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Drug safety results of over 5,000 patients showed significant reductions in patient mortality while 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.
Phase III trials
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. 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,” Karin Weyer, Coordinator, Diagnostics, Laboratories & Drug Resistance, Global TB Programme at WHO, Geneva said in an email to The Hindu. 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 no new safety signals have emerged for both adults and children,” she said. “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,” Soumya Swaminathan, Deputy Director-General (Programmes), WHO, Geneva said 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.
Source : https://www.thehindu.com/todays-paper/tp-features/tp-sci-tech-and-agri/unethical-to-withhold-bedaquiline-while-waiting-for-phase-iii-results/article25217686.ece
