A comprehensive partner and activity mapping exercise...A comprehensive partner and activity ... Background Project Scope And Methods Categorical Framework Study Findings by Category

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.

www.worldhealthmap.org

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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

Contents

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Executive Summary

Internationally quality-assured (IQA) sec-ond-line drugs (SLD) are essential to treat and cure drug-resistant forms of tubercu-losis (TB), but only a fraction of patients around the world who need these drugs re-ceive 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 man-agement of these drugs. This is exacerbat-ed by limited TB care delivery capacity in many high-burden settings and a fractured donor and implementer landscape com-pared to other disease areas. From July 2015 through April 2016, building upon background research on this topic, a sur-vey and interview review was conducted to map out and interface with the leading international partners, funders, and imple-menters 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 bud-gets of these projects and their context in the larger global fight against TB. This proj-ect was conducted by a team of research-ers from Duke University’s Sanford School of Public Policy and Advance Access & De-livery, 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 da-tabase created.

The goal of this exercise was to take a first step to provide useful visualizations and da-ta-driven tools to inform decision-making by global partners, reduce programmatic over-lap where appropriate, take advantage of shared strengths, and address clear gaps in the areas of intervention where needed. This study focused necessarily on more es-tablished international development assis-tance 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 im-plementation 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 ac-tivities, with most activities involving mul-tiple institutional partners. Information was also collected on 20 additional projects that were deemed to be either suspend-ed, or only marginally in-scope. The in-scope categories included procurement, regimen complexity, delivery challenges, forecasting, affordability, and market in-centives, 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 affect-ing all TB patients globally, however 66 countries are identified as receiving spe-cific financial support for these activities from identified sources (totaling $785.6M USD over that time period).

• In terms of funding, among the sev-en 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, re-spectively, 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 no-ticeable drop in planned funding occurs in the procurement category, with the vast majority of funding being planned for utili-zation by 2017.

• 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 ad-dressing 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-in-come and lower-middle income countries received an expectedly large share of the pledged resources, but several high-bur-den countries (in both raw number of pa-tients and percentage terms) with relative-ly stronger economies received a much smaller share of resources than their dis-ease 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 inter-view phase:

1. SLD stock outs continue to be a chal-lenge despite improvements and new mechanisms designed to decrease fre-quency of these events

2. Countries where many or most patients seek care in the private sector do not ef-fectively or frequently share best prac-tices with one another through a system-atic mechanism


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 mar-ket

4. Slow progress generating complet-ed, rigorous clinical trials data for new drugs is a major blockage keeping na-tional 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 chal-lenge during shipping, storing, and doc-umenting 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 mul-tidrug-resistant forms of TB (MDR-TB) in 2015. Some 480,000 new MDR-TB cases emerged that same year, with a global to-tal 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 treat-ment 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 appro-priately treated with medications they need. The need to address drug supply and ac-cess 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 sec-tor, are prioritizing their efforts in different

ways to address these challenges. How-ever, well-planned and executed initiatives are often done without close coordination – which can lead to duplication or missed op-portunities, 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 unad-dressed, that overlaps are avoided, that linkages between programs can occur, and that lessons learned are more systematical-ly shared amongst stakeholders. In 2015, the Global Fund and the Lilly MDR-TB Part-nership launched a TB Program Mapping exercise to identify all ongoing efforts and major initiatives to address IQA SLD sup-ply, procurement, and access challenges, and to identify the existing linkages, part-nerships, 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 commu-nity in its collective efforts to improve ac-cess to IQA SLD.

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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 interna-tional 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 coordi-nating 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 com-munity to add value and increase the im-pact 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 fo-cused on access to IQA SLD. Not included in the scope of this exercise were projects primarily focused on research and devel-

opment 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 com-ponent addressing access or delivery gaps for the IQA drug market.

Within the scope of this project, the follow-ing sub-categories were created to under-stand the range of activities performed by each entity, organization, or partnership. These are informed primarily by the frame-works 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 Man-

agement• Regimen Complexity• Regulatory Complexity• Price Affordability• Delivery Challenges

Importantly, in interviews and online sur-veys, this exercise allowed interviewees to self-identify their efforts within these cate-gories, rather than the research team as-signing stated activities to these catego-ries. Where desk research (no response to survey or interview request) was the prima-ry source of information on a project, dis-cernable 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, proj-ect budgets, partner organizations, proj-ect contacts, milestone dates, and activity timelines. Over the course of the next two months, all project leads were contacted by email sent from a group of stakeholders at Lilly MDR-TB Partnership, The Global Fund, and Duke University to request their partici-pation in the mapping exercise.

Each contact who agreed to participate was first asked to fill out a Qualtrics survey in-tended to summarize project goals, approx-imate budget range, primary funders, activ-ity timeline, partner organizations, regions where the project is working, and other proj-ects they might be aware of working in a similar space. Participants were also asked to participate in a 30-45 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 tak-ing notes and ensuring the details of the in-terview were properly recorded.

The main goal of the telephone interviews was to better understand how project rep-resentatives linked their work to one or more of the seven market categories listed above. Through the interview process, in-terviewees also identified the forums and coordinating mechanisms whereby this information could be shared and used as a catalyst for discussions amongst stake-holders, leading to new projects and more effective approaches to current and future work in these areas.

Of the 60 projects the research team ini-tially 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 email 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.


Categorical Framework

Seven broad categories were identified as primary market factors affecting access to IQA SLD MDR-TB therapy. This categoriza-tion serves to outline the main challenges facing TB projects globally, and highlights areas of improvement for market function-ality. While it is analytically useful to distin-guish 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, with-in one category can be seen throughout many other categories, according to inter-viewees. Definitions of these categories are drawn from the definitions in use by the WHO and Management Sciences for Health, with some influence from other en-tities’ 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, re-gardless of survey prompting or interview-er guidance. This study ultimately reflects how representatives from different projects themselves would describe their work with-in the scope of this exercise. These catego-ries are defined, and relevant to this exer-cise, as follows:

MARKET INCENTIVESMarket 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.

FORECASTINGForecasting can represent a range of pre-dictive 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 MANAGEMENTProcurement can refer to tendering, order-ing, transportation, and administrative fa-cilitation of SLD, on both the national and global levels. Despite improvements, pro-curement in the SLD market is character-ized by delays and administrative holdups that reflect the challenges found throughout the other categories, according to inter-viewees.

REGIMEN COMPLEXITYRegimen 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, re-infection, and low cure rates all contribute to the complexity of treating MDR-TB, ac-cording to interviewees.

REGULATORY COMPLEXITYRegulatory complexity can refer either to the evidentiary, financial, and administra-tive 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 ex-tremely lengthy series of processes that re-quire licensures, guideline adherence, and adequate funding.

AFFORDABILITYAffordability can be understood as the rela-tionship between the purchasing organiza-tion’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 manu-facturing 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, domes-tic transfer, and clinically/programmatically appropriate utilization of these drugs for pa-tients is a key consideration that can involve many different institutional, governmental, and private sector stakeholders.

MARKET INCENTIVES FORECASTING PROCUREMENT AND SUPPLY CHAIN MANAGEMENT

REGIMEN COMPLEXITY

REGULATORY COMPLEXITY AFFORDABILITY DELIVERY CHALLENGES


Study Findings by CategoryCATEGORY CONTEXT

Market incentives for the purposes of this study are any activity that incentivizes manufac-turers 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 coun-tries, 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 incen-tives 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.

MARKET INCENTIVES

Number of projects: 8 Total reported budget of projects that identify this focus category: $26,706,666.67

The following 8 projects are working to address issues related to market entrance, in-cluding 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

*Notes on project timelines: From the information gathered about the nine market incen-tive projects, the majority of activity falls within the first two and a half years, with 3-5 projects per year from 2018-2020.

*Notes on funding landscape: With over $26 million dollars being spent on market incen-tives 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 2016. Following this period, there are no major lags in funding.


FORECASTING

Number of projects: 14Total reported budget of projects that identify this focus category: $117,563,281.17

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

*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 2017.

*Notes on funding landscape: The funding for forecasting projects has significant invest-ment in the next three years, with over $111M invested across 2014-2017. This level of funding drops by 2018, with less than $30M per year from 2018-2020 in this category, and dropping to no funding in 2020.

CATEGORY CONTEXT

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, mor-bidity 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 to-wards 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 agen-cies 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 pay-ment delays, according to interviewees.


PROCUREMENT AND SUPPLY CHAIN MANAGEMENT


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 project timelines: The majority of project activities in this category occur be-tween 2015-2017. While there is a drop off in activity post 2017, there are at least 7-10 projects occurring per year through 2020.

*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 adminis-trative facilitation of products at a given set of institutions or organizations. Accurate fore-casting 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 perfor-mance indicators in this area, according to interviewees. Customers (be they clinics, hos-pitals, organizations, or government entities) determine quantities of reserve, minimum, and maximum stock based on consumption and projected lead-time. Refining these fore-casting and quantification techniques to achieve accurate stock levels and temporally regular ordering are important procurement factors that can directly affect supply avail-ability, quality, and price levels.

Compared with first line treatments, SLD also have a much longer duration of use, some-times 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.


REGIMEN COMPLEXITY


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 meth-ods 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 2016-2020• 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)

*Notes on project timelines: Starting with over 15 projects per year in 2015, 9 to 12 proj-ects are active after 2017 *Notes on funding landscape: Projects working to improve barriers around regimen com-plexity 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 2020.

CATEGORY CONTEXT

Regimen complexity is a factor that represents the processes and requirements for pre-scribing 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 treat-ment. 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 treat-ment. 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 re-quirements, 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]

1http://www.who.int/medicines/areas/rational_use/en/


REGULATORY COMPLEXITY


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 reg-istration, 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

*Notes on project timelines: The 12 projects working on regulatory complexity issues appear to be spread evenly in activity across the 2014-2020 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.

CATEGORY CONTEXT

There are many regulatory hurdles countries must jump in order to obtain access to new SLD. Such regulatory complexities involve medicine registration and processing, regula-tory 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 regula-tory 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 pro-cured 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 as-sure 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 Medi-cines Control Council is considered stringent by international bodies at the time of the re-search 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.


AFFORDABILITY


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, com-munication 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:

• 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 2020.

*Notes on funding landscape: Funding for projects addressing affordability remain low, but fairly consistent, across the 2014-2020 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 2020.

CATEGORY CONTEXT

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, avail-ability of subsidies, customer/market demand and ability to pay, regimen and regulatory complexity, and delivery challenges. With regard to individual buyers, affordability is of-ten 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 man-ufacturing complexity, inefficiencies and fragmentation throughout the market landscape, made-to-order procurement, and poor forecasting among customers and their procure-ment agents.


DELIVERY CHALLENGES


The following are examples of the 19 projects that are working to identify and tackle chal-lenges related to the delivery of IQA SLD:

• 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 2016-2020• 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 11-14 projects per year working to address issues related to delivery challenges.

*Notes on funding landscape: Funding for projects addressing delivery challenges re-mains relatively high throughout the 2014-2020 period, with $25M-$29M annually for the first three years and more than $10M for each year until 2020.

CATEGORY CONTEXT

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 soci-ety 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 short-ages/stock-outs mid-regimen for patients, according to interviewees.


Review of Stakeholder Identified Forums

Below are the forums identified by proj-ect contacts during the research process. These serve as important events held fre-quently or annually for the sharing of in-formation by projects working to address supply and access challenges of interna-tionally quality-assured second-line drugs against tuberculosis. This is included in the

project’s scope to understand how informa-tion 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.

Forum DescriptionSummarized from interview content and publicly available information

RESULTS Inter-national Confer-ence

This conference is an advocacy event held in Washington, DC every summer, according to interviewees, where attendees learn methods for effective advo-cacy 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 deliv-ery challenges category.

TB Alliance Stakeholders Meeting

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 formu-lations 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.

Wolfheze Confer-ence (Europe)

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.

American Lung Association Meet-ing

The “Four Corners” TB/HIV conference, hosted by the American Lung Associ-ation 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.

GDF Annual Stakeholder Meeting

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.


International AIDS Society Conference

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-specif-ic 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.

Clinton Health Access Initiative (CHAI) Supplier/Buyer Summit

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 sup-pliers 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.



Union Confer-ence

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 stake-holder 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.

World Health Or-ganization (WHO) Strategic and Technical Adviso-ry Group (STAG) for Tuberculosis Meeting

STAG-TB group is made up of 23 experts that represent academic and re-search institutions, public and private TB programs, and patients and civil soci-ety advocates. This group meets annually to review and provide technical and policy recommendations for the WHO’s TB-related activities.

Critical Path to TB Drug Regimens (CPTR) Initiative

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 diag-nostic companies, public health organizations, policymakers, and civil society and patient advocates.

Findings on Spending, Activity, and Timelines SPENDING ANALYSIS

The below are preliminary summary find-ings in terms of political and economic fac-tors for in-scope project locations:

• Regarding funding reported for specif-ic 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 specifi-cally on countries suffering from severe poverty (32.9% of expenditures in low income countries alone).

• In terms of WHO regions, the AFR (Af-rica) region receives 36% of the total planned expenditures according to this review, with SEAR (South East Asia) re-ceiving 44%.

• There is a notable lack of identified in-vestment in many countries with strong existing manufacturing, regulatory, and technical capacity, which are nonethe-less high burden TB countries as des-ignated by the WHO. For example, the so-called “BRICS” bloc -- Brazil-Rus-sia-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 do-mestic sources in the future but there are certainly pressing, unaddressed challenges in each of the BRICS, ac-cording 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 in-scope projects. However, some projects have indicated a “global” designation with-out 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 coun-tries in terms of expenditures in-scope are high-burden TB countries, and 13 of the top 20 countries in terms of expenditures in-scope are high-burden MDR TB countries.


Figure 1. Total projects by WHO region, 2014-2020

Figure 2. Total reported budget by WHO region, 2014-2020

According to the distribution of funding, there is a clear focus on countries grap-pling with poverty--$783M USD in funding is dedicated to low income and lower-mid-dle 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 recipi-ents of planned in-scope spending. The Af-rican WHO region receives notably higher resource commitments for in-scope activi-ties, 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 ex-plained 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, bi-lateral and multilateral foreign aid funding due to 1) the presumption of stronger exist-ing 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 exclusive-ly by the government and many drugs are provided by public institutions. Upper-mid-dle 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 Feder-ation, but despite its projects spanning all the conceptual areas, the total foreign in-vestment 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 re-lated to TB in the country, administrative and regulatory barriers for humanitarian drug donations, as well as existing potential market investment in quality drug produc-tion by way of a large domestic pharmaceu-tical industry.

In terms of funding, among the seven over-lapping categories of activity, procure-ment, regimen complexity, and regulatory complexity are relatively well funded over the next five years ($222m USD, $154m USD, and $139m USD, respectively, total-ing $515M USD). Forecasting and delivery challenges follow closely behind this group in support ($118m USD and $123m USD), with affordability and market incentives to-gether drawing only modest planned sup-port ($47m USD and $27m USD, respec-tively) over the next five years in decreasing order. The most noticeable drop in planned funding occurs in the procurement catego-ry, with the vast majority of funding being planned for utilization by 2017.


Figure 4. Categorical budget expense identified by year

Figure 3. Categorical activities identified by year

In terms of overlaps or programmatic “cen-ters of gravity”, the programmatic activities more often identified by projects as key areas of work were procurement (24), reg-imen complexity (20) and delivery challeng-es (19). As noted above, the lack of funding and work addressing the other four cate-

gorical areas may reflect the difficulty in de-signing and rigorously assessing success-ful “market-shaping” or affordability and market incentives projects across so many stakeholders, regulators, and economic or administrative systems.

Conclusion

The challenges facing the IQA SLD stake-holder landscape are varied and complex in the donor and partner networks that the research team identified and studied. Ma-jor cross-cutting challenges identified by interviewees include:

• a fractured partner landscape with poor communication and few regional events to coordinate activities

• potentially inefficient use of donor funds for in-scope projects

• technical and administrative challenges in the target counties and globally for registration, procurement, forecasting of SLD

• high cost and complexity of SLD regi-mens, and unknown attributes of future regimens

The research team identifies these areas as potential gaps to be addressed:

• lack of direct spending or partner-ship-building focus on high burden countries

• lack of partnership building with very high-burden countries that have signif-icant technical, institutional, and finan-cial resources of their own to contribute in this area

Despite these varied challenges, there is at least considerable agreement among stakeholders on the which challenges exist. This should set the stage for effective action given adequate coordination and synergis-tic planning over time, if paired with efficient use of existing resources and exploration of new channels of support. Already, ma-jor positive synergistic overlaps are clear and include a stakeholder landscape with a strong focus on:

• forecasting, procurement, and reducing SLD regimen complexity

• support for low-income and lower-mid-dle income economies

• significant up-front financial investment for in-scope activities

This stakeholder mapping review rep-resents an initial attempt to identify overlap-ping priorities, program focus areas, and pledged/budgeted activities to support the implementation of this work. Please refer to the TB Drug Access Atlas at workhealth-map.org that utilizes this review’s data-base. It provides new ways for stakehold-ers to learn about the partner landscape by searching creatively for new gaps and overlaps, identifying new partnerships, and creating a path to reduce the massive hu-man and economic toll taken each year by tuberculosis around the world.

A comprehensive partner and activity mapping exercise...A comprehensive partner and activity ... Background Project Scope And Methods Categorical Framework Study Findings by Category

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