10

Developing and Strengthening the Drug Supply Chain for Drug-Resistant TB

Key Messagesa

•   The global need for anti-TB drugs is not currently being met.

•   Barriers in the drug supply chain include small markets, a limited ability to forecast need, short shelf lives, a lack of financial incentives, and lax regulation that permits subpar treatment to reach patients.

•   Public–private partnerships will be needed to overcome these barriers.

•   Linking the anti-TB drug supply chain to existing systems, such as those for HIV or malaria, could facilitate access to anti-TB drugs.

•   Data and information that underpin drug supply chains form their own information supply chains capable of tracking the risk of infection, preventing the emergence of DR TB, and improving patient follow-up.

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a Identified by individual speakers.

Earlier in the same week that the workshop was held in Beijing, the IOM released a report on developing and strengthening the global supply chain for SLDs (IOM, 2013). Several presenters at the workshop also were involved in the preparation and release of that report, and they reviewed its most important messages and placed them in the context of the workshop’s deliberations. As Mingting Chen, China CDC, pointed out, an affordable and quality-assured drug supply is crucial in national TB plans, and the issue is particularly relevant in China, which has manu-



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10 Developing and Strengthening the Drug Supply Chain for Drug-Resistant TB Key Messagesa • The global need for anti-TB drugs is not currently being met. • Barriers in the drug supply chain include small markets, a limited ability to forecast need, short shelf lives, a lack of financial incentives, and lax regulation that permits subpar treatment to reach patients. • Public–private partnerships will be needed to overcome these barriers. • Linking the anti-TB drug supply chain to existing systems, such as those for HIV or malaria, could facilitate access to anti-TB drugs. • Data and information that underpin drug supply chains form their own information supply chains capable of tracking the risk of infection, preventing the emergence of DR TB, and improving patient follow-up. a Identified by individual speakers. Earlier in the same week that the workshop was held in Beijing, the IOM released a report on developing and strengthening the global supply ­ chain for SLDs (IOM, 2013). Several presenters at the workshop also were involved in the preparation and release of that report, and they reviewed its most important messages and placed them in the context of the workshop’s deliberations. As Mingting Chen, China CDC, pointed out, an affordable and quality-assured drug supply is crucial in national TB plans, and the issue is particularly relevant in China, which has manu- 109

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110 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS facturers with the capability to produce almost all FLDs and SLDs. China also has developed the policy that all FLDs and SLDs are included in the country’s basic drug list—meaning that medical insurance, not the patient, will pay for them. Mingting Chen explained that research revealed a bio- equivalence of 80 percent for FLDs available on the market in China. To further improve the quality of drugs, China also is working to support local manufacturers of anti-TB drugs in their application for WHO prequalifica- tion. Mingting Chen observed that, although considerable efforts have been made to enhance the quality of anti-TB drugs in China, work remains to be done in collaboration with other countries and TB experts. Overcoming Barriers in the Global Supply Chain1 Successful treatment of TB requires changes throughout the health system, said Barry R. Bloom, Harvard University Distinguished Service Professor and Joan L. and Julius H. Jacobson Professor of Public Health, Department of Immunology and Infectious Diseases, Harvard School of Public Health. “If we had a new effective drug regimen for MDR TB,” he said, “we couldn’t get it where it needs to be.” Failure to reach patients is the result not just of an inconsistent drug supply but also of missteps in the larger system. Although TB treatments had an 84 percent success rate in curing patients between 1995 and 2010 and mortality has fallen by 33 percent, Bloom pointed to the 5 million deaths from the disease during that same period as an indicator of how improvements to the system could yield great progress. The IOM (2013) report on the global supply chain for SLDs shows that supply chains for drugs for other diseases, such as HIV and malaria, are more effective than those for TB drugs. Supply chains have many levels, Bloom pointed out, and their complexity can be challenging. They originate with the materials needed to produce the drugs and progress to manufacturing and formulation, storage, distribution, and use. The active pharmaceutical ingredient (API) is the most important component, and 80 percent of the APIs for TB drugs are made in China. The final product is distributed through warehouses, which source drugs for district or local clinics in various countries. Many SLDs have only one producer, meaning that if a problem occurs with a batch, there is an immediate shortage of the drug. Japan’s recent tsunami led to a shortage of isoniazid, not just in Asia or Africa but in the United States as well. The availability of APIs also has been limited 1  This section is based on the presentation by Barry R. Bloom, Harvard University Dis- tinguished Service Professor and Joan L. and Julius H. Jacobson Professor of Public Health, Department of Immunology and Infectious Diseases, Harvard School of Public Health.

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DEVELOPING AND STRENGTHENING THE DRUG SUPPLY CHAIN 111 because producers in China have not been prequalified by WHO to sell drugs internationally. The need for anti-TB drugs is not being met, Bloom emphasized. In 2000, the GDF and Green Light Committee (GLC) were created as a pilot project to enable DOTS-Plus for both TB and MDR TB. However, treat- ment rates for MDR TB have remained low, and between 2000 and 2009, an estimated 1.5 million MDR TB patients died. In the past year, WHO has made changes to increase the number of suppliers of finished medicines and the number of approved APIs in an effort to reduce delays and lower prices. But the stipulation that essentially all drug procurement must go through the GLC is a bottleneck, Bloom said, seriously affecting the ability to get drugs to patients. In the GDF system, requests from countries go to the GLC secretariat with technical support and advice from WHO. The GDF reviews a coun- try’s request to buy drugs. If the GDF approves the request, it sends the funds needed to purchase the drugs to the country, which then can make the purchase. Every step can take months to complete. “From the time of an order, it could take at least a year to get the drugs that were ultimately approved to the country that needed them,” Bloom said. He called the duration of these delays “intolerable.” Barriers arise at several points in the supply chain, Bloom explained. The market for most SLDs is small, and the ability to forecast how much medication will be needed in the future is limited (see also Box 10-1). When suppliers overestimate, they lose money, so they are more likely to under­ estimate, which leads to a shortage of drugs. Many SLDs remain on the shelf for 2 years or more, and the companies that make them have few financial incentives to do so. The drugs also are costly, leading health ministries to focus on FLDs as a less expensive option. In addition, regulation is lacking, with the result that many drugs may have a low or below-standard dose of the API, and there is a potential market for fake and substandard drugs. Reliable forecasting requires on-the-ground information, including the number of patients enrolled in every TB program, the number taking drugs, and the required lead times for manufacturing and shipping each drug. In addition, buffers are necessary to prevent breaks in the continuity of care. An 80 percent accurate forecast 2 months into the future is a worthwhile goal, Bloom said, with projections extending at least 24 months. Forecasting requires functional information systems. Bloom suggested that linking to existing systems, such as those for HIV and malaria, could jumpstart an enhanced approach to TB treatment. Pooling requests from various countries and potentially aggregating procurement would provide better forecasts of the total numbers of needed drugs. A working capital fund also is critically needed to pay up front for production based on these forecasts. Members of pharmaceutical companies indicated at the 2012

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112 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS BOX 10-1 The Challenge for Manufacturersa The key problem for drug manufacturers, said Dan Collins, Global Health Programs and Access Department, Corporate Affairs, Eli Lilly and Company, is unpredictability of demand combined with low order vol­ umes. Small manufacturers face high costs in getting drugs to patients, ­ and obtaining approval for drugs is time-consuming. A majority of coun­ tries with a high burden of disease require both in-country regulatory approval and approval from WHO, increasing the time and cost required to bring a drug to market. Competition and forecasting, said Collins, will improve the market, allowing suppliers to plan for the future and eliminate stockouts, as well as reduce prices, while also enhancing the ability of governments and other funders to determine their budgets. The public and private sectors need to partner to find solutions, Collins ­ suggested, which could include technical support related to good manu­ facturing practices and quality assurance. Eli Lilly has technical expertise to bring to bear, he said, as well as experience building relationships with NGOs, government officials, regulators, and other organizations. That experience can be leveraged to find solutions. a This box is based on the presentation by Dan Collins, Global Health Programs and Access Department, Corporate Affairs, Eli Lilly and Company. IOM workshop (IOM, 2013) that they would be willing to help with forecasting and bundling shipments, Bloom added, but they have not been asked to do so. Quality assurance could be handled by bar-coding packaging from qualified producers. Training is required to counter a lack of expertise in many countries in supply chain management and quality assurance. “We need to encourage the local production that becomes global production,” Bloom said, “and with that, strengthen the vigilance and the quality-control regulation to be sure that what is being taken by patients is the highest quality possible.” Bloom also proposed establishing a partnership between private and public organizations. Neither sector has all the tools necessary, he said, but a partnership between the two could lead to significant supply chain improvements. Private-sector pharmaceutical companies have mastered many of the necessary components of an efficient supply chain, but the market for most TB drugs is too small to interest them. A new mechanism

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DEVELOPING AND STRENGTHENING THE DRUG SUPPLY CHAIN 113 is necessary, he said, one that can engage the private sector, manufacturers, distributors, governments, and donors. Currently, Bloom added, even if drugs are prequalified by WHO, 27 countries must go through additional national regulatory processes. Q ­ uality-assured drugs for malaria required 9 to 15 months to be ­ evalidated r in some African countries. That time must be shortened, Bloom said. Innovative financing mechanisms could provide more money for TB drugs, for which funding is lacking for both drug-susceptible and drug-resistant forms of the disease. The IOM (2013) report suggests many mechanisms for addressing financing issues, including advance product commitments and models for negotiating lower prices. Making the necessary changes, Bloom concluded, will require strong and visionary leadership. It also will require continuing education, infor- mation sharing, and behavior change. The Affordable Medicines Facility for Malaria (AMFm) program included a component on information and behavior change, and the countries that failed to meet the benchmark evalu- ations failed in the information component. “We need to think of a much simpler and more efficient way of presenting the complexities of TB and the supply chain,” Bloom concluded. A systems Perspective on the Global Supply Chain2 A systems perspective on the global supply chain is needed to ensure an uninterrupted supply of quality-assured drugs when and where when they are needed, said Rifat Atun, Imperial College, London. For many diseases, not just TB, the United Nations (2012) has reported that the availabil- ity of essential medicines is low worldwide. In some areas, data indicate that the average availability of drugs used to treat common conditions is 51.8 percent and 68.5 percent, respectively, in public- in private-sector health institutions—too low to cover affected populations. Clearly, weak supply chains hinder access to essential medicines and technologies and need to be strengthened, said Atun. The first step toward improving supply chains, Atun suggested, is to understand them in their entirety, as many discussions have focused on selected components of supply chain management systems. At their core, most supply chain management systems comprise a series of manufacturers, along with a storage facility that is central or belongs to a specific region or district. Drugs are moved from storage to clinics and patients. In most countries, they also reach patients through private entities, distributors, and retailers. In many systems, the manufacturers that produce the API may be 2  This section is based on the presentation by Rifat Atun, Professor of International Health Management, and Head, Health Management Group, Imperial College London.

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114 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS different from those that produce the final drug. Hence, additional manu- facturers farther upstream in the supply chain create the starting materials for a drug’s final form, whether it is an injectable or a pill. Even before manufacturing begins, however, drugs must go through a series of hurdles. R&D, which includes several phases of clinical trials, product approval through regulatory authorities, and registration of the drug, can take 10 to 12 years and is characterized by attrition at every step. Of 100,000 entities that enter the discovery process, only 1 drug on average makes it to the market. Supply chains also take many different forms. Some are automated, allowing patients to order drugs on the Internet and receive them in the mail. In other cases, health workers literally carry drugs to patients. Where supply chains do not work, patients may be brought to the source of drugs instead of the other way around. A problem anywhere in the supply chain can prevent a drug from reaching the end user. Even when supply chains are in place, a mismatch between demand and supply can occur. If forecasts of need are unpredictable, as is the case with drugs for MDR TB, orders fluctuate, and manufacturers cannot develop production plans or adjust for future demand. The result is periods of s ­ upply–demand asymmetry and fluctuation in drug prices. Both “push” and “pull” mechanisms are necessary to improve the supply chain for SLDs, said Atun. Push strategies might include tax breaks for R&D, public–private drug development partnerships, and fast-track approval for new products, as well as direct funding for R&D from govern­ ments. Examples of potential pull strategies include innovative financing mechanisms (such as integrated international financing institutions) and innovative financing instruments (such as advance market commitments, volume guarantees, and social impact bonds). Finally, and critically, plat- forms to enable functionality—appropriate regulatory environments, strong health systems, and a mix of public and private delivery of services—also are necessary. A successful systems approach, Atun explained, would com- bine push and pull strategies with such enabling platforms to get drugs and diagnostics to patients as efficiently as possible. Atun offered several examples of novel supply chain management sys- tems for drugs for other diseases. AMFm, established by the Global Fund, was successful in reducing prices of innovative malaria drugs by providing indications of increased demand while cofinancing the purchase of certain volumes, thereby reducing the use of ineffective generic malaria drugs previ- ously preferred by patients as a less costly alternative. The Global Fund also worked to overcome issues of fragmented procurement for anti­etroviral r drugs by establishing voluntary pooled procurement and instituting a trans- parent Price and Quality Reporting (PQR) mechanism for all the key drugs included in the regimens commonly used to treat AIDS. The principal

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DEVELOPING AND STRENGTHENING THE DRUG SUPPLY CHAIN 115 recipients of Global Fund grants received technical support through a consortium with expertise in supply chain management and pooled pro- curement to help simplify the procurement and supply chain management process. PQR data, available on the Global Fund website and verified by local Global Fund agents, capture every funded transaction. These data are accessible to the public, grant recipients, and partner agencies. Price transparency made it possible to reduce prices, Atun said, with 91 percent of transactions falling to or below international reference prices within a few years of implementation of the PQR system, and more consistent prices overall across countries receiving Global Fund financing. To introduce improvements at all points along the supply chain so as to enhance access to effective medicines, a 10- to 20-year view is neces- sary. “We need to create an environment where innovation is encour- aged and innovations are adopted by countries and health systems,” Atun said. Empowered decision makers and institutionalized processes also will enhance the functioning of the supply chain. Information in the Global Supply Chain3 “Information is a public health intervention,” said Dale Nordenberg, Chief Executive Officer, Novasano Health and Science. Data and informa- tion supporting a global supply chain make up their own supply chain. Data require a functional, comprehensive supply chain to support the drug supply and public health programs. A good information supply chain can track the risk of infection, prevent the emergence of DR TB strains, and improve contact tracing and follow-up. Without attention to these informa- tional supply chains, suggested Nordenberg, “we’ll build technologies, and they will function in specific locations, but never really support a robust flow of data and information.” Information distribution faces many challenges, particularly in the con- text of rural health care. Many areas lack a standardized process for patient management, and record keeping varies among locations and patients. Transportation is unreliable, and communication problems are common. More than 50 percent of people in rural areas fail to seek medical care. Care is delivered in a wide range of places, Nordenberg pointed out, but each country needs to identify the critical information points. If the SLD supply chain depends on creating technological capabilities from the ground up in every country, establishing a comprehensive system will take far too long. An information supply chain uses data as raw material, synthesizing the data and transferring them from place to place. Human resources are 3 This section is based on the presentation by Dale Nordenberg, Chief Executive Officer, Novasano Health and Science.

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116 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS necessary to drive the development, maintenance, and operations of this supply chain, and standard operating procedures keep the system func- tioning smoothly. There exist many different approaches to managing the information supply chain, and these approaches can be integrated to best serve the needs of a particular sector. Electronic medical records (EMRs) are central to many information systems. They provide the ability to track patients, their treatments, and the results of those treatments. To create a robust information system, as many EMRs as possible are needed, Nordenberg said. The key attributes of the EMR are its collaborative development and open-source nature. The data are designed to be easily managed, supporting reports to WHO and application to public health problems, as well as forecasting of the need for drugs. The EMR also can be designed with mobile devices in mind for ease of use. However, Nordenberg cautioned against ignoring the peripheral systems that facilitate tracking efforts. Core variables contained in an EMR include demographics, drug regi- men, treatment status and outcome, laboratory data, any adverse effects, and socioeconomic factors. Nordenberg suggested that teams could quickly assess where TB patients are being treated in a specific country and where data are needed to build that country’s capacity to transfer and use information. Nordenberg recommended a two-phase solution, beginning with criti- cal information points and moving toward the development of more robust solutions over the long term. Measurable performance metrics are critical to a successful information system, Nordenberg added. Improved drug coding standards and standardized reporting elements for drug stocks and status are necessary, as well as technology planning that looks across diseases, avoiding a silo-based approach. Finally, Nordenberg emphasized the impor- tance of tracking activity across various drugs and programs, including not only SLDs but also clinical care, infection control, and epidemiological activity. Launching New Anti-TB Drugs4 Xian Janssen Pharmaceuticals is preparing for the launch of a new drug to treat MDR TB, explained Oskar Slotboom, Head, Vaccine and Infectious Diseases, Xian Janssen Pharmaceutical Ltd., Johnson & ­ ohnson. J The process from discovery to market authorization has already taken 12 years. From a business point of view, the fact that only a few patients can be reached, together with significant drug funding issues and a lack of forecasting ability, makes launching new drugs for MDR TB a daunting 4  This section is based on the presentation by Oskar Slotboom, Head, Vaccine and Infectious Diseases, Xian Janssen Pharmaceutical Ltd., Johnson & Johnson.

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DEVELOPING AND STRENGTHENING THE DRUG SUPPLY CHAIN 117 proposition for companies. Companies also are concerned about issues with adherence to drug regimens, as lack of adherence can lead to the buildup of resistance and thus compromise the future utility of a drug. Janssen developed its drug without expecting commercial success. If both large and small companies saw commercial potential in developing new drugs for MDR TB, they would invest more in innovation, and a more diverse market would emerge, Slotboom continued. Janssen is trying to ensure that patients can be reached by getting its drug registered in more than 30 countries and expects to meet WHO guide- lines for prequalification. The company is concerned about appropriate use and hopes to avoid contributing to the emergence of resistant TB strains in the future by using a strategy called rational distribution, whereby it limits where the drug will be made available to avoid issues arising in how the drug is administered. This strategy entails working primarily with national programs and certain private clinics, Slotboom explained, as well as sup- porting current efforts to educate health care professionals. For this drug, some supply chain issues will be less severe than is the case with many other drugs, Slotboom said. The company has been work- ing to bring its production of the drug up to high capacity and can do so quickly. It also is working with global companies and organizations with experience in the MDR TB field to address potential supply chain problems. Slotboom suggested that treating more patients may be the only way to make significant improvements in the industry’s overall supply chain. The current volume of drugs used in MDR TB treatment is so small that any supply chain system will be very inefficient and cumbersome. By contrast, the GAVI Alliance (“GAVI”) and UNICEF (United Nations Children’s Fund), for example, handle more than 100 million doses of many vaccines and drugs used to treat other diseases through fairly efficient supply chain organizations. A larger volume of drugs also would facilitate forecasting and advance market commitments. Slotboom argued that shifting more money to the development of rapid MDR TB diagnostic capabilities would contribute to an increase in drug volume. Finally, Slotboom discussed the problem of “marketing” the disease, which he said has helped gain financial support to combat other diseases, such as AIDS and polio. People like Bill Gates, he pointed out, have lent this work considerable momentum. Attracting such support “requires a clear and simple message that people can say yes to,” he cautioned. Other potential drug candidates in late-stage development give cause for optimism, suggested Slotboom. He concluded by emphasizing the need for continued investment by both the public and private sectors if this potential is to be realized.

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