In the Spotlight
Evidence-based in vitro drug development tool qualified by the European Medicines Agency
An urgent need for new drugs
Tuberculosis (TB) is second only to HIV in deaths, worldwide, from an infectious disease. According to the World Health Organization, more than 9 million people fell ill with tuberculosis and 1.5 million died from this disease in 2013. On the other hand, new cases of TB have been decreasing each year, since 1992, in the US. The disease thrives primarily in regions of poverty and poor health care.
While treatments against TB currently exist, there is an urgent need for new drugs for several reasons. The organism that causes human disease, Mycobacterium tuberculosis, is resistant to killing by many types of antibiotics, and treatment with less than four different antibiotics, simultaneously, can lead to the development of drug resistant strains. Resistance can also occur if the antibiotics are misused, such as with incomplete (must be taken as prescribed for six to nine months) or incorrect (e.g., dose, length of time, drug combination, counterfeit drug) courses of treatment, or when the drugs are not available. Multidrug-resistant TB, and the rarer extensively drug-resistant TB, can be transmitted in the same manner as drug-susceptible TB, and treating them is more toxic, expensive, and less effective.
To prevent the development of drug resistance, novel treatment regimens for TB are needed that will involve combinations of new drugs. To expedite their development and availability to patients, these new drugs will need to be tested in various combinations early in the development cycle, as compared to “the traditional approach of adding or substituting a single drug at a time into existing regimens.” The traditional pathways of drug development and regulatory approval are just too slow for assessing new TB drugs and drug regimens, and the many possible drug combinations, doses, and treatment durations.
A collaborative and multifaceted approach
An innovative approach to address the need for new, more effective, and better-tolerated treatments and treatment regimens for TB was launched with the creation of the TB Alliance in 2000. The highly collaborative projects undertaken by the TB Alliance’s global network of public and private organizations have resulted in “the largest TB drug pipeline in history” (TB Alliance Portfolio; State of TB Alliance’s Discovery Portfolio video).
The TB Alliance, along with the Critical Path Institute and the Bill and Melinda Gates Foundation, established the Critical Path to TB Drug Regimens (CPTR) in 2010. The CPTR is “a broad collaboration of product developers; government, regulatory, and multilateral agencies; donors; academia; advocates; and NGOs that aims to accelerate the development of new, safe, and highly effective tuberculosis treatment regimens with shorter therapy durations.”
CPTR’s approach to accelerate the development and approval of new TB drug regimens involves establishing partnerships to test drug combinations early in their development, as well as developing the regulatory science, infrastructure, and drug-susceptibility diagnostic tests to support this strategy.
One of the successes of CPTR’s novel collaborative approach is the subject of the remainder of this article – the recent regulatory qualification/adoption of the Hollow Fiber System Model for Tuberculosis as a drug development tool.
A novel in vitro preclinical tool
One of the goals of the CPTR initiative is “the evidence-based evaluation of translational tools that support the effective decision making to advance new agents from the preclinical to clinical development space.” To address this goal, preclinical tools to assess in vitro and in vivo efficacy, drug safety and toxicology, PK/PD analyses using appropriate biomarkers, drug metabolism, drug interaction potential, and pharmaceutical profiles could be developed, evaluated, and submitted to regulatory authorities. Success is achieved when a new tool becomes “qualified” or “endorsed” by a regulatory authority as fit for its defined purpose, and then can be used to expedite the drug development process and to support regulatory submissions.
In 2015, the Hollow Fiber System Model for Tuberculosis (HFS-TB) became the first nonclinical drug development tool developed by CPTR working groups to be qualified by a regulatory authority, the European Medicines Agency (EMA).
The HFS-TB has the potential to accelerate TB drug development due to its ability to rapidly and reliably assess the efficacy of individual drugs or multiple drug regimens, and identify optimal drug combinations, doses, and dosing schedules. The optimized drug regimens can then be used in the design of human clinical trials. The EMA also cited the potential for identifying drug combinations with synergistic or additive activity without causing the emergence of resistant strains as a “major advantageous feature.”
Potential impact on animal testing
A recent open-access supplement of the journal Clinical Infectious Diseases is composed of six articles about the HFS-TB model. The different regulatory pathways taken by the CPTR team with the EMA and the US Food and Drug Administration (FDA) are described in the article by Romero, Clay, and Hanna (2015). Cavaleri and Manolis (2015) explain EMA’s approach and qualification of HFS-TB, and Chilukuri, et al. (2015) provide the FDA’s perspective.
The submission to EMA was for a qualification opinion, which is EMA’s procedure “for discussion and data sharing on novel methodologies. A qualified method is a method that is accepted by the Committee of Human Medicinal Products (CHMP) to be used in regulatory submissions.” The nine-page EMA document, Qualification opinion on in-vitro hollow-fibre-system model of tuberculosis (HFS-TB), summarizes the background information and qualification exercise submitted to EMA, provides a list of EMA’s concerns/limitations on the data submitted, and provides the EMA opinion. The EMA concluded that “the totality of evidence …support the qualification of the HFS-TB system.”
A key advantage of the HFS-TB system was said to be its superior performance over animal models for TB drug development. Various problems with the animal models, such as the half-life of some drugs being very different from that in humans, are reported in the scientific literature (e.g., Gumbo, et al., 2009; Pasipanodya, et al., 2013), and also explained in the EMA report. The CPTR team provided support for their claims that “the HFS-TB offers distinct advantages to current in vivo model systems for evaluating efficacy, resistance potential, and dose determination….” The EMA opinion concluded that the HFS-TB model cannot replace preclinical animal or clinical data, but, among other benefits, can be used to reduce the number of regimens that are tested in vivo at the nonclinical and clinical phases, and limit the doses tested in vivo. Reduced testing needs would typically also reduce development time and costs.
Submission to FDA used their Voluntary Exploration Data Submission (VXDS) mechanism. “The VXDS program is a non-regulatory, flexible mechanism for scientific exchange between FDA and external scientists [where] a greater understanding …may ultimately enhance therapeutic product development and/or advance regulatory science and policy.” As a result, the FDA described HFS-TB’s utility as part of an update to the FDA guidance on TB drug development. In the related publication, FDA scientists described potential regulatory applicability for the HFS-TB tool, although support did not seem to be as strong as with EMA. An updated draft of FDA guidance on TB drug development is not yet available for review/comment.
A blueprint for innovative collaboration
An overarching goal of the TB Alliance and CPTR initiative is to provide new multi-drug regimens that offer faster, safer, and more effective treatments for TB and drug-resistant TB. Participants recognized early on that this would require a new paradigm. In addition to developing a new pipeline of drugs, success would also require “changing the way TB drug development is conducted.” Thus, their multi-dimensional strategy supportsand catalyzes “advances in regulatory science, the development of infrastructure, and other progress needed to accelerate the pace of development and introduction of novel regimens.”
This spirit of innovative collaboration and a common commitment among CPTR partners “serves as a blueprint for collaboration in other disease areas for which combination therapy is standard, such as cancer and Hepatitis C.” The framework could also serve as a model for addressing other complex challenges that require both scientific innovation and regulatory solutions.