Clinical management decision | Clinical trial design | Implications for clinical management |
Duration of use | Phase II trial design limited the duration of the drug under investigation to 24 weeks; drug duration was chosen for ease of endpoint analysis rather than optimal duration to maximise treatment outcomes | WHO guidance initially limited use of Bdq and Dlm to 24 weeks; clinicians were unable to prolong duration for patients requiring extension of Bdq or Dlm beyond 24 weeks due to resistance or intolerance to other second line medications, which can contribute to high rates of culture reversion and treatment failure25 |
Use in special populations | Children, adolescents, and pregnant women excluded from eligibility in Phase II trials, with time delay between adult and paediatric new drug investigations | Despite an USFDA pregnancy category B rating for Bdq (animal studies fail to show a risk to the fetus), there is ongoing reluctance to use the drug in pregnancy, due to the lack of data and subsequent WHO recommendation for its use; the delay between adult and paediatric new drug investigations means most children and adolescents in need of novel MDR-TB drugs will not receive them26 |
Drug–drug interactions | Potential additive toxicities, most notably QT prolongation with Bdq, Dlm, the fluoroquinolones, and clofazimine, required further investigation at the time of regulatory approval, leaving questions regarding the concurrent use of multiple QT prolonging agents, how to design an appropriate clinical monitoring schedule with electrocardiography, and whether patients should be hospitalised for close monitoring when starting treatment | WHO redefined pharmacovigilance requirements in 2015 in order to strengthen the monitoring and management of patients on Bdq and Dlm,20 requiring significant investment at country level to establish and maintain monitoring systems |
Combination use of Bdq and Dlm | Phase II trials did not allow for concomitant use of the two drugs | For patients with severe patterns of resistance, with few treatment options remaining, the use of novel drugs in combination was a necessity for many patients prior to WHO’s recommendation on combination use in 201727–29 |
Bdq, bedaquiline; Dlm, delamanid; TB, tuberculosis.