8


The Second-Line Drug Supply Chain

Key Messages

  • A paradigm shift is taking place with respect to the second-line drug supply chain—from reliance on the GLC mechanism to countries’ assuming responsibility for the supply of quality drugs for their populations.
  • Under a grant from the Global Fund to Fight AIDS, Tuberculosis and Malaria, the Russian Health Care Foundation, in collaboration with the WHO and Partners In Health, has made many accomplishments in combating TB and MDR TB, including overseeing regular delivery of quality-assured second-line drugs.
  • A partnership between Eli Lilly in the United States and Biocom in the Russian Federation led to Biocom’s being prequalified for the production of cycloserine. If Biocom receives approval from WHO, it expects to supply drugs to countries that receive assistance from the Global Drug Facility program.

Presenters on the supply chain for second-line TB drugs described a new paradigm for the drug supply for drug-resistant TB and offered three different perspectives on MDR TB treatment and the drug supply chain in Russia.



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8 The Second-Line Drug Supply Chain Key Messages • paradigm shift is taking place with respect to the second-line A drug supply chain—from reliance on the GLC mechanism to coun- tries’ assuming responsibility for the supply of quality drugs for their populations. • nder a grant from the Global Fund to Fight AIDS, Tuberculosis U and Malaria, the Russian Health Care Foundation, in collaboration with the WHO and Partners In Health, has made many accomplish- ments in combating TB and MDR TB, including overseeing regular delivery of quality-assured second-line drugs. • partnership between Eli Lilly in the United States and Biocom in A the Russian Federation led to Biocom’s being prequalified for the production of cycloserine. If Biocom receives approval from WHO, it expects to supply drugs to countries that receive assistance from the Global Drug Facility program. Presenters on the supply chain for second-line TB drugs described a new paradigm for the drug supply for drug-resistant TB and offered three different perspectives on MDR TB treatment and the drug supply chain in Russia. 87

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88 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA A NEW PARADIGM FOR THE DRUG SUPPLY FOR DRUG-RESISTANT TB1 Major changes are now under way in the delivery and production systems for drugs needed to treat MDR TB, said Zintl. These changes will affect both the mechanisms and the patterns of supply for second-line drugs for MDR TB, and they represent a significant opportunity for national producers of reliable, high-quality anti-TB drugs. The establishment of the GLC in 2000 represented a new paradigm in MDR TB care. As noted in Chapter 2, the WHO previously had counseled against treating patients with MDR TB in resource-limited settings. The fear at the time was that the effort to treat MDR TB patients would drain resources and distract attention from the more achievable goal of treating patients with drug-sensitive TB. The mandate for the GLC was to ensure that programmatic treatment was proper for MDR TB patients and that there was access to quality-assured second-line drugs at affordable prices. The GLC was also designed to enable, support, and monitor the Directly Observed Treatment Short course (DOTS)-Plus program. “The GLC was formed so that the new pilot projects did not increase the risk of MDR TB through poor-quality programs,” said Zintl. “The committee controlled access and provided discounted prices for relatively limited supplies of quality-assured drugs.” In 2006, WHO officially changed its policy to call for treatment of MDR TB patients in all countries with a significant MDR TB burden. In the first 10 years of the GLC’s existence, only about 20,000 MDR TB patients were treated in GLC-approved projects—an average of 2,000 patients per year. As the incidence of MDR TB rose, the GDF, which works on behalf of the GLC to supply second-line drugs, struggled to secure adequate quantities of these drugs. In addition, it became clear that acquired drug resistance is an increasingly serious problem (see Chapter 4). In many countries with high burdens of MDR TB, moreover, patients can and do acquire second-line drugs on their own or through medical provid- ers who do not deliver the drugs under proper programmatic conditions. Market data show that sales of second-line drugs have been rising rapidly in countries with high burdens of MDR TB, as would be expected given the increase in the disease. Under these circumstances, the paradigm of the GLC’s approving proj- ects one at a time for small numbers of patients began breaking down, said Zintl. This paradigm was leading to extensive delays and backlogs in the numbers of patients awaiting treatment because of a lack of drugs. It was posing a threat to multilateral funding for countries that could not access 1 This section is based on the presentation of Paul Zintl, Partners In Health.

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89 SECOND-LINE DRUG SUPPLY CHAIN drugs from the GDF. And it was resulting in patients being placed on less- than-adequate regimens. A major resolution adopted by the World Health Assembly in May 2009 marked a significant change in direction. The resolution identified MDR and XDR TB as threats to global public security. It noted that fewer than 3 percent of MDR TB cases were being treated according to WHO standards and with quality-assured drugs, and urged member states to achieve universal access to diagnosis and treatment of MDR and XDR TB. Drug supply and quality were a major focus. The resolution noted that there had been inadequate demand from countries for high-quality or quality-assured drugs and that as a result, the supply of drugs available through the GLC had been limited. This inefficient drug market was a major bottleneck to treating patients with MDR and XDR TB, said Zintl. The resolution urged member states to ensure that an uninterrupted supply of second-line drugs would be made available to patients. It stated that countries should make available a supply of drugs that meet WHO prequalification standards or strict national regulatory standards. The reso- lution also asked member states to help ensure that the drugs would be sold only by prescription and through registered providers and that fixed-dose combinations would receive priority. WHO is working on guidelines that will characterize strict national regulatory standards. However, the impor- tant change, said Zintl, is that countries now should accept this responsibil- ity for themselves so that neither inadequate supplies of second-line drugs nor poor-quality drugs will continue to accelerate the spread of MDR and XDR TB. The resolution requested that the WHO Director General help coun- tries harmonize their national drug regulatory standards with international standards, thus enabling national pharmaceutical manufacturers to gener- ate products of assured quality that can be sold in international markets. The Director General also is to work with countries on the development of quality indicators and to assist with monitoring and evaluation of the implementation of the measures called for in the resolution. In this new environment, Zintl said, the role of the GLC is likely to evolve to that of monitoring and providing support and encouragement. The GLC will still monitor the risks of poor-quality implementation and drugs, but planning for the scale-up of MDR TB control has grown beyond the GLC’s capabilities over the last 10 years. Brazil, India, and other coun- tries will lead in this transition, Zintl suggested. “Brazil has been manufac- turing quality drugs,” he said, “albeit not WHO-prequalified, and treating large numbers of patients with these drugs for years. India is on the same path. China seems to be doing so as well. Other countries have an oppor- tunity to follow that [lead].” The risks of poor program implementation and poor-quality drugs are

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90 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA still quite serious. Indeed, because of the magnitude of scale-up plans, these risks are even greater. Zintl expressed the hope that the GLC and WHO will create the necessary mechanisms to monitor these risks and encourage countries themselves to ensure proper program implementation and qual- ity drugs. National pharmaceutical companies now have an incentive to supply both domestic and international markets if they develop high-quality drugs and become prequalified, said Zintl. He emphasized the need for strong national and regional leadership in encouraging proper program implemen- tation and high-quality drugs. MDR TB TREATMENT AND THE DRUG SUPPLY CHAIN IN THE RUSSIAN FEDERATION2 Three speakers at the workshop discussed important aspects of the treatment of MDR TB in Russia. Goliaev described the efforts of the Rus- sian Health Care Foundation to implement health care and social proj- ects; Golubkov addressed the issue of ensuring a sufficient drug supply; and Potashnikov presented the perspective of a Russian pharmaceutical company. Implementation of Health Care and Social Projects A nongovernmental organization established in 1996, the Russian Health Care Foundation has completed projects representing investments of $400 million, including two leading World Bank projects implemented in Europe and Central Asia, Goliaev said. The foundation has been the princi- pal recipient of an $88 million grant from the Global Fund to Fight AIDS, Tuberculosis, and Malaria to improve detection and treatment of TB and MDR TB, including TB in prisons; to build the capacity of partner orga- nizations; and to improve HIV therapy in TB patients. Under this grant, it has trained thousands of specialists and instructors in the management of TB and has established a training and best practice center for disseminating good practices. It has provided equipment and supplies to laboratories and health care facilities and has supported the external evaluation of hundreds of TB diagnostic laboratories. The Russian Health Care Foundation, in collaboration with WHO and Partners In Health, helped territories receive GLC approval to treat MDR TB in 26 regional and 4 Federal TB Research Institutes, with approved projects using concessionally priced second-line 2 This section is based on the presentations of Dmitry Goliaev, Russian Health Care Foun- dation; Alex Golubkov, Partners In Health; and Benjamin Potashnikov, Biocom, Russian Federation.

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91 SECOND-LINE DRUG SUPPLY CHAIN drugs. About $2 million was provided to five federal research institutes to strengthen the TB monitoring system, and the foundation supplied and helped repair equipment and software for prison hospitals and laboratories. To build capacity among partners, the foundation has worked closely to implement the WHO program for combating TB in Russia. It provided financial support for 79 health facilities to establish diagnosis and reference units that provide counseling to TB and HIV patients before and after test- ing. It has helped write, publish, and disseminate more than 52,000 copies of training manuals, educational booklets, guidelines, and pamphlets on TB and HIV for all types of health care professionals. It also has held regional conferences on TB and HIV. As part of an integrated approach to MDR TB therapy, the foundation has overseen the regular delivery of drugs for the full course of therapy and has worked to guarantee the quality of anti-TB drugs through Good Manu- facturing Practices (GMP) certification and a multistage quality control process. One course of treatment under the GLC initiative costs $3,450 per patient, whereas it would cost 5 to 10 times more on the Russian market, according to Goliaev. Patient therapy is carried out according to international protocols and is conducted under the direct observation of medical staff. The expected cure rate of MDR TB treatment is about 55 percent, said Goliaev. Patients receive social support to improve treatment adherence. Also, the Global Fund project helped improve infection control measures in many regions of Russia. Problems facing the foundation include the increase in MDR TB patients, insufficient application of chemotherapy standards, late detection, insufficient patient compliance with treatment, a lack of monitoring for che- motherapy, and the ineffectiveness of initiatives to encourage sick people to undergo treatment. Only 68 percent of TB specialist posts are being filled, and current staffs are rapidly aging. As a result, the lack of qualified human resources is one of the problems in TB control in Russia today. There is also a lack of administrative support at the territorial government level. To counter these problems, said Goliaev, the foundation is working to ensure adherence to treatment standards and observation of chemotherapy, is increasing social support programs to reduce treatment default rates, and is enhancing the quality of laboratory investigations. The goal, he said, is to provide quality-assured drugs, including second-line anti-TB drugs, on a continual and comprehensive basis. Ensuring a Sufficient Drug Supply Golubkov described the implications of recent policy changes for his organization. Partners In Health has been combating MDR TB in Tomsk

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92 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA since 2000, prior to the establishment of the GLC. As noted by Goliaev, once the GLC had been instituted, drugs for MDR TB became available for just under $3,500 per year. As Partners in Health began treating MDR TB in more sites around the world, drugs became more difficult to acquire; waits of 9 to 12 months were common. The prices for drugs then began to increase. For example, only one company, from Japan, was eligible to supply GLC-approved kana- mycin, and that company was not registered in Russia. Partners In Health therefore had to turn to U.S. suppliers for kanamycin. Another problem with importing drugs into Russia is that they must be approved by the humanitarian commission to be tax exempt; however, the commission conducts just a few meetings each year, which can slow down approvals. Golubkov expressed the opinion that this may become a bigger issue in the future. With tens of thousands of new cases in Russia, Partners In Health will be unable to provide treatment to all of the people who need it. The reforms under way in the GLC should make it possible to avoid having a single sup- plier for a drug. Another step forward would be to establish a partnership between the regulatory authorities in Russia and international regulatory authorities. Still another option would be to increase the number of Rus- sian companies qualified by WHO to be included on the list of producers of drugs and to supply them through the GLC. All of these steps would improve the drug supply management system and make drugs more rapidly available, said Golubkov. In addition, he noted, Russia has a strong research capacity, and he suggested that the country should be involved in the search for new and more effective drugs against MDR TB. Perspective of a Russian Pharmaceutical Company Potashnikov explained how Biocom was prequalified for the produc- tion of cycloserine through collaboration with Eli Lilly. Biocom is a phar- maceutical manufacturer located in Stavropol in southern Russia. It was established in 1991 and upgraded in 2001, and since 2005 has been regis- tered for the production of generic drugs. In 2007 Eli Lilly transferred the technology for cycloserine production to Biocom, and together the two companies decided to take part in WHO’s prequalification program for suppliers through the Global Drug Facility program. Consultations with WHO, in which Biocom received considerable help from WHO experts, proceeded through 2008. One complication has been the differing requirements of Russian authorities and WHO. In 2009,

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93 SECOND-LINE DRUG SUPPLY CHAIN Biocom submitted an application to the prequalification program, and the application was modified in response to review in early 2010. If Biocom receives approval from WHO, it expects to supply drugs to countries that receive assistance from the Global Drug Facility program, including those receiving assistance from Partners in Health. By 2011 it hopes to have its drugs registered in many of the countries of the former Soviet Union and in other countries as well.

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