TB develops in one million children annually and is a leading cause of pediatric death. In 2010, WHO recognized that children were not being adequately dosed, though no companies responded by producing new formulations. Practical barriers—including a lack of accurate data on the childhood TB burden, limited uptake of existing products and perspectives of pediatric TB as a low priority—hindered formulation and introduction. In 2013, TB Alliance launched STEP-TB to forge cross-sector collaborations for the development and delivery of child-friendly, correctly dosed medicines. These life-saving treatments were introduced in December 2015 and have since seen widespread global uptake.

The STEP-TB project’s primary goal was increasing access to correctly dosed, properly formulated, affordable, high-quality TB medicines for children. The objective is in line with the SDG Goal 3 targets of ending preventable deaths among children under five, and ending the epidemics of AIDS, tuberculosis, malaria and other communicable diseases. The project’s goal of ensuring access to improved TB medicines also focuses on meeting the SDG Goal 3 target of achieving universal health coverage, including access to safe, effective, high-quality and affordable essential medicines.

We achieved impact against each of these targets through a series of best practice interventions: Building the evidence base: Further evidence was needed to understand the true magnitude of the childhood TB burden and to understand how to best ensure children have access to life-saving treatments. Investments in burden estimation, market sizing, understanding private sector treatment channels, and mapping procurement and regulatory pathways yielded an improved understanding of the problem and potential strategies for addressing access barriers.

- Leveraging evidence to catalyze the market: Armed with evidence that the burden of pediatric TB was almost double previous estimates and with strategies to overcome existing access hurdles, TB Alliance successfully engaged two quality-assured generic suppliers to enter this previously neglected market.

- Mobilizing cross-sector partnerships for maximum impact: TB Alliance leveraged its product development partnership model to forge innovative cross-sector collaborations among a broad network of industry, public sector, donor agencies, multilaterals, NGOs, academic institutes and civil society partners. Together, the initiative mobilized collective capacity and resources toward a shared goal of developing and delivering an improved child-friendly TB treatment.

- Breaking down silos: Reaching children with TB meant breaking down the silos that historically existed between TB-specific and maternal and child health programs. By partnering with UNICEF and child-health stakeholders, TB Alliance spurred broad uptake of improved treatments.

By marshaling global partners in response to this dire situation and engaging with pharmaceutical and public health partners to develop better medicines for children with TB, we achieved the following objectives:
• Developed appropriately formulated, quality-assured and child-friendly first-line pediatric TB medicines
• Guaranteed availability for children globally
• Eliminated or greatly reduced market barriers to ensure sustainable access
• Increased long-term commitment of countries to adopt improved medicines
• Developed clear pathway and best practices for introduction, which can be leveraged for other treatment access efforts

The availability of child-friendly TB medicines in the correct doses represented an important initial step toward ensuring widespread access to better treatments and improved treatment outcomes worldwide. The achievements to date provide an important model for leveraging innovative approaches and collaborations to rapidly introduce life-saving medicines for similarly fragile markets in support of the 2030 Agenda. The success also underscores the importance of building innovative partnerships with manufacturers, high-burden countries and other global health players as a vital aspect to the fight against neglected diseases like TB. The new medicines are now reaching children around the world, creating an environment for future action in the fight against TB and further innovation in treatment.

TB Alliance launched STEP-TB in partnership with WHO, with support from partners including Australian Aid, Irish Aid, Unitaid, USAID and UK Aid. STEP-TB worked with national TB programs, Management Sciences for Health, UNICEF, the Global Fund, Stop TB Partnership’s Global Drug Facility and a broad network of country-based partners.

Dr. Immaculate Kathure of the Kenya National TB Program shares: “With appropriate treatments available in our country, we can make rapid progress in finding and treating children with TB and take a major step toward achieving a TB-free generation.”

See a full list of partners here: https://www.tballiance.org/child-friendly-medicines

Given that introducing improved medicines to the market was the cornerstone of the project, pharmaceutical partnerships were an essential aspect in developing, commercializing and registering the pediatric TB formulations. Macleods Pharmaceuticals was the first company to bring the products to the market with a fixed-dose drug combination (FDC), which was made available through broad registration across the highest burden countries and through the Stop TB Partnership’s Global Drug Facility (GDF) in December 2015.
In April 2016, Cote d’Ivoire, followed closely by India, became the first country to register the new child-friendly medicines. Papua New Guinea placed its first order for medicines through the GDF in mid-2016. And in September 2016, Kenya became the first country to introduce the new child-friendly TB medicines at a national scale, which provided a model for successful national adoption for other countries. Lessons learned from early adopters were featured in workshops held in conjunction with the Union World Conference on Lung Health, the UN High Level Meeting on Tuberculosis and other global fora, serving as powerful models for action both within TB programs as well as across the global health sector. Lessons learned and best practices from the project have been compiled as part of WHO’s Best Practices in Child and Adolescent TB report, published in 2018, and will continue to serve as a model for successfully mobilizing access to life-saving treatments for neglected markets.
To date, 88 countries have ordered enough treatment courses to reach 75% of children with TB who have been reported to national TB programs globally since launch. The number of treatments delivered is on course to exceed one million by World TB Day 2019, ensuring that the highest TB burden countries now have access to optimized child-friendly medicines to fight TB. The project continues to monitor data on the number of treatment courses purchased, the countries that are accessing treatment and the regulatory approvals secured to ensure progress at a continued pace, as well as monitoring for emerging barriers to access.

Without STEP-TB, the pediatric TB treatment landscape would still be fragmented and stagnant today. Despite TB being the leading infectious cause of death worldwide and a leading cause of death for children globally, no companies were willing to invest, innovate and enter this critical market. The primary achievement of TB Alliance, WHO and partners was increasing access to correctly dosed, properly formulated, affordable, high-quality medicines to fight childhood TB. The broader impact achieved included:
1. Improved products widely available at an affordable cost of less than 10 cents per day
a. The price was widely accepted, as it fell below the median price for pediatric treatments that were historically used for the 6-month treatment course.
b. Availability was ensured through broad registration and availability through GDF was the central procurement mechanism for countries securing TB drugs with donor funding.
c. At this time, 88 countries have ordered improved medicines and by World TB Day 2019 uptake is expected to reach one million treatment courses.
2. Children receive palatable TB medicines in correct doses
a. Clinicians and parents no longer need to crush bitter-tasting adult TB medicines to approximate a suitable dose for children. The new medicines quickly disperse in water and are fruit-flavored to improve tolerability.
b. These medicines are expected to improve adherence and treatment outcomes, reducing the potential for development of drug-resistant TB in children who complete treatment.
3. A better understanding of the TB burden among children
a. Improved estimates of disease burden were published in the WHO Global TB Report, highlighting that one million children develop TB annually, almost double previous estimates, leading to increased support of resource mobilization, advocacy and planning efforts.
b. Improved estimates of the global pediatric TB market helped entice pharmaceutical companies to enter the pediatric TB market.
c. Improved understanding of hurdles to treatment access encouraged the development of a strategic response to barriers, policy change drivers and regulatory pathways in priority countries.
4. Raising visibility of pediatric TB within the broader child survival agenda
a. Partnering with UNICEF drove integration focused on linking tuberculosis with global programs for maternal and child health, HIV and nutrition.
b. Launch of the “Louder than TB” campaign mobilized a coalition of over 50 global partners, helping raise awareness of TB as a crucial issue on the maternal and child health and survival agenda.
5. Revitalizing the pediatric TB drug market through cross-sector and industry collaboration
a. Improved market intelligence data were critical to the work with pharmaceutical companies on an introduction strategy and with countries on programmatic and procurement plans.
b. TB Alliance and partners reshaped the market for pediatric TB drugs by reducing barriers to entry, working with the pharmaceutical industry, mobilizing strong demand and preparing countries for uptake through technical assistance and broad stakeholder engagement.
6. Model for future development of innovative medicines for children
a. Best practices from the initiative have been codified and included in WHO’s Best Practices in Childhood and Adolescent TB report to inform future practice.

Multiple barriers existed at the project’s inception which could have precluded successful introduction of improved child-friendly medicines around the world. Previous suppliers were not broadly registering new treatments given regulatory hurdles and both real and perceived opportunity costs, which raised concerns about likely return on investment. As a result, only about 30% of the potential market had been benefiting from access to child-friendly FDCs. Research undertaken through the STEP-TB project highlighted that although there were significantly more children with pediatric TB than previously thought—nearly double that of previous estimates—only a small fraction was receiving treatment through existing TB programs. The majority of children were either not being properly diagnosed, were seeking care through primary or MCH channels, or were being treated in the private sector. Additionally, uptake of new treatments had been slow in the past, as programs required assistance in developing accelerated transition plans between the old and new medicines.
The project’s approach to addressing the challenges around introduction and scale-up of the new drugs fell into three areas of work: (i) an initial area of work devoted to expanding and stabilizing the market for the new formulations through broad registration; (ii) in-country support for policy adoption, and procurement and supply chain management, transition and budget re-programming; (iii) work to increase demand for new products through improved training and strengthened linkages with the child health and private sectors.
STEP-TB overcame access challenges to expand the market for child-friendly formulations. First, TB Alliance negotiated affordable pricing for the pediatric medicines after conducting a critical assessment of the market in collaboration with partners including GDF, WHO, Unitaid, USAID, the Global Fund and others. Second, TB Alliance leveraged donor support to help identify accelerated regulatory pathways and to defray costs associated with regulatory filing in the largest, highest-burden countries that had previously been excluded from the market. Third, TB Alliance worked with partners with broad geographic presence, including MSH and WHO country offices, to support countries in transitioning to integrate new pediatric treatments. Finally, leveraging its position as a product development partnership, TB Alliance forged strategic collaborations with UNICEF and with pediatric associations in priority countries to provide training and to support appropriate diagnosis and strengthen treatment and reporting linkages for children treated outside the TB sector.
STEP-TB reshaped the market for pediatric TB medicines by reducing barriers to entry, catalyzing the launch of the improved child-friendly products and mobilizing unprecedented levels of demand in this historically fragmented landscape.

Rather than rely on short-term provision of donated products, to ensure sustainability, TB Alliance performed market research to understand pricing acceptability and to measure a country’s ability to pay for the treatments. This effort included stakeholder consultations with payers—including national procurement officers, the Global Fund, USAID and Unitaid—as well as those facilitating procurement, including WHO and GDF. Armed with this evidence, we were able to negotiate sustainable and affordable pricing for the regimen at $15.54 for a full, six-month course of treatment. Long term affordability was key to ensuring widespread access for those who needed TB medicines most. We also broadly registered the FDCs and provided technical support for integration into national essential medicines lists, budgets and Global Fund grants, where applicable. This support helped to ensure the long-term sustainability of the intervention.

For small and fragmented markets with public health needs, consolidating demand and accelerating access to products is crucial to preventing market collapse. Expanding the target market for the project to include a strong focus on middle-income, high-burden countries also proved imperative to creating adequate scale for a relatively low volume product. A key learning, which is applicable to future product introduction, is that procurement pathways and adoption drivers in middle-income settings differ greatly from those in lower-income countries, requiring targeted strategies. Across the spectrum of countries in the project, national experts play a significant and vocal role in either enabling or delaying the adoption of new treatments. Therefore, a strategy for empowering local opinion leaders with the knowledge and tools to mobilize new treatments is critical for ensuring rapid adoption and uptake. The project also saw a cascade effect when early adopter countries generated visibility of their early uptake successes, thereby catalyzing subsequent waves of adoption.
The achievements and lessons learned from the STEP-TB project can serve as a model for product introductions of other treatment options or innovative, new health tools and the rapid scale-up for similarly fragile markets. Learnings from the STEP-TB model are already being deployed to support the scale up of other commodities to improve treatment, prevention and diagnosis of TB, including the catalyzing access to (1) child-friendly medicines for the treatment of latent TB infection; (2) child-friendly second line drugs to combat the existing threat of drug-resistant TB; and (3) forthcoming novel regimens for multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB).

The success of the TB Alliance-led pediatric TB initiative is the result of strong public-private partnerships and collaboration from many stakeholders to realize a clear, high-impact vision: a better TB treatment for kids. Before these medicines were introduced, caregivers and providers were forced to crush or split multiple, bitter-tasting pills in an attempt to achieve the recommended dose for children, ultimately contributing to poor treatment outcomes. There was little commercial appetite to produce pediatric TB treatments, given perceptions that it was a small and unviable market. Childhood TB was regularly overlooked in official statistics and in both global and local priority-setting. TB in children was underreported overall and was often mistaken for other childhood illnesses such as pneumonia and malnutrition.
Today, children around the world are being treated with new TB medicines in the correct dose and in child-friendly, fruit-flavored forms. Close to one million patients across 88 countries have felt the impact of this initiative. Evidence generation to define market potential and identify hurdles to commercial entry and scale up served to catalyze participation in this previously neglected market.
Engagement with partners outside of the TB sector— including institutions focused on HIV, maternal and child health, primary care and nutrition—proved vital to this success, as most children with TB are seen by health care providers outside of national TB programs. TB Alliance’s partnership with UNICEF and other child health stakeholders helped mainstream childhood TB within the MCH agenda and continuum of care for women and children. Collaborations with additional technical partners aided in the introduction of the new formulations. Affordable pricing and integration of the FDCs into national procurement channels will support their long-term sustainability.
Looking ahead, countries are well-positioned to continue their utilization of these improved medicines for children with TB. Much more remains to be done to find the significant number of missing cases and correct issues of underdiagnosis. Armed with the right tools, a major step has been made in the fight to end childhood TB.

TB Alliance landing page for childhood TB, including full list of partners: https://www.tballiance.org/child-friendly-medicines
Publication on lessons learned from the STEP-TB Project: https://www.tballiance.org/sites/default/files/child-resources/New_Pathways_for_Childhood_TB_Treatment.pdf
Fact Sheet on Child Friendly Medicines: https://www.tballiance.org/sites/default/files/child-resources/Fact%20Sheet-TB%20Alliance%20Pediatric.pdf
WHO Fact Sheet on the new TB medicines for children: https://www.tballiance.org/sites/default/files/child-resources/Fact%20Sheet-TB%20Alliance%20Pediatric.pdf
WHO, Best Practices in Child and Adolescent Tuberculosis Care,
https://apps.who.int/iris/bitstream/handle/10665/274373/9789241514651-eng.pdf?ua=1