Global TB Community Advisory Board Advocacy Campaigns
Treatment Action Group (TAG), along with other stakeholders in tuberculosis (TB) product development and access, identified the need for TB research-literate community activists. In 2011, TAG initiated a global TB Community Advisory Board (TB CAB) to act in an advisory capacity to institutions conducting clinical trials of new TB drugs, regimens, and vaccines, and provide input on study design, early access, regulatory approval, postmarketing, and implementation strategies.
The TB CAB is dedicated to increasing community involvement in TB research and to mobilizing political will around key TB product development issues.
The broad goals of the TB CAB are to
- interact strategically with developers of TB drugs, diagnostics, and vaccines at key moments in the development process;
- influence research and rollout decisions of developers from a community perspective;
- learn about the priorities and plans of the TB research world, then activate TB CAB members’ networks to educate them and build an advocacy platform to influence the TB research community;
- bring special attention to neglected areas of TB research—e.g., pediatrics and TB/HIV coinfection;
- drive high-quality research and accelerate/support regulatory approval processes; and
- interact with TB research funders and policy makers to drive development and uptake of new TB tools.
2011–2012 ADVOCACY WORK
The TB CAB urged regulators and drug developers to take action on four important issues:
- Harmonizing European and U.S. regulatory guidance on accepted endpoints to streamline and accelerate drug development
- Evaluating the safety of using bedaquiline (marketed as Sirturo) and delamanid (the two most advanced candidates in clinical development for TB) together, as they likely will be used once approved
- Enabling preapproval access to these drugs for select providers to administer them to patients with no other treatment options
- Lowering the price of the GeneXpert machines and MTB/RIF test cartridges to expand access to rapid TB diagnosis
The TB CAB called on the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), Otsuka, Janssen, the South African Medicines Control Council (MCC), and Cepheid to enable safe and effective tools and treatments to detect and fight TB to reach those who urgently need it as quickly as possible:
HARMONIZING EMA AND FDA REQUIREMENTS
In May 2012, the TB CAB advocated for stringent regulatory authorities to ensure that their microbiological endpoint requirements for clinical trials were harmonized. The TB CAB also advocated for the FDA and EMA to require TB drug developers to ensure the safety of their drugs used in combination with other drugs in late-stage development as a requirement for approval.
In June 2012, the FDA responded that requiring drug-drug interaction (DDI) studies as a precondition to approval is extreme and done only in rare cases; a labeling requirement and commitment to phase IV postmarketing surveillance is more likely if there are concerns about co-administration with other drugs entities. The FDA confirmed that early culture conversion is being accepted as a clinical endpoint for accelerated approval and discussed the potential of looking at symptomatic endpoints, which could be used to expedite approval.
In July 2012, the EMA responded that they would transmit the TB CAB suggestions to the EMA main Scientific Committee, the CHMP, for consideration.
In January 2013, following the December 2012 FDA public advisory committee hearing, bedaquiline was approved by the FDA for the treatment of MDR-TB in the United States.
EVALUATING THE SAFETY OF BEDAQUILINE AND DELAMANID
In May 2012, the TB CAB advocated for Janssen and Otsuka to work with a third party, such as the AIDS Clinical Trials Group (ACTG) or the TB Alliance, to ensure that sufficient data are available to inform guidance for appropriate use of delamanid and bedaquiline in combination once approved. The TB CAB also advocated for both drug developers to accelerate, in Janssen’s case, the process of recruiting cohorts for their pediatric studies and, in Otsuka’s case, the process of planning and initiating their study of delamanid in children. The TB CAB encouraged Janssen and Otsuka to participate in discussions with the TB Alliance about a potential XDR-TB rescue study and offered support for developing and rolling out Otsuka’s compassionate use (CU) or expanded access program (EAP).
As of fall 2012, Janssen and Otsuka have engaged in discussions with the National Institutes of Health (NIH) about conducting these necessary DDI studies to evaluate the safety of bedaquiline and delamanid in combination. Janssen is working with the TB Alliance to accelerate the availability of new TB drug regimens, but stated that the other drugs proposed for inclusion in the rescue study are at least a year away from having minimal safety data available. Otsuka stated that they would not participate in the rescue study before receiving regulatory approval.
PREAPPROVAL ACCESS TO BEDAQUILINE
In early April 2012, the TB CAB sent a letter to the South African Medicines Control Council (MCC) and the South African Ministry of Health urging them to take action to expedite compassionate use access for persons with drug-resistant strains of tuberculosis. The TB CAB had heard from Janssen that the MCC’s August 2011 decision to provide Médecins Sans Frontières (MSF) with authorization to administer the compassionate use of bedaquiline had been verbally retracted and as a result Janssen would stop distributing the drug until they received clarification from the MCC.
The MCC registrar of medicines responded to the TB CAB, stating that the current available data are limited and premature, and that the MCC y believes providing patients with access to bedaquiline would be better achieved through an open-label clinical trial design. The letter also stated that the National Department of Health is planning to submit a clinical trial protocol for review to the MCC and relevant ethical committees and that, once received, the review will be expedited.
In December 2012, after much advocacy to allow for preapproval access to bedaquiline, the MCC authorized a clinical access program. Patients infected by highly resistant strains of TB with no other treatment options will be able to receive the drug at four sites in South Africa and will be closely monitored to collect more safety data on bedaquiline. In December 2012, Janssen filed for approval of bedaquiline with the MCC; the MCC has agreed to do a fast-track registration review of bedaquiline.
EXPANDED ACCESS TO THE GENEXPERT MTB/RIF DIAGNOSTIC SYSTEM
In April 2012, the TB CAB wrote a letter to Cepheid, the manufacturer of GeneXpert, a rapid and highly sensitive system for detecting Mycobacterium tuberculosis (MTB) infection and rifampicin (RIF) resistance (). The TB CAB requested that Cepheid
- bring down the price of GeneXpert machines;
- bring down the price of the Xpert MTB/RIF cartridges from US$17 to US$7 for South Africa, UNITAID, and other public health–sector and multilateral donors and providers;
- create a tiered pricing system for private-sector providers in high-burden countries; and
- provide audited accounts of the current manufacturing costs of the machines and cartridges.
In early July 2012, an agreement to reduce the price of Xpert MTB/RIF cartridges was made between the manufacturer and pooled purchasers UNITAID, the President’s Emergency Plan for AIDS Relief (PEPFAR), the United States Agency for International Development (USAID), and the Bill & Melinda Gates Foundation. However, the 40 percent cartridge price reduction to US$10 applies only to a set number of preapproved public-sector purchasers in resource-poor countries with high burdens of multidrug-resistant TB (MDR-TB) and TB/HIV coinfection. In addition, the price of the GeneXpert machine itself is still unacceptably high at US$17,000 per device.