Time of great change in TB drug development

Speech delivered to Critical Path to TB Drug Regimens meeting, Washington DC

Mark Harrington
Nov. 9, 2011, 2:45 p.m.
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We are living in a time of great change and excitement in TB drug development. The last year has witnessed a number of epochal changes, including the approval and rollout of the most rapid test for TB ever discovered, the GeneXpert; the combination TB drug studies in the relapse mouse model of Eric Nuermberger and Jacques Grosset at Johns Hopkins with support from the TB Alliance; the progression of TMC207 into late phase II and of OPC67683 into phase III; and the first new regimen EBA study, NC-001 also from the Alliance. However the outside world is largely unaware of these advances. Unlike malaria where there is great excitement over new vaccine research results, or HIV where there is excitement -- and controversy -- over how best to implement new research results on the role of antiretroviral treatment in earlier disease for both treatment and prevention of infection -- the TB research world has not effectively communicated its recent progress to the public, policymakers, affected communities, and governments. To increase community involvement and to mobilize political will, in the past two days TAG convened the first meeting of the international TB Community Advisory Board (TB CAB), with activist and public health participants from Belgium, Brasil, India, Kenya, Portugal, South Africa, the UK, and the US. The TB CAB is comprised of individuals who are extensively involved in networks of HIV and TB activists and with deep research and activist experience. We spent a day sharing and learning and then on the second day met in sequence with the TB Alliance, Tibotec, and Otsuka, in productive meetings which were a useful starting point for our work. We came up with some immediate action recommendations which we would like to share: 1. This meeting [the CPTR] is about developing TB regimens, not TB drugs alone. Yet the two new drugs which are the farthest along in development -- bedaquiline (TMC207) and delamanid (OPC6783) -- both of which are being studied in persons with MDR-, pre-XDR, and XDR-TB -- and both of which are entering phase III studies and which are likely to be submitted to regulatory authorities in the coming year -- have not been studied together in the pharmacokinetic studies which will tell us how they interact and whether they are safe to use together. However, when they are approved they are likely to be used together in the field because people with extensively drug resistant TB desperately need effective new oral drugs to shorten their time to culture conversion, and hopefully, cure. Therefore we call upon Otsuka and Tibotec to support the necessary PK studies to demonstrate whether the drugs are safe to use together; and we call on EMA and FDA to demand that the companies provide these data as a condition for accelerated approval. 2. In a related manner, we need greater harmonization among drug sponsors, regulators, providers, and national health authorities to expedite expanded and early access and compassionate use of the new TB drugs as they enter phase III. While Tibotec has already initiated and Otsuka is likely to initiate compassionate use/expanded access programs, to take one example, in South Africa, the Medicines Control Council (MCC) and the Department of Health (DOH) must work together to facilitate access to these investigational agents to people with pre-XDR and XDR-TB. 3. Similarly, we need sponsors of new drugs and regimens to place greater priority on developing progressive and parallel (rather than sequential) pediatric investigational programs for new agents as they enter phase III rather than waiting for phase III to be completed as over one million of the new TB patients each year are infants, children, and adolescents. 4. Sponsors need better communication and involvement of regulatory agencies, which need to harmonize their requirements for accelerated approval for new TB drugs and regimens. Currently the EMA has different standards for such approval than the US FDA which has been less clear about what is required. We have new drugs and regimens which shorten the time to culture conversion -- and hopefully cure -- and these drugs and regimens need to be regulated in a flexible, enlightened, and harmonized fashion using 21st century regulatory science to facilitate their rapid evaluation, approval, and delivery. 5. Finally, going back to my point earlier about communication and political will, we all need to do a better job of explaining our work in the outside world, to obtain the political will, resources, and support necessary to expedite this research, so that the 450,000 people with new MDR-TB each year and the 8 million people who get active TB disease annually can be diagnosed and cured faster. It's time to end the social injustice, exclusion, and failures of social justice and public health which condemn so many unjustly and unnecessarily to become sick and to die from TB.