Setting up pharmacovigilance based on available endTB Project data for bedaquiline

Abstract

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the ‘advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort

“…Despite a heterogeneous study population from 16 countries, monitoring and reporting were highly uniform. Distinct from prior observational reports [ 9–14 ], the present study deployed a single, externally supported monitoring schedule that included monthly electrocardiograms and audiometry, reported solicited and unsolicited AEs, used standardized a priori definitions of AEs of interest, graded events according to a single severity scale, and received support from a central PV unit [ 4 , 15 , 16 ].…”

“…Although these events remain uncommon, attention is required to avoid polypharmacy and the use of beta-blockers as prevention for QT prolongation. Patients at risk for QT prolongation require increased monitoring [ 16 ].…”

Safety and Effectiveness Outcomes From a 14-Country Cohort of Patients With Multi-Drug Resistant Tuberculosis Treated Concomitantly With Bedaquiline, Delamanid, and Other Second-Line Drugs

“…In addition, SAEs were reported to the MSF pharmacovigilance (PV) unit in Geneva, Switzerland, to local authorities as applicable in each study country and, as appropriate, to drug manufacturers. A full description of the SAE cases, including demographics, relevant preexisting conditions, TB history, concomitant or prior drugs, tests results and investigations, and TB drugs was reported to the PV unit [ 20 ]. After preliminary medical review by the PV unit officers, difficult cases, particularly unexpected SAEs that were possibly drug-related, were reviewed by the medical review board (MRB), which included at least 2 PV officers and 2 experienced MDR-TB experts.…”

Pregnancy and Birth Outcomes in Patients With Multidrug-Resistant Tuberculosis Treated With Regimens That Include New and Repurposed Drugs

“…Data on pregnancy, birth, and treatment outcomes were systematically collected by the Médecins Sans Frontières (MSF) pharmacovigilance unit (PVU) supporting 2 observational studies. The endTB observational study was a multicenter prospective cohort study enrolling patients with MDR/RR-TB who initiated treatment with new and repurposed drugs under routine care from April 2015 through September 2018 in 17 countries [ 6 , 7 ]. The ongoing Strengthening Evidence on Optimal Treatment of Multidrug-Resistant Tuberculosis (STEM-TB) cohort extended the endTB observational study in 3 countries by enrolling patients receiving 9-month all-oral bedaquiline-containing regimens under operational research conditions beginning in September 2020.…”