TABLE 2.

Organisation of active pharmacovigilance (PV) for new drugs and regimens in programmatic settings

Country	Type of PV/aDSM package (time frame) Type of TB patient (number of sites)	Type of forms and reporting lines	Report assessment	CA	Strengths	Challenges
Ethiopia	aDSM intermediate package (April 2017)# All DR-TB patients starting NDs¶ (3)	NDs: SAE on GDF forms TICs → NPVC and NTP; NTP → GDF (within 24 h) STR and repurposed drugs: yellow form (and Excel-based form) TICs → NPVC and NTP (monthly)	Reporting overseen by Medical Officers at TICs SAE reports reviewed by experts on the CRC at the central level	Treating physician/team at respective TIC and reported to NPVC and NTP	National aDSM advisory group in place Active discussion between NTP, NPVC and technical partners (especially CTB and PiH (endTB project)) Programmatic aDSM implementation plan developed SAE reports reviewed by CRC Both electronic and paper aDSM reporting forms available at TICs	Poor internet access at most TICs hinders reporting of SAE within 24-h period National aDSM advisory group not regularly involved in aDSM activity planning No sub-national aDSM advisory groups Limited staff and lack of capacity for CA at NPVC Complex reporting requirements lead to duplication of work (national, international (GDF, UMC), programmatic, project-based (endTB Project)) Weak linkage between CRC's clinical management decisions and CA
Kyrgyzstan	aDSM intermediate package (Jan 2017) All TB patients (all)	Yellow forms (paper) TIC → PV staff at NTP → DDP	1 PV staff at NTP oversees PV data collection, assisted by 1 PV staff from KNCV (CTB) 3 PV staff from DDP review reports	3 PV staff from DDP assess events with experts from different disciplines	PV section at DDP has knowledgeable staff Good collaboration between DDP, NTP and KNCV/CTB Key staff at TB centres, DDP, MoH and clinical pharmacologists from the medical educational facilities trained on PV	Lack of staff in DDP and no PV officers at Oblast level, leading to: • no systematic CA • no regular feedback from DDP to the reporters of AE Additional workload on DR-TB coordinators and drug supply managers KNCV staff currently reports SAEs (for Bdq- and/or Dlm-containing regimens) to GDF
Tajikistan	aDSM intermediate package (December 2016) All MDR-TB patients (7)	Special aDSM page in patient file Data transferred from patient file to customised database by KNCV/CTB	Reports assessed by PV/PMDT focal persons of KNCV/CTB National Thematic Working Group assesses reports	CA subgroup under the National Thematic Working Group on aDSM	Private laboratory contracted with funding of CTB ensures timely high-quality monitoring tests with sample transportation Intensive regular monitoring and supervision have improved recording and reporting in pilot sites, including of AEs	Little capacity at PV centre CA done by the treating clinicians only Reports not submitted to UMC System ensuring timely and high-quality monitoring tests paid by CTB KNCV staff reports SAEs (for Bdq- and/or Dlm-containing regimens) to GDF
Indonesia	Active PV+ (Recruitment Aug 2015–Oct 2017) All patients on Bdq (5) aDSM core package (Oct 2017)§ DR-TB patients on ND&R (all)	CEM: special form PV officer on-site → NTPƒ 1 PV staff at NTP assisted by KNCV/CTB oversees data collection aDSM: paper form (based on yellow form) → NTP and NPVC within 24 h	PV focal person of NTP with KNCV/CTB PMDT focal person retrospectively assess reports	NPVC and NTP conduct irregular CA meetings	PV focal person at NTP 1 PV officer available in each pilot site implementing CEM for Bdq and 1 PV focal person at the NTP Direct links set up between NTP and NPVC	Assessment of AEs by clinical expert teams not systematically done Late CA (NPVC understaffed) Frequent staff changes, not all sites had a PV officer at all times of data collection No PV officers for sites that have no CEM cohort aDSM core package not well implemented
Myanmar	aDSM core package (Aug 2017) DR-TB patients on ND&R and repurposed drugs (2)	PMDT sites (within 24 h) → NTP aDSM focal point → NCCA and national PV database (within 72 h) → WHO aDSM database (within 30 days of SAE detection)	aDSM focal person of NTP	Clinical professors through the NCCA (within 15 days of SAE detection)	Clinical professors collaborate closely with NTP, and lead CA Feedback on CA to NTP within 15 days after reporting Working on application of membership to WHO Programme for International Drug Monitoring assisted by NTP and partners	Lack of HR in NPVC Multiple tasks assigned to the NTP aDSM focal point Need for upgraded equipment, calibration and maintenance in facilities for clinical monitoring
Vietnam	aDSM intermediate package (2018) DR-TB patients on STR (all) CEM pilot (2011–2015) MDR-TB patients (9) and patients on Bdq (3)	PMDT sites → NPVC → national PV database (Excel sheet) → WHO global aDSM database and (specific AEs of interest) ADR reports to VigiBase® of UMC	NPVC staff	NPVC with National Advisory Committee (professors, pharmacists)	Strong collaboration between the NTP and NPVC Reports can be filled in directly on computer via modifiable PDF and sent to NPVC by e-mail NPVC has a network of clinical experts that can be consulted during CA	High workload of NPVC staff Active PV has further increased administrative burden of clinicians, leading to late reporting and incomplete/low quality reports Different forms of active PV (first CEM, now aDSM) initially led to confusion with clinicians and underreporting for aDSM Low capacity of DR-TB clinicians to measure and interpret ECGs and audiometry reports

aDSM: active drug safety management and monitoring; CA: causality assessment; DR: drug-resistant; TB: tuberculosis; ND: new drugs; SAE: serious adverse event; GDF: Global Drug Facility; TIC: treatment initiation site (Ethiopia); NPVC: national PV centre; NTP: national TB programme; STR: shorter treatment regimen (for certain eligible forms of DR-TB); CRC: clinical review committee; CTB: Challenge TB (Flagship TB project of USAID); PiH: Partners in Health (NGO); UMC: Uppsala Monitoring Centre (Collaborating Centre of the WHO for PV); DDP: Department of Drug Procurement (of Kyrgyzstan); MoH: Ministry of Health; AE: adverse event; Bdq: bedaquiline; Dlm: delamanid; MDR: multidrug-resistant; PMDT: programmatic management of DR-TB; ND&R: new drugs and regimens; CEM: cohort event monitoring; HR: human resources; NCCA: National Core Committee for aDSM; WHO: World Health Organization; ADR: adverse drug reaction. ^#: active monitoring done at one of the sites from late August 2016 under the Unitaid-supported EndTB project; ^¶: eight sites now can use new drugs, with the shorter treatment regimen being introduced in all PMDT treatment sites from April 2018; ⁺: the project started as a CEM project, but because not all PV officers were retained, or able to collect information on all AEs occurring, for four of the five sites in practice CEM became the aDSM intermediate package; ^§: as of May 2019, this is not yet fully implemented; ^ƒ: originally done through e-TB Manager, but because that did not work well, later data were collected retrospectively from paper forms and added to a Microsoft Excel file.