In a Phase IIb trail, bedaquiline drug for MDR-TB treatment was found to be cardiotoxic and hepatotoxic, and it also caused more deaths. Review of evidence in 2015 showed a reduction in mortality but there were unexplained serious adverse events of respiratory origin. While Phase III trial results are yet to become available, data from over 5,000 patients show significant reduction in mortality while and no new safety signals have emerged.

In a recent Rapid Communication, the World Health Organisation (WHO) made important changes in the regimens to treat patients with multidrug-resistant TB (resistant to isoniazid and rifampicin). Two of the injectables (kanamycin and capreomycin) previously used for treating MDR-TB patients are to be replaced with a fully oral drug regimen. And bedaquiline drug, specifically developed for treating MDR-TB patients, has been included in the fully oral regimen. The injectables have been removed as they cause hearing loss (ototoxicity) and have increased risk of treatment failure and relapse. The changes in the MDR-TB regimen apply to both adults and children, though limited data are available for children. The new WHO guidelines for MDR-TB treatment will be released later this year.

The new guidelines are not based on data from any Phase III trial of bedaquiline. In fact, no Phase III trial has been completed yet. WHO, therefore, relied on data of 50 studies and trials involving over 12,000 patients from 26 countries, including several countries where bedaquiline was used, to explore the safety and efficacy of the drug.

Safety and efficacy of the drug

But in the absence of Phase III trial results, how was WHO convinced about the safety and efficacy of the drug? “WHO has recommended that all patients receiving newer drugs such as bedaquiline be closely monitored using dedicated and standardised active pharmcovigilance [monitoring the effects of drugs] measures. WHO has also established a global Active TB Drug Safety Monitoring and Management (aDSM) database to generate evidence on safety of MDR-TB regimens utilising the newer TB drugs,” Dr Karin Weyer,  Coordinator, Diagnostics, Laboratories & Drug Resistance, Global TB Programme at WHO, Geneva says in an email. The data from this programme as well as safety data from observational studies and programmatic use of the drug in over 5,000 patients were analysed. “Results showed significant reductions in patient mortality while and no new safety signals have emerged for both adults and children from these data,” she says.

“In contrast to the Phase IIb data, we have data of much larger number of patients and mortality is significantly lower in the bedaquiline group. This should reassure the sceptics,” says Dr. Soumya Swaminathan, Deputy Director-General (Programmes), WHO, in an email.

The Phase IIb trial involving smaller number of MDR-TB patients showed that the drug was cardiotoxic and hepatotoxic (toxic to the liver) and seemed to cause more deaths. In June 2013, WHO published interim guidance for bedaquiline use, recommending its use in MDR-TB patients only when other treatment options were not possible. And in December 2012, the U.S. Food and Drug Administration granted accelerated approval to the drug for use in “serious or life-threatening conditions”. WHO again reviewed available evidence based on five studies at the end of 2015 and released a report in June 2016. The review showed a reduction in mortality in patients receiving bedaquiline, but there were unexplained serious adverse events of respiratory origin. Hence, the original WHO interim guidance was retained.

Question of ethics

Against this background, why did WHO not wait for the Phase III trial results before revising its guidelines? “Part of the WHO core mandate is to ensure that MDR-TB patients have access to life-saving treatment. For bedaquiline, there is much more data available already (than for delamanid drug, for example) that it drastically cuts down on patients dying from disease and improves the chance for cure while not creating any new safety concerns. Given the complexity of MDR-TB treatment, the low cure rate currently reported globally for treatment success and the evidence from postmarketing surveillance, the use of bedaquiline (and other second-line medicines) is warranted in order to provide life-saving treatment to patients. Treatment can, therefore, not ethically be withheld while waiting for the phase III trial to be completed,” says Dr Weyer.

According to her, the data for delamanid is much less definitive, despite the fact that a phase III clinical trial has been completed; Phase III trial using delamanid did not show any significant difference in curing the disease or reducing deaths thus belying the initial promise.

“Phase III trials are important because they strengthen the certainty in the evidence when reviewed by international practices such as GRADE [Grading of Recommendations Assessment, Development and Evaluation], which is also used by WHO for public health policy development,” Dr. Weyer says. “[But] trials are often mounted around specific research objectives and do not usually address all possible concerns that decision-makers may have. The WHO, therefore, uses the international GRADE method to formulate evidence-based policy recommendations.”

The GRADE approach allows the findings from studies of different types to be summarised with a comprehensive assessment of certainty of their results based on standardised parameters. These findings are then collated into a formal recommendation, which often contains clearly specified conditions for implementation.

None of the second-line medicines for MDR-TB treatment are without adverse effects. But most of the adverse effects can be managed if detected rapidly, with the exception of ototoxicity (hearing loss), which is irreversible and associated with the injectable drugs. “This why WHO is stressing the need for active drug safety monitoring and management as a core principle of clinical care in MDR-TB,” Dr. Weyer stresses.

To make detailed information on clinical management of MDR-TB patients, including monitoring and managing drug adverse effects, WHO is currently updating the Companion Handbook. It will be released together with the upcoming new WHO guidelines.

Published in The Hindu on October 13, 2018