TOP STORIES

Breakthrough for TB Drug Development Tools

Critical for developing new TB drug regimens is the ability to develop and obtain regulatory qualification for prognostic biomarkers and surrogate endpoints. Advancing these drug development tools requires analyzing various clinical trial data sets—a daunting task without a standard way to view the information across studies. The CPTR Data Standards Workgroup (DSI-WG) has tackled this challenge and produced the first consensus TB data standards.

CPTR plans to use the new CDISC TB data standard, along with CDISC SDTM, for analysis of legacy TB clinical trial data and for new studies going forward. CDISC therapeutic area standards are supplements to the CDISC SDTM (Structured Data Tabulation Model) base clinical data standard. These supplements enable CDISC classification of therapeutic area information not represented within SDTMCDISC (Study Data Tabulation Model Clinical Trial Data Interchange Standards Consortium) clinical data standards. They are important tools for collaborative data sharing and enable the aggregation of data from multiple projects which can yield new insights on subtle signals present in the data. Data standards can also shorten the time to inspect and analyze regulatory submissions.

The Workgroup, chaired by Enrique Aviles (C-Path), Eileen Navarro (FDA), and Bron Kisler (CDISC), achieved a major milestone this month by releasing CDISC TB data standard v.1.0 for public review. Comments on the standard’s ‘controlled terminology’ were due by May 25 and comments on the ‘user guide’ are due by June 8. Please put “CDISC TB User Guide” in the subject line of your email.

This milestone is the culmination of an incredible team effort led by Bess LeRoy (C-Path) and Jane Deifenbach (Pharmstat) and included several focus group discussions comprised of members of all of the CPTR Regulatory Science WG participants. The development of an official data standard is critical for the aggregation and evaluation of clinical trial data that will be important for other CPTR work group efforts including liquid culture biomarker qualification and the development of a TB disease progression model.

To learn more about the draft data standard, two recent webinars are now available for viewing at CPTRInitiative.org. The first webinar, conducted on May 17, provides a general overview of the data standards and CDISC process. The second webinar that was held on May 21 provides an in-depth review.

A Message from the CPTR’s Chair of the Advisory Panel:

Hans-Greorg-EichlerHans-Georg Eichler, Senior Medical Officer, European Medicines Agency and Chair of CPTR Advisory Panel, discusses the major regulatory, scientific, and other topics. “Clearly one of the most promising approaches is to develop regimens instead of individual drugs,” he says. “Now, this is where the challenge for the regulators comes in.” To view this video click here.

 

REGULATORY SCIENCE

INNOVATION Q&A: Qualifying A Model For TB Drug Selection

Tawanda-GumboNew models are critical to designing and developing the best TB drug regimens. CPTR is playing a central role in obtaining regulatory qualification for the hollow fiber model—a qualified tool that will allow scientists to more quickly develop improved regimens, in part through designing better animal studies that more closely predict research outcomes in humans.. Here, we interview Tawanda Gumbo, MD, Associate Professor of Internal Medicine, UT Southwestern Medical Center in Dallas, Texas, who focuses on integrating pharmacokinetics, pharmacodynamics, and pharmacogenomics and is a leader in the CPTR Preclinical Sciences Workgroup’s Hollow Fiber Qualification Team.

  1. What is the purpose of qualifying this tool?
    The role of the qualified tool will be to (a) determine the pharmacokinetic/pharmacodynamics properties of anti-tuberculosis drugs, (b) design drug regimens that kill much better than current regimens, (c) rank anti-tuberculosis drug regimens with 1-2 month studies, and (c) utilize engineering simulations to predict doses in patients as well as the outcome in tuberculosis on treatment. This model can also be used to better design studies of animal tuberculosis studies examining therapeutics.
  2. What is the hollow fiber model and why is it so promising for TB research and accelerating a new regimen?
    The hollow fiber model of tuberculosis, or as we have nicknamed it, “the glass mouse,” consists of two components – a pharmacokinetic system connected to a hollow fiber cartridge. We can mimic the human concentration-time profiles of 1-4 drugs in each system, with drugs administered at different schedules via computerized syringe pump. In the hollow fiber cartridge, analogous to the lung, we have Mycobacterium tuberculosis in different metabolic profiles: log phase, or semi-dormant under acidic conditions, or non-replicating under hypoxic conditions, or within macrophages. The bacteria are in the peripheral compartment of the system where drug diffuses to and fro easily. Thus, we can study different phases of anti-tuberculosis therapy and sample bacteria for total population, drug resistance, molecular events in time, microarrays, and many other markers, and relate them to the changes of drug concentration with time. One can also examine several hypotheses such as non-adherence, pharmacokinetic mismatch and others. Importantly, we can examine novel regimens and the ability to accelerate microbial kill, shut down drug-resistance, and shorten therapy.
  3. Why are you working toward a qualified model—what is the importance?
    One of the interesting findings in the hollow fiber system has been how well it predicts therapeutic events in patients. Such aspects as microbial kill rates, time to emergence of resistance, and efficacy of one or two and three drug combinations closely mirror those in patients. Recently, we have shown how data from this system is predictive. First, we generated the pharmacokinetic variability hypothesis of acquired drug resistance and therapy failure in this system. We then used the results in computer-aided clinical trial simulations to predict rates of resistance emergence and rates of therapy failure in tuberculosis patients. This was published in the Journal of Infectious Diseases in December 2011. After that, we performed a meta-analysis of prospective clinical trials, which confirmed the predictions of this system (just published ahead of print in Clinical Infectious Diseases). We have submitted another prospective clinical trial.
  4. Has CPTR been an effective model for collaboration on this qualified tool?
    Yes. First, it has allowed the hollow fiber model to be examined in the context of other standard tools that are already being used for tuberculosis work, mainly mice and Guinea pigs. In addition, CPTR has helped to organize the materials, timeline and the group of experts that I will work with for the technical details of the qualification process.
  5. What will be the impact of achieving a qualified model?
    First, drug combinations can be examined quickly, at various dose combinations, with results available within 2-4 months. The system can speedily handle many drug combinations which can be combined in a mathematically rational fashion. Second, the issue of drug resistance can be examined right at the beginning of drug regimen design, since resistance emerges very easily in this model and is very easy to quantify. Third, dose schedules and sequencing of drugs in combination regimens are fairly easy to perform with precision since parts of the system are under computerized control. Fourth, it is more straightforward to perform clinical trial simulations that project findings to patients from this model since the impact of dynamic drug concentrations can easily be quantified. Thus, the impact will be faster design of drug regimens and mathematically reliable methods to translate to the clinic and to project to populations of patients. We anticipate this will vastly accelerate drug regimen design as well as bring costs down. In essence it greatly improves the efficiency of R&D in tuberculosis drug development.
  6. There are many challenges in TB drug development. What has been the key to advancing this work to date?
    I would say we have benefited from 5 particular trends. One has been the renewal of focus on solving the problem of tuberculosis, with resources by private/public partnerships, philanthropy, the NIH, TB Alliance, and the Gates Foundation, to name but a few. This has allowed development of tools such as this one. The second has been advances in molecular biology, which has given us tools to better examine responses of Mycobacterium tuberculosis to drugs under different environments that make the bacteria tolerant to drugs. Third has been development of the sciences of pharmacokinetics/pharmacodynamics as well as mathematical modeling, which give a scientific framework for analysis of drug regimens and their doses, and is easily amenable to engineering simulations. Fourth, has been the benefit from many minds that spend time thinking about this problem, people I have worked with in academia and the pharmaceutical industry, and collaborators without whom most of this could not have been possible. Finally, on a personal level, the freedom to work and make this dream possible is through the support from the UT Southwestern Medical Center leadership (my home department in the institution) and recently the Office of Global Health.

REGIMEN DEVELOPMENT

TB Alliance Launches Second Combination Drug Trial
First clinical trial to test a novel drug regimen in both TB and MDR-TB patients

In advance of World TB Day, the TB Alliance announced the launch of NC-002, a new Phase 2 clinical trial testing a drug regimen with the potential to reduce the duration of treatment for TB and some forms of MDR-TB to 4 months—paving the way for shorter, simpler, and better therapies to help stop the pandemic. The new regimen being tested holds particular promise for some MDR-TB patients, as the regimen shows the potential to decrease treatment by 80% and the cost of treatment by 90% compared with today’s current treatment for MDR-TB.

NC-002 tests the new TB drug candidates PA-824 and moxifloxacin in combination with the existing TB drug, pyrazinamide in a new clinical paradigm. Through the use of drug-sensitivity testing, patients that are sensitive to the regimen will be enrolled in the clinical trial, whether they have been previously been classified as “drug-sensitive” or “drug-resistant” patients. The NC-002 trial treats patients for two months and will take place at 8 sites around the world, helping to strengthen clinical capacity.
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CPTR Hosts World TB Day Briefing featuring US Gov’t Representatives

On March 19 in Washington DC, CPTR hosted Cure All: A briefing on the most promising TB drug research. Hosted at the Kaiser Family Foundation, the event featured a panel of senior representatives from a number of US government organizations, as well an announcement of a new regimen trial by the TB Alliance.

“There really is reason for optimism with TB because of the state of the TB research,” said Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID), in his keynote address. Other event speakers included Christine Lubinski (IDSA), Dr. Janet Woodcock, (US FDA), Robert Clay (USAID), and Dr. Mel Spigelman (TB Alliance).

Topics addressed included current research initiatives underway in TB pathogenesis, including development of drugs, vaccines, and diagnostics, and the supporting resources and systems required for approval and introduction of new TB technologies. One recurring theme throughout the talks was the need for cross-sector collaboration, as the TB epidemic is multifaceted and requires interventions of various types of stakeholders.
Click here for an event summary

RESEARCH RESOURCES

Third Community Engagement Forum Will Leverage Knowledge, Inform Best Practices

The TB Alliance is hosting its third Community Engagement Forum from June 18-21, 2012 in Cape Town, South Africa. This forum is targeted to individuals who have a direct role in leading, managing, and implementing site-level community engagement (CE) programs and activities around tuberculosis (TB) drug clinical trials. These individuals include Community Liaison Officers (CLOs), Community Advisory Board (CAB) members, and other research staff that have a role in the implementation of CE activities at their site. This forum promotes cross-site engagement, sharing, and learning. It also provides opportunities for skills and capacity building.

This year’s forum will highlight the importance, benefits, and challenges of implementing CE in TB drug research and, through the sharing of individual site-level experience, will help to identify best practices as well as common barriers to CE program implementation in TB clinical trials.

Other aspects of the forum will focus on:

  • Increasing knowledge about the current status of ongoing TB drug studies
  • Good Participatory Practice (GPP) guidelines
  • Building specific skills such as measuring the impact of CE programs on clinical trials with new monitoring and evaluation (M&E) tools and
  • Advocacy around TB drug studies and the introduction of new TB drug regimens.

The forum will provide both an educational opportunity and hands-on practice, with the goal of exposing forum participants to skills and tools that they can utilize at their sites.

At the conclusion of the forum, participants are expected to be able to:

  • Lead high quality, interactive research literacy training activities appropriate to the setting of TB research
  • Monitor and evaluate the impact of community engagement (using the CE M&E Toolkit)
  • Incorporate Good Participatory Practice (GPP) guidelines into their CE program strategies and
  • Begin to engage in advocacy around TB drug research and development

The CPTR Stakeholder and Community Engagement Workgroup is coordinating with this forum as an opportunity to engage with some of the CE practitioners involved in CPTR clinical trial sites. The group’s goal is to pull together the experiences and strategies of the forum participants to work towards solutions to common challenges with the aim of establishing some best practices for CE in TB clinical trials.