TB vaccine research

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99 DEVELOPMENT OF NEW TB DIAGNOSTICS AND DRUGS by enhancing the ability to evaluate the effectiveness of and response to candidate vaccines. Finally, Hamburg stressed that assessments of existing and new treat- ments for TB should include children—both those with and without HIV infection—as well as formulations that are appropriate for pediatric popu- lations. Multiple countries could benefit from studies that were well done and that addressed, from the beginning, critical data requirements for regu- latory review and approval. Regulatory authorities could help by encourag- ing companies to pursue such efforts. THE NEED FOR COLLABORATION Success in the development of new TB diagnostics and drugs will depend on outreach and collaboration, said Hamburg. Regulators must be active participants in research and development through partnerships with academia, industry, and government agencies. Regulatory authorities should not be waiting at the end of the pipeline to see what emerges. They should be involved as product ideas are developed and as products go through the research and development process to inform strategies for data collection, identify emerging concerns, and ensure that advances in clinical trial analytics or biomarkers are being integrated into research activities. Regulatory authorities also have a responsibility to monitor drugs and other medical products once they enter the marketplace to ensure safety and appropriate use throughout the products’ life cycle. Hamburg expressed her desire to see the FDA play an active role throughout the development of safe and effective tools to combat TB for the benefit of the American people and the world. Finally, she emphasized the importance of the shar- ing of clinical trial data across regulatory authorities to answer important questions of safety and efficacy.

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