A comprehensive partner and activity mapping exercise

Transcription

1 Supply and access initiatives for internationally quality-assured second-line drugs against tuberculosis: A comprehensive partner and activity mapping exercise Assembled in 2017 in collaboration with And with additional guidance and support from The Global Fund and the Sanford School of Public Policy at Duke University.

2 Contents Executive Summary Background Project Scope And Methods Categorical Framework Study Findings by Category Review of Stakeholder Identified Forums Findings on Spending, Activity, and Timeline Conclusion

3 Executive Summary Internationally quality-assured (IQA) second-line drugs (SLD) are essential to treat and cure drug-resistant forms of tuberculosis (TB), but only a fraction of patients around the world who need these drugs receive them each year. This shortfall reflects a complicated, challenging global market for these drugs, and a complex system of national and international governance and administration regarding the manufacture, procurement, forecasting, and stock management of these drugs. This is exacerbated by limited TB care delivery capacity in many high-burden settings and a fractured donor and implementer landscape compared to other disease areas. From July 2015 through April 2016, building upon background research on this topic, a survey and interview review was conducted to map out and interface with the leading international partners, funders, and implementers working to improve this situation regarding IQA SLD against TB. This review synthesized publicly available information on these initiatives with interviews with these groups on the priorities, linkages, and budgets of these projects and their context in the larger global fight against TB. This project was conducted by a team of researchers from Duke University s Sanford School of Public Policy and Advance Access & Delivery, a US-based non-profit. The outputs from this research include: The following narrative report on the stakeholder and partner landscape A visualization tool called the TB Drug Access Atlas (currently found at worldhealthmap.org), based on the database created. The goal of this exercise was to take a first step to provide useful visualizations and data-driven tools to inform decision-making by global partners, reduce programmatic overlap where appropriate, take advantage of shared strengths, and address clear gaps in the areas of intervention where needed. This study focused necessarily on more established international development assistance providers but will be augmented in the future to include other regional efforts or national-level initiatives in-scope. The audience for this review and associated tools ranges from international and national policy-makers, the partners identified in the review themselves, and global health implementation researchers. The findings do not assign value to the projects in terms of direct outcomes, but rather identify existing work within the scope of this project on a global level. A summary of findings is as follows: 40 defined projects and partnerships were identified working on in-scope activities, with most activities involving multiple institutional partners. Information was also collected on 20 additional projects that were deemed to be either suspended, or only marginally in-scope. The inscope categories included procurement, regimen complexity, delivery challenges, forecasting, affordability, and market incentives, and regulatory complexity. Projects within the scope of this review are implementing in-scope work in 72 countries from 2014 through 2020 with a total reported global budget of $829.6M. Some projects identify their work as affecting all TB patients globally, however 66 countries are identified as receiving specific financial support for these activities from identified sources (totaling $785.6M USD over that time period). In terms of funding, among the seven overlapping categories of activity, procurement, regimen complexity, and regulatory complexity are relatively well funded over the next five years ($222m USD, $154m USD, and $139m USD, respectively, totaling $515m USD). Delivery challenges and forecasting follow closely behind this group in support ($123m USD and $118m USD), with affordability and market incentives together drawing only modest planned support ($47m USD and $27m USD, respectively) over the next five years in decreasing order. The most noticeable drop in planned funding occurs in the procurement category, with the vast majority of funding being planned for utilization by Mirroring the financing situation fairly closely, the programmatic activities more often identified by projects as key areas of work were procurement (24), regimen complexity (20) and delivery challenges (19). The lack of funding and work addressing the other four categorical areas may reflect the difficulty designing and assessing successful market-shaping or affordability/ market incentives projects across so many stakeholders, regulators, and economic systems. In terms of spending distribution, low-income and lower-middle income countries received an expectedly large share of the pledged resources, but several high-burden countries (in both raw number of patients and percentage terms) with relatively stronger economies received a much smaller share of resources than their disease profile may have suggested. India is a notable exception to this trend, being the only so-called BRICS nation with very high spending on in-scope projects (in fact, $269M USD of $294M USD allotted to BRICS countries). In terms of direct interviewee feedback on global challenges, the following were recurring issues identified during the interview phase: 1. SLD stock outs continue to be a challenge despite improvements and new mechanisms designed to decrease frequency of these events 2. Countries where many or most patients seek care in the private sector do not effectively or frequently share best practices with one another through a systematic mechanism 2 worldhealthmap.org 3

4 3. No global market review thus far for small SLD sector inspires confidence for a new manufacturing market entrant in terms of predictability, frequency of forecast updates, or the size of the market 4. Slow progress generating completed, rigorous clinical trials data for new drugs is a major blockage keeping national health authorities from utilizing new drugs and regimens 5. Efficiency issues for funding agencies, including lack of engaged oversight and accountability for many sub-recipients in this space 6. Poor logistics in country a frequent challenge during shipping, storing, and documenting SLD Background According to World Health Organization (WHO) estimates, an average of 3.9% of new cases of tuberculosis (TB) and 21% of previously treated TB cases had multidrug-resistant forms of TB (MDR-TB) in Some 480,000 new MDR-TB cases emerged that same year, with a global total of 580,000 cases of MDR-TB including retreatment cases, and close to 250,000 people died of these strains of the disease. Detection of MDR-TB cases has improved over the years, and efforts are in place by the highest burden countries to increase the number of patients patient diagnosed and treated. Yet, timely access by patients to IQA SLD as part of evidence-based treatment continues to be a serious concern. Market barriers and challenges all along the global and local supply chains mean that the gains made in diagnosing patients could be lost if those patients aren t appropriately treated with medications they need. The need to address drug supply and access problems is even more urgent with the promise of newer, more effective drugs and less toxic regimens on the horizon. The global health community, including large donor organizations, technical experts, governments, NGOs, and the private sector, are prioritizing their efforts in different ways to address these challenges. However, well-planned and executed initiatives are often done without close coordination which can lead to duplication or missed opportunities, even among otherwise closely linked organizations. It is widely accepted that order to replicate successful models and avoid repeating errors, visibility into the SLD supply and access initiatives against TB is critical, to ensure that no major gaps are left unaddressed, that overlaps are avoided, that linkages between programs can occur, and that lessons learned are more systematically shared amongst stakeholders. In 2015, the Global Fund and the Lilly MDR-TB Partnership launched a TB Program Mapping exercise to identify all ongoing efforts and major initiatives to address IQA SLD supply, procurement, and access challenges, and to identify the existing linkages, partnerships, and coordinating mechanisms where these issues are discussed and planned. This effort was not designed to evaluate these projects for effectiveness or value, but to provide information on the partner landscape for the benefit of global organizations and the broader TB community in its collective efforts to improve access to IQA SLD. 4 worldhealthmap.org 5

5 Project Scope and Methods During the summer of 2015, the research team finalized the scope of this project and the primary research methods to be used, based on the initial scope of work as well as targeted feedback from multiple international stakeholders in the IQA SLD space. PROJECT SCOPE The goals of this mapping exercise were as follows: Map the current major initiatives to address IQA SLD supply and access challenges Identify the existing forums and coordinating mechanisms where these issues are discussed Establish channels or tools to ensure this information is shared, updated and acted on The exercise was designed to create a product that could be used by the TB community to add value and increase the impact of current and future activities. The parameters were set to include the ongoing existing and planned or funded activities of projects that were fully or partially focused on access to IQA SLD. Not included in the scope of this exercise were projects primarily focused on research and development of new drugs. However, projects addressing regimen complexity of existing therapies or other strategies intended to increase market availability for drugs once they are approved by stringent regulatory authorities were included in the scope of this exercise. Finally, this exercise did not take into account projects that were mainly focused on access or delivery of non-iqa drugs, unless there was a significant component addressing access or delivery gaps for the IQA drug market. Within the scope of this project, the following sub-categories were created to understand the range of activities performed by each entity, organization, or partnership. These are informed primarily by the frameworks set forth in multiple documents by Management Sciences for Health (MSH) and the WHO to understand and address market dynamics issues in health systems contexts. They include: Market Incentives Forecasting Procurement and Supply Chain Management Regimen Complexity Regulatory Complexity Price Affordability Delivery Challenges Importantly, in interviews and online surveys, this exercise allowed interviewees to self-identify their efforts within these categories, rather than the research team assigning stated activities to these categories. Where desk research (no response to survey or interview request) was the primary source of information on a project, discernable activities in-scope were assigned to these categories by the research team. METHODS The research team used a combination of publicly available information via websites and reports to populate a spreadsheet of project drivers, regions of work, project budgets, partner organizations, project contacts, milestone dates, and activity timelines. Over the course of the next two months, all project leads were contacted by sent from a group of stakeholders at Lilly MDR-TB Partnership, The Global Fund, and Duke University to request their participation in the mapping exercise. Each contact who agreed to participate was first asked to fill out a Qualtrics survey intended to summarize project goals, approximate budget range, primary funders, activity timeline, partner organizations, regions where the project is working, and other projects they might be aware of working in a similar space. Participants were also asked to participate in a minute telephone interview with a member of the research team. Interviews were conducted either by telephone or Skype at the convenience of the project contact and were attended by at least two members of the research team, one leading the interview and the other taking notes and ensuring the details of the interview were properly recorded. The main goal of the telephone interviews was to better understand how project representatives linked their work to one or more of the seven market categories listed above. Through the interview process, interviewees also identified the forums and coordinating mechanisms whereby this information could be shared and used as a catalyst for discussions amongst stakeholders, leading to new projects and more effective approaches to current and future work in these areas. Of the 60 projects the research team initially identified, 21 phone interviews were conducted and 26 pre-interview Qualtrics surveys were completed. Multiple efforts were made to reach the project leads in cases where the team did not receive an response. In the end 40 projects were considered firmly in-scope, with another 20 projects with informational collected by the team that were either suspended or only marginally in-scope. 6 worldhealthmap.org 7

6 Categorical Framework Seven broad categories were identified as primary market factors affecting access to IQA SLD MDR-TB therapy. This categorization serves to outline the main challenges facing TB projects globally, and highlights areas of improvement for market functionality. While it is analytically useful to distinguish the major categories in this way, it is important to remember that in reality, all seven categories are intricately dependent on one another. The effects of a significant change, whether positive or negative, within one category can be seen throughout many other categories, according to interviewees. Definitions of these categories are drawn from the definitions in use by the WHO and Management Sciences for Health, with some influence from other entities categorizations, such as UNITAID s market drivers. It is crucial to note that interviewees may have somewhat different interpretations of each of these categories and how they may or may not overlap, regardless of survey prompting or interviewer guidance. This study ultimately reflects how representatives from different projects themselves would describe their work within the scope of this exercise. These categories are defined, and relevant to this exercise, as follows: MARKET INCENTIVES Market incentives can apply to patients, institutional customers, or most typically to manufacturing firms, as approaches to increase their involvement within the IQA drug market. This category of activities can facilitate market entrance, participation, and functionality via financial, institutional, or informational innovations or reforms. FORECASTING Forecasting can represent a range of predictive methods that quantify needs within a specified time frame. Strong forecasting is an integral part of the market, according to interviewees, as forecasting inaccuracies or a slow refresh cadence can negatively affect all other market dynamics, according to interviewees. PROCUREMENT AND SUPPLY CHAIN MANAGEMENT Procurement can refer to tendering, ordering, transportation, and administrative facilitation of SLD, on both the national and global levels. Despite improvements, procurement in the SLD market is characterized by delays and administrative holdups that reflect the challenges found throughout the other categories, according to interviewees. REGIMEN COMPLEXITY Regimen complexity can refer to activities that simplify or streamline treatment options for patients. Depending on the regimen, MDR-TB treatments can take upwards of 24 months to complete. The length of treatment time, adverse reactions to medications, reinfection, and low cure rates all contribute to the complexity of treating MDR-TB, according to interviewees. REGULATORY COMPLEXITY Regulatory complexity can refer either to the evidentiary, financial, and administrative burden to register drugs in different settings, or to a country s qualification to receive IQA medicines from multilateral procurement agencies. This can be an extremely lengthy series of processes that require licensures, guideline adherence, and adequate funding. MARKET INCENTIVES FORECASTING PROCUREMENT AND SUPPLY CHAIN MANAGEMENT AFFORDABILITY Affordability can be understood as the relationship between the purchasing organization s ability or willingness to pay, and the purchase price of an SLD order. Beyond the purchase price, all costs that go into monitoring, storing, and maintaining of SLD stocks are considered part of the overall cost of the order. Purchasing cost is directly affected by the market stability and manufacturing competition. DELIVERY CHALLENGES Delivery challenges can be understood as the practical linking of drug procurement efforts to functioning treatment projects. Once SLD arrive at a clinic, organization, or national stockpile, the storage, domestic transfer, and clinically/programmatically appropriate utilization of these drugs for patients is a key consideration that can involve many different institutional, governmental, and private sector stakeholders. REGIMEN COMPLEXITY REGULATORY COMPLEXITY AFFORDABILITY DELIVERY CHALLENGES 8 worldhealthmap.org 9

7 Study Findings by Category MARKET INCENTIVES Number of projects: 8 Total reported budget of projects that identify this focus category: $26,706, The following 8 projects are working to address issues related to market entrance, including manufacturer incentives to develop new IQA products or expand/maintain IQA production and/or patient incentives to choose IQA quality drugs: Active Pharmaceutical Ingredient Market Information Services (API MDIS) TB CORE - Promoting the Quality of Medicines program. STEP-TB (Speeding Treatment to End Pediatric TB) MDR-TB Strategic Rotating Stockpile Program(SRS) UNITAID EndTB project Country-level Drug Price and Supply Security project CHAI MDR-TB Access Program TB Product Procurement and Market Shaping Working Group CATEGORY CONTEXT Market incentives for the purposes of this study are any activity that incentivizes manufacturers to develop new IQA products or to expand/maintain IQA production in the market. They also refer to patient incentives to choose IQA treatments over non-iqa products in some cases, as the interviews unfolded. These two sub-categories can either intersect and be mutually reinforcing, or may potentially work at cross-purposes. Quality assurance is an important aspect of MDR-TB treatment: the use of non-iqa drugs can cause serious problems for patients and can promote the spread of MDR-TB. In some high burden countries, due to high treatment prices, patients are not incentivized to choose IQA treatments, especially patients within the private sector. There is little to no oversight of the treatment and handling of drugs within the private sector in several high burden countries, which often leads to incomplete, or incorrect treatment regimens and the use of non-iqa drugs. Making MDR-TB treatment more affordable is an important step towards ensuring that all patients receive appropriate care, and there is a clear linkage between the market incentives and affordability categories. Alongside a dearth of demand is the problem of incentivizing patients with resources and options to choose IQA drugs. MDR-TB requires a much more complex treatment regimen than non drug-resistant TB. Patients must receive chemotherapy for up to 24 months. Many patients report severe side effects to SLD and often must be hospitalized during treatment. For patients living in low-income settings, two years of forgone productivity can be a serious deterrent from treatment. The lack of new drugs in the MDR-TB drug market, restrictive guidelines surrounding new drug, and the slow pace of utilization of new drugs like bedaquiline and delaminid, is a serious hindrance in the global fight against MDR-TB, according to interviewees during this time period. *Notes on project timelines: From the information gathered about the nine market incentive projects, the majority of activity falls within the first two and a half years, with 3-5 projects per year from *Notes on funding landscape: With over $26 million dollars being spent on market incentives projects over the next five years according to the information gathered, the majority of funding is invested in the first two years, with a decrease between 2015 and Following this period, there are no major lags in funding. 10 worldhealthmap.org 11

8 CATEGORY CONTEXT FORECASTING Number of projects: 14 Total reported budget of projects that identify this focus category: $117,563, The following 14 projects are working to address issues related to forecasting including quantification and predictive forecasting at country and global levels: Active Pharmaceutical Ingredient Market Dynamics Information Services (API MDIS) USAID Bedaquilline Donation program Systems for Improved Access to Pharmaceuticals and Services (SIAPS) TB Care II Communicable Diseases Health Service Delivery (COMDIS-Health Service Delivery) STEP-TB (Speeding Treatment to End Pediatric) program MDR-TB Strategic Rotating Stockpile (SRS) TB Alert Zimbabwe Global Drug Facility s Early Warning Stock-Out System Country-level Drug Price and Supply Security project Clinton Health Access Initiative MDR-TB Access Program Strategic National Stockpile Program (SNS) Global Drug Resistant TB Initiative (GDI) Country-level Drug Price and Supply Security Project Forecasting is the predictive process of quantifying needed commodities in a specific timeframe. In the public health context, forecasting answers the question of how much medicine is needed, in quantities and in terms of cost, to meet the health demand of the population. Estimates are generated by analyzing data such as consumption rates, morbidity data, drug prices and demographics. Inaccurate forecasting can lead to serious problems regarding procurement, storage, access and ultimate delivery of IQA SLDs. Identifying the main challenges impeding accurate forecasting is an essential step towards improving the dysfunctional MDR-TB market according to many interviewees. The current IQA and non-iqa SLD market writ large is not conducive to planning ahead despite intense efforts to pool orders at the Global Drug Facility (GDF) and other agencies on this category for IQA drugs, of which the GDF is the largest customer. Due to this, instead of manufacturing on a make-to-stock basis, manufacturers are waiting for specified orders to be placed to begin the manufacturing processes (a make-to-order approach). Some stockpiles, when they exist, are found at multilateral institutions like the GDF, supported by UNITAID resources and others, according to interviewees. This need for outside institutional assistance for IQA purchases is primarily because there are long delays between forecast updates among customers, due to poor diagnostic tools and algorithms, administrative problems, limited delivery capacity, and/or governmental payment delays, according to interviewees. *Notes on project timelines: The majority of project activity in the category of forecasting occurs between 2015 and 2017, with only 2-6 projects per year post *Notes on funding landscape: The funding for forecasting projects has significant investment in the next three years, with over $111M invested across This level of funding drops by 2018, with less than $30M per year from in this category, and dropping to no funding in worldhealthmap.org 13

9 PROCUREMENT AND SUPPLY CHAIN MANAGEMENT Number of projects: 23 Total reported budget of projects that identify this focus category: $221,927, The following are examples of the 23 projects that are addressing issues related to the procurement of SLD, including issues around inventory sustainability and elimination of stockouts and overstocks: TB Product Procurement & Market Shaping Working Group Accelerator for Impact (a4i) Communicable Diseases Health Service Delivery (COMDIS-HSD) Active Pharmaceutical Ingredient Market Dynamics Information Services (API MDIS) USAID Bedaquiline Donation program USAID s Systems for Improved Access to Pharmaceuticals and Services (SIAPS) USAID Challenge TB Program Help Ethiopia Address the Low TB Performance Project HEAL-TB TRACK TB Program Control and Prevention of Tuberculosis Project (CAP-TB Project) STEP-TB (Speeding Treatment to End Pediatric TB) MDR-TB Strategic Rotating Stockpile (SRS) program Project Axshya SPARK-TB UNITAID s EndTB project MSF Access Campaign Clinical Access to Bedaquiline Program International Federation Red Cross MDR-TB Program Global Drug Facility s Early Warning Stock-Out System Country-level Drug Price and Supply Security project Strategic National Stockpile Program Global Drug Resistant TB Initiative (GDI) Clinton Health Access Initiative MDR-TB Access Program *Notes on funding landscape: Projects working on improving the procurement process for SLD have significant investment through 2018, after which funding drops to below $5m USD annually. CATEGORY CONTEXT The process of procurement refers to ordering, tendering, transportation, and administrative facilitation of products at a given set of institutions or organizations. Accurate forecasting with a reasonably frequent refresh cadence must first determine an estimated amount of needed supplies within a specific timeframe, at which point orders are placed with suppliers through various approaches. The time, ease, and accuracy of orders are all potential ways to assess procurement, and these can be considered some key performance indicators in this area, according to interviewees. Customers (be they clinics, hospitals, organizations, or government entities) determine quantities of reserve, minimum, and maximum stock based on consumption and projected lead-time. Refining these forecasting and quantification techniques to achieve accurate stock levels and temporally regular ordering are important procurement factors that can directly affect supply availability, quality, and price levels. Compared with first line treatments, SLD also have a much longer duration of use, sometimes a shorter shelf life, and more severe side effects (requires ancillary drugs to treat the side effects). All of these factors ultimately contribute to a difficult procurement landscape for storage and transfer of SLD, according to interviewees. *Notes on project timelines: The majority of project activities in this category occur between While there is a drop off in activity post 2017, there are at least 7-10 projects occurring per year through worldhealthmap.org 15

10 CATEGORY CONTEXT REGIMEN COMPLEXITY Number of projects: 20 Total reported budget of projects that identify this focus category: $154,099, The following are examples of the 20 projects that are working to address issues related to regimen complexity and variation, including dosing selection, and prescribing methods or policies: Union MDR-TB Working Group Critical Path to TB Drug Regimens Active Pharmaceutical Ingredient Market Dynamics Information Services (API MDIS) USAID Bedaquiline Donation program USAID s Systems for Improved Access to Pharmaceuticals and Services (SIAPS) USAID Challenge TB Program Help Ethiopia Address the Low TB Performance HEAL-TB TRACK TB Program TB Care II STEP-TB (Speeding Treatment to End Pediatric TB) STREAM Clinical Trial Project SPARK-TB Stop TB Global Plan to Stop TB The Sentinel Project UNITAID s EndTB project MSF s 3P (Push Pull Pool) Project International Federation Red Cross MDR-TB Program Country-level Drug Price and Supply Security project Clinton Health Access Initiative MDR-TB Access Program Global Drug Resistant TB Initiative (GDI) Regimen complexity is a factor that represents the processes and requirements for prescribing and dosing SLD in this context. Many interviewees argue that understanding and simplifying treatment regimens is an essential part of MDR-TB market stabilization. It is estimated that a majority of patients with MDR-TB are currently not being treated with IQA SLD or with recognized regimens, in part due to the regimen complexity of MDR-TB treatment. Compared to nondrug-resistant TB, MDR-TB treatments have a longer duration, are more expensive, are poorly tolerated. While all of these factors influence the complexity of MDR-TB treatment, the major challenges identified are the duration and cost of treatment. According to the WHO, the rational use of medicines requires, 1) patients receive medications appropriate to their clinical needs, 2) in does that meet their individual requirements, 3) for an adequate period of time, and 4) at the lowest cost to them and their community. 1 Reducing regimen complexity is identified as playing a key part in fulfilling all these requirements on the administrative, clinical, and economic levels, according to interviewees. [Note: subsequent research and discussion on new regimen non-inferiority is available as of this publication] *Notes on project timelines: Starting with over 15 projects per year in 2015, 9 to 12 projects are active after 2017 *Notes on funding landscape: Projects working to improve barriers around regimen complexity are well funded over the course of the first two years this project looked, with steady decrease in funding over the final three years, and ending at a little over $3M USD in worldhealthmap.org 17

11 CATEGORY CONTEXT REGULATORY COMPLEXITY Number of projects: 12 Total reported budget of projects that identify this focus category: $139,161, The following are examples of the 12 projects that are working to address issues related to regulatory complexity, including issues surrounding pre-qualification, in-country registration, regulatory harmonization, and issues surrounding the registration of medicine to ensure that individual products meet the criteria of efficacy, safety, and quality: TB Product Procurement & Market Shaping Working Group Accelerator for Impact (a4i) Critical Path to TB Drug Regimens Active Pharmaceutical Ingredient Market Dynamics Information Services (API MDIS) TB CORE - Promoting the Quality of Medicines program. Project Axshya UNITAID s EndTB Project MSF Access Campaign MSF 3P Project (Push, Pull, Pool) Clinical Access to Bedaquiline Program Country-level Drug Price and Supply Security project Zero TB Cities Project There are many regulatory hurdles countries must jump in order to obtain access to new SLD. Such regulatory complexities involve medicine registration and processing, regulatory harmonization, and pre-qualification guidelines. Developing new drugs for MDR-TB is an important aspect of providing better treatment options to patients; however, for some countries, the process of obtaining new drugs can be long and arduous. For example, most countries require that new treatments obtain pre-qualification by a stringent regulatory authority. The course a newly developed drug must take before arriving in a clinic is extensive and rigorous. As described by several interviewees, before a drug can be procured in the IQA system, it must acquire approval from a stringent regulatory authority, be eligible for procurement with donor funding, pass the WHO Prequalification process to assure quality and safety, and ultimately be registered or allowed in the beneficiary country through proper channels. There are many opportunities for impediments throughout the regulatory process given that among high-burden countries, only the South African Medicines Control Council is considered stringent by international bodies at the time of the research project, according to interviewees. Regardless of stringency, individual countries participating in IQA donation programs may nonetheless have a difficult time registering and working successfully to smooth the regulatory path for donations. The distinction in many countries between donations and imports can be extremely difficult to navigate, according to those interviewed. *Notes on project timelines: The 12 projects working on regulatory complexity issues appear to be spread evenly in activity across the period. *Notes on funding landscape: Similar to regimen complexity, but with a less significant up front investment, projects working on regulatory complexity issues are well funded over the course of the first four years this project, but funding is minimal (less than $4M USD) over the final three years. 18 worldhealthmap.org 19

12 CATEGORY CONTEXT AFFORDABILITY Number of projects: 17 Total reported budget of projects that identify this focus category: $47,206, The following are examples of the 17 projects that are working to address issues related to affordability, including costs associated with placing and monitoring an order, communication costs, the cost of preparing an order or tender and subsequent negotiations, the staff time involved in routine checking of inventory levels, costs of receiving goods and related special fees, and administrative costs: The affordability of IQA SLD is directly affected by a number of economic and institutional factors, including but not limited to: manufacturing cost, size and nature of orders, availability of subsidies, customer/market demand and ability to pay, regimen and regulatory complexity, and delivery challenges. With regard to individual buyers, affordability is often dependent on their countries economic factors, involvement of state or private, and outside financial support. Interviewees identified agency issues as reasons for prices being insensitive to normal signals, specifically that those agreeing to spend the money to purchase drugs are not the ones incurring the cost, as the originating funds come from taxpayers or other donors into the international trust funds like the Global Fund. High cost of SLD generally also result from many factors described by interviewees, including manufacturing complexity, inefficiencies and fragmentation throughout the market landscape, made-to-order procurement, and poor forecasting among customers and their procurement agents. TB Product Procurement & Market Shaping Working Group Union MDR-TB Working Group International Federation Red Cross MDR-TB Program USAID Bedaquiline Donation Program Active Pharmaceutical Ingredient Market Dynamics Information Services (API MDIS) Control and Prevention of Tuberculosis Project (CAP-TB) TB Health Action Learning Initiative (THALI) STEP TB (Speeding Treatment to End Pediatric TB) MSF Access Campaign MSF 3P Project (Push, Pull, Pool) Clinical Access to Bedaquiline Program Enhanced Quality Drugs and Utilization of Innovative Diagnostics for TB (EQUIP) Country-level Drug Price and Supply Security project Clinton Health Access Initiative MDR-TB Access Program Zero TB Cities Project Global Drug Resistant TB Initiative (GDI) UNITAID EndTB Project *Notes on project timelines: The majority of the projects addressing affordability of SLD are active through 2017, however, the number of projects decreases from 13 projects to 9 projects from the end of 2017 to *Notes on funding landscape: Funding for projects addressing affordability remain low, but fairly consistent, across the period. Funding slightly increases after the first year, peaking at $8.9M USD in 2016 before decreasing slightly to just above $7M USD the following three years, before falling to $5.8M USD in worldhealthmap.org 21

13 CATEGORY CONTEXT DELIVERY CHALLENGES Number of projects: 19 Total reported budget of projects that identify this focus category: $122,899, The following are examples of the 19 projects that are working to identify and tackle challenges related to the delivery of IQA SLD: The actual delivery of SLD in programmatic context presents a number of challenges and this category is linked closely to many of the others, in the opinion of interviewees. In this way it acted as a broader umbrella to capture challenges of getting the SLD to the patient, in many contexts. The lengthy process of delivery begins when IQA SLD are sent by suppliers to customers or clients, with data on receipt reported back. The phase of programmatic distribution of drugs from importation agency to governments or civil society programs is complex and often riddled with delays, and can be further exacerbated by poor inventory control, stock management, with slow responses to health center or hospital needs in-country or in regional pooled procurement schemes. Throughout this process, there is potential for poor storage, loss of drugs, inaccurate reporting, or shortages/stock-outs mid-regimen for patients, according to interviewees. TB Product Procurement & Market Shaping Working Group Union MDR-TB Working Group International Federation Red Cross MDR-TB Program Systems for Improved Access to Pharmaceuticals and Services (SIAPS) TB Health Action Learning Initiative (THALI) TB Alert India TB Alert Zimbabwe Stop TB Global Plan to Stop TB Stop TB Partnership Technical Assistance Project The Sentinel Project UNITAID EndTB project Enhanced Quality Drugs and Utilization of Innovative Diagnostics for TB (EQUIP) emocha MDR-TB Mobile Health Project Country-level Drug Price and Supply Security project Indus Hospital Community-Based MDR-TB Treatment Program Zero TB Cities Project Global Drug Resistant TB Initiative (GDI) TB REACH Waves 4&5 USAID Challenge TB Program *Notes on project timelines: While there are a number of projects working in this sector in 2016, post 2016 there remain projects per year working to address issues related to delivery challenges. *Notes on funding landscape: Funding for projects addressing delivery challenges remains relatively high throughout the period, with $25M-$29M annually for the first three years and more than $10M for each year until worldhealthmap.org 23

14 Review of Stakeholder Identified Forums Forum Description Summarized from interview content and publicly available information Forum Below are the forums identified by project contacts during the research process. These serve as important events held frequently or annually for the sharing of information by projects working to address supply and access challenges of internationally quality-assured second-line drugs against tuberculosis. This is included in the International AIDS Society Conference Clinton Health Access Initiative (CHAI) Supplier/ Buyer Summit project s scope to understand how information is currently being exchanged, by which stakeholders, and at what frequency. This can help assess if and how new tools can be used to help facilitate these discussions, particularly among policymakers who may not have extensive knowledge of the global TB situation and relevant stakeholders. Description Summarized from interview content and publicly available information The International AIDS Society (IAS) Conference is an annual community and scientific meeting to discuss and share efforts to treat and prevent HIV and diseases that affect those at risk or living with HIV. There are often TB-specific events given the high rate of TB deaths among people living with HIV, and the increasing harmonization of The Global Fund and bilateral partners efforts against both diseases. This meeting has high relevance for delivery challenges and regimen complexity categories. This is a relatively new but regular, invitation-only ad-hoc assembly of major customers for SLD. Held in South-Asia in 2014 and Southeast Asia 2015 given the geographical density of suppliers from India (69 of 81 GDF IQA drug suppliers alone), China and Eastern Europe. This is a way to directly deal with each step company involved with the second-line TB drug manufacturing process and to minimize order complexity and maximize scale. This meeting has high relevance for affordability, market incentives, and forecasting categories. RESULTS International Conference TB Alliance Stakeholders Meeting Wolfheze Conference (Europe) American Lung Association Meeting GDF Annual Stakeholder Meeting This conference is an advocacy event held in Washington, DC every summer, according to interviewees, where attendees learn methods for effective advocacy to translate into policy. The focus is on translation of science for advocacy in the area of public health, but also extends into the fields of poverty reduction and other socioeconomic issues. This meeting has high relevance for the delivery challenges category. At this meeting chaired by the TB Alliance, partners share new drug regimen development news in detail and discuss the prospects of these potential new approaches to treating all forms of TB. Particular foci include pediatric formulations and child-friendly regimens, as well as new approaches to regimen design for most difficult strains of MDR-TB. This meeting has high relevance for delivery challenges and regimen complexity categories. The Wolfheze Conference was identified by interviewees as a meeting of TB policy makers and researchers. This meeting is organized and hosted every two years by KNCV Tuberculosis Foundation in collaboration with WHO Euro and ECDC. The conference pulls together representatives from national TB programs alongside policy makers from the WHO and ECDC. This conference presents the opportunity to disseminate lessons and opportunities between various European and Central Asian countries. The conference focuses on delivery challenges, particularly on the regional level. The Four Corners TB/HIV conference, hosted by the American Lung Association brings together experts to more widely discuss Lung Disease, but also to host scientific discussions specific to TB infection and disease, including some focus on regimen design. The annual GDF stakeholder meeting provides a forum for discussing issues around procurement, forecasting, quality control, supply chain issues, and other market dynamics for both first and second-line drugs. Attendees include both multilateral organizations and funders as well as drug manufacturers and other partners. 24 worldhealthmap.org 25

15 Findings on Spending, Activity, and Timelines Forum Union Conference World Health Organization (WHO) Strategic and Technical Advisory Group (STAG) for Tuberculosis Meeting Critical Path to TB Drug Regimens (CPTR) Initiative Description Summarized from interview content and publicly available information The Union World Conference on Lung Health is the preeminent annual TB meeting, focusing on TB specific issues in challenging settings and elsewhere. This five-day conference is also a meeting place for groups within the stakeholder pool to hold side meetings for coordination and facilitation of wider partnerships. The meeting involves representatives from most countries in the world, to discuss advocacy, affordability, delivery challenges, regimen design and complexity, and less often procurement and forecasting. STAG-TB group is made up of 23 experts that represent academic and research institutions, public and private TB programs, and patients and civil society advocates. This group meets annually to review and provide technical and policy recommendations for the WHO s TB-related activities. Held in Washington D.C., the goal of this annual meeting is to advance the development, delivery, and regulatory pathways of new TB drug regimens and diagnostics. This meeting represents leaders from pharmaceutical and diagnostic companies, public health organizations, policymakers, and civil society and patient advocates. SPENDING ANALYSIS The below are preliminary summary findings in terms of political and economic factors for in-scope project locations: Regarding funding reported for specific countries, there is a notable focus on countries grappling with poverty at a significant level (99.6% of the $785.6m planned in-country expenditures are targeting low-income and lower-middle income countries), and more specifically on countries suffering from severe poverty (32.9% of expenditures in low income countries alone). In terms of WHO regions, the AFR (Africa) region receives 36% of the total planned expenditures according to this review, with SEAR (South East Asia) receiving 44%. There is a notable lack of identified investment in many countries with strong existing manufacturing, regulatory, and technical capacity, which are nonetheless high burden TB countries as designated by the WHO. For example, the so-called BRICS bloc -- Brazil-Russia-India-China-South Africa -- make up about half of TB patients in the world, but are only receiving 37% of planned expenditures on drug quality despite all being high burden TB countries. India alone receives 91% of those funds. These dynamics may make sense for forecasting/quantification projects but raise strategic questions regarding the lack of programs addressing delivery challenges, procurement, regimen and regulatory complexity in high-burden settings. These gaps could eventually be supplemented adequately by domestic sources in the future but there are certainly pressing, unaddressed challenges in each of the BRICS, according to interviewees. EXPANDED FINDINGS AND NOTES: SPENDING AND ACTIVITY DISTRIBUTION Within the scope of this review, 72 countries are identified as receiving project support through 2020, of which 66 were identified specifically as receiving project funding. Within these 66 cited countries, planned expenditures by in-scope projects total $785.6M of the $829.6M reported by all inscope projects. However, some projects have indicated a global designation without providing specific country information, so the total countries spending on in-scope projects includes high-income economies that are not listed in the database, as well as funding that is left undesignated to specific countries and not included in this analysis. Nearly three-quarters of this $785.6M just under $584m USD is dedicated to the 30 high-burden TB countries, and $596m USD are dedicated to the 30 high-burden MDR TB countries. But, this does not include some of the highest burden countries. They do not universally take up the highest funding spots: only 14 of the top 20 countries in terms of expenditures in-scope are high-burden TB countries, and 13 of the top 20 countries in terms of expenditures inscope are high-burden MDR TB countries. 26 worldhealthmap.org 27

16 Figure 1. Total projects by WHO region, Figure 2. Total reported budget by WHO region, According to the distribution of funding, there is a clear focus on countries grappling with poverty--$783m USD in funding is dedicated to low income and lower-middle income countries as designated by the World Bank with particular focus (as noted in Figures 1 and 2) on South East Asia and Africa. In terms of gaps, there is a notable lack of focus on several high-burden middle- to upper-middle income countries the Brazil, China, Cambodia, Indonesia, Russia, and Thailand are all outside the top 20 recipients of planned in-scope spending. The African WHO region receives notably higher resource commitments for in-scope activities, due to many likely factors, including 1) intense donor activity and national partners for HIV and poverty reduction programs already and 2) high HIV-coinfection rates driving more attention. Whether this reality is a case of path dependence (working with partners that are already known even if burden is lower), or is a strategic choice is beyond the scope of this review. NOTES ON BRICS SPENDING FOR IN- SCOPE ACTIVITIES Only two BRICS countries are on the top 20 list (India and South Africa). This may be explained by the fact that the high prevalence raw case load of TB and DR-TB patients in upper-middle and high income countries in the certain BRICS member states, are nonetheless subject to lags in external, bilateral and multilateral foreign aid funding due to 1) the presumption of stronger existing technical and institutional capacity, or 2) political reluctance to provide or accept donor funds in these settings (ex: Russian Federation, China). Countries like Brazil have similarly low external investment (less than $1.7m USD) identified for in-scope projects, as TB programs are run exclusively by the government and many drugs are provided by public institutions. Upper-middle income countries are receiving $66.3M USD in funding for TB in-scope projects. The only high-income country receiving funding in this study is the Russian Federation, but despite its projects spanning all the conceptual areas, the total foreign investment in those projects is under $2m USD. This low total despite the extensive drug-resistant TB burden may be explained by the quite large domestic investment related to TB in the country, administrative and regulatory barriers for humanitarian drug donations, as well as existing potential market investment in quality drug production by way of a large domestic pharmaceutical industry. In terms of funding, among the seven overlapping categories of activity, procurement, regimen complexity, and regulatory complexity are relatively well funded over the next five years ($222m USD, $154m USD, and $139m USD, respectively, totaling $515M USD). Forecasting and delivery challenges follow closely behind this group in support ($118m USD and $123m USD), with affordability and market incentives together drawing only modest planned support ($47m USD and $27m USD, respectively) over the next five years in decreasing order. The most noticeable drop in planned funding occurs in the procurement category, with the vast majority of funding being planned for utilization by worldhealthmap.org 29