NEW YORK, NY, U.S.A. - Treatment Action Group (TAG) is disappointed by the failure of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) to recommend marketing approval for delamanid, a new drug in development for multidrug-resistant tuberculosis (MDR-TB). The drug, one of the first new compounds to fight tuberculosis (TB) in over 40 years, has demonstrated safety and clinical benefit against multidrug-resistant TB (MDR-TB) in clinical trials to date. The decision by the CHMP was based on the duration of treatment (two months) in the phase IIb randomized controlled trial (Trial 204). It considered that the trial was too short to establish the effectiveness of delamanid in treating TB when added to other anti-TB medicines. Without new treatment options such as delamanid, treatment for people who have the disease will remain intolerable, toxic, lengthy, and ineffective, and patients - of which the European Union and its neighboring countries have many - will continue to die.
"The EMA’s refusal to recommend the approval of a new drug that has more evidence of safety and efficacy than nearly all existing drugs for MDR-TB is both myopic and deeply disappointing," said Mark Harrington, executive director of Treatment Action Group. "The EMA appears to be willing to delay wide availability and access to a drug with considerable evidence of clinical benefit - including a possible survival advantage - and proven ability to shorten time to TB culture conversion. The EMA is failing to respond to the drug-resistant TB crisis - which affects Europe more than any other region in the world - with appropriate twenty-first-century regulatory approaches."
Delamanid, a new drug to fight TB, is currently enrolling patients in its phase III clinical trial, after phase II studies indicated improved efficacy and survival: in a comparison of patients taking a background regimen of MDR-TB drugs, those who also took delamanid for six months were 35 percent more likely to be cured than those who took the drug for two months or less, and about seven times less likely to die after 24 months of follow-up. Yet because the six-month data were from an open-label (rather than a randomized) trial, the EMA is preventing this likely lifesaving drug from being available in European Union member countries. If Otsuka, delamanid’s sponsor, appeals to the EMA and is unsuccessful, delamanid could languish an additional three years before EMA approval. Otsuka is also waiting to hear a response regarding its filing with the Japanese regulatory authority.
Treatment Action Group is baffled at how a sophisticated agency such as the EMA can make such an egregious error by not approving delamanid. Regulatory flexibility in the face of the global emergency of drug-resistant TB is urgently needed. This decision is another indication that regulators worldwide, with the exception of the U.S. Food and Drug Administration (FDA), are completely unprepared for responding appropriately to global health threats such as drug-resistant TB, and that they are not ready to deal with innovation in the TB field. The EMA has now set a terrible example for developing countries, which face enormous drug-resistant TB problems.
"MDR-TB patients need access to better treatments now," said Wim Vandevelde, chair of the Global TB Community Advisory Board and member of the European AIDS Treatment Group. "While Otsuka waits for regulatory approval, it must also make the drug available immediately for patients in urgent need under compassionate use mechanisms that allow for pre-approval access."
Treatment Action Group urges Otsuka to roll out compassionate use programs and expanded access studies in high-burden countries as soon as possible to ensure that treatment is available for those people who may have run out of treatment options. Compassionate use allows the patients access to the drug through pre-approval access programs.
More evidence is needed to confirm delamanid’s safety and efficacy, but phase III trial results are expected within three years. In that period of time, 1.5 million people will be diagnosed with drug-resistant TB, and many of them will die, while others, poorly treated or untreated, will continue to transmit the airborne disease. Bedaquiline, another novel drug for MDR-TB, received accelerated approval by the FDA in December 2012 based on its phase II trial results, but enrollment in its sponsor, Janssen’s, phase III trial, has yet to begin. Most other drugs currently used to treat drug-resistant TB have not been rigorously tested in clinical trials for TB.
"The EMA’s failure to license delamanid increases the likelihood that bedaquiline will be used as a single new agent in failing DR-TB regimens, enhancing the risk of the emergence of resistance, and delaying the chance to use these two promising new drugs together in people at the greatest risk of disease progression and death," commented TAG’s Harrington. "We urge them to reconsider their dangerous decision."