Global programmatic use of bedaquiline and delamanid for drug-resistant TB treatment: progress, challenges, and possible solutions Dr. Vivian Cox Chair, DR-TB Scale-Up Treatment Action Team (DR-TB STAT) Task Force USAID/STBP MDR-TB Clinical Consultant

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Outline Global progress on introduction of newer drugs Uptake of BDQ and DLM in the PAHO region Barriers to newer drug access Potential solutions

Timeline: introduction of bedaquiline and delamanid December 2012 FDA grants accelerated approval for bedaquiline June 2013 WHO releases interim guidelines for use of bedaquiline to treat DR-TB March 2014 EMA conditionally approves bedaquiline April 2014 EMA conditionally approves delamanid October 2014 WHO releases interim guidelines for use of delamanid to treat DR-TB May 2015 WHO adds bedaquiline and delamanid to Essential Medicines List April 2015 Janssen/USAID launch bedaquiline donation program Otsuka announces FighTBack Initiative delamanid donation program October 2015 Georgia becomes first country to receive donated bedaquiline October 2016 WHO guideline update on the use of shorter MDR-TB regimen WHO releases guidance on delamanid use for DR-TB in children March 2017 WHO releases GDG meeting report on the use of bedaquiline for DR-TB September 2017 WHO releases statement on off-label use of bedaquiline and delamanid December 2017 Five years after bedaquiline approval

Progress of global BDQ introduction 10,164 patients have received BDQ as of 1 July 2017 13,825 orders from the Global Drug Facility Registered in 18 countries; under assessment in 16 (11/30 high DR-TB burden countries without submission) 80% of BDQ access in South Africa and Russia 3,441

Global BDQ implementation *As of 1 July 2017

Progress of global DLM introduction 688 patients have received DLM as of 1 July 2017 3,238 orders from the Global Drug Facility Registered in 6 countries; under assessment in 4 (25/30 high DR-TB burden countries without submission) 79% of DLM access through Unitaid endTB project *adjusted to exclude compassionate use of DLM in November 2016

Global DLM implementation *As of 1 July 2017

Global Progress: BDQ and DLM *adjusted to exclude compassionate use of DLM in November 2016

Global progress: BDQ and DLM versus minimum estimated global need *calculation of global estimated need for newer drugs adjusted to reflect cumulative number of patients started on treatment for RR-TB in 2015 and 2016

14% (OOS 5%)

Uptake of BDQ and DLM: PAHO region Brazil is a high-burden TB country and Peru is a high-burden MDR-TB country Overall it is estimated that there are more than 7,000 persons in the PAHO region who needed newer drugs over the two year period between 2015 and 2017 Fewer than 150 people in the PAHO region have received newer drugs under program conditions, just over 2% of those who needed them PAHO countries that have introduced newer drugs under program conditions: Peru, Haiti and the Dominican Republic Brazil: compassionate use access for newer drugs Delamanid orders via GDF only for Dominican Republic (4 treatments) Bedaquiline orders via GDF for Dominican Republic (34 treatments), Peru (211 treatments), Haiti (20 treatments), Bolivia (3 treatments)

Reported barriers to newer drug introduction (1) Guidelines Interpretation of WHO guidelines in country context Guideline revision process, including training Concerns about off label use and use in special populations, especially with donation program drugs Establishing PV / aDSM Wanting to collect own efficacy data Adding newer drugs to a long, toxic regimen Cost, registration, importation Health system strengthening

Reported barriers to newer drug introduction (2) Guidelines Cost, registration, importation BDQ: donation program or tiered pricing; DLM: GDF pricing Registration (BDQ: 18 countries; DLM: 6 countries) Health system strengthening Weaknesses in current DR-TB programme Restriction of newer drug use to few centralized facilities Requirement to hospitalize cases to initiate newer drugs Lack of monitoring equipment Lack of SL LPA and/or phenotypic DST Weak community support systems for DR-TB patients Poor support from Ministry of Health

Contrast in access to BDQ and DLM Timeline of WHO recommendations doesn’t fully explain differential use Potential reasons for gap in access: Cost – purchase from GDF started in Feb 2016, only if GF-eligible Registration – proactivity of Janssen (e.g. CRP) Early access programmes – built clinical experience in country Country level decisions – sequential systems for BDQ then DLM BD dosing – impact on DOTS programmes and resources

Global access to newer drugs: potential solutions WHO guideline recommendations update Expand/re-organize technical assistance to countries to absorb current and future innovations Streamline pre-qualification and registration processes for new drugs Engage and educate communities on newer drugs Set targets Country targets Regional targets Access, registration, time to patient targets Set targets before access is needed Engage with civil society to create accountability

Acknowledgements