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[This article was published in 2009 and updated in May 2012. Read the update here.]

A global clinical development program, developed and managed by the Global Alliance for TB Drug Development (TB Alliance) and Bayer HealthCare, is evaluating the commonly prescribed antibiotic moxifloxacin for use in a new, first-line tuberculosis (TB) treatment. If successful, the clinical trial program will deliver what may be the first new TB drug approved in more than 40 years—one that saves lives because it will be part of an affordable, shorter TB regimen that is widely accessible and adoptable by economically disadvantaged countries and health care systems in the developing world.

Of no less importance, though, are the lessons learned in overcoming the challenges leading up to this historic partnership, as well as those encountered during this TB drug registration program, which is one of the first to be conducted according to modern regulatory standards. The TB Alliance and Bayer partnership, along with various supporting public and academic organization relationships, represents a potential win-win situation between a not-for-profit organization and a profit-oriented pharmaceutical company that has an existing commercially available drug that has been successful in the global market. The partnership is ahead of its time with innovative strategies that can benefit the field of TB drug development and accelerate the progress of new treatments for neglected diseases.

New Drug for TB Desperately Needed

Tuberculosis usually attacks the lungs but can also affect the central nervous, lymphatic, circulatory, genitourinary and gastrointestinal systems, as well as bones, joints and even skin. It is responsible for killing nearly 1.8 million people worldwide every year. The World Health Organization (WHO) estimates that one-third of the world’s population is infected with Mycobacterium tuberculosis, the organism that causes TB, resulting each year in nine million new cases of active TB.

China and India alone account for 35 percent of all estimated new TB cases each year. An estimated one billion will be newly infected between 2000 and 2020; 200 million will fall ill and 35 million will die. Making the problem even worse, multidrug- resistant tuberculosis (MDR-TB) is an emerging infectious disease threat classified as a category C priority pathogen by the National Institutes of Health.

Today, therapy for drug-sensitive TB is based on a four-drug regimen to prevent the development of drug resistance. That regimen consists of isoniazid, rifampin, pyrazinamide and ethambutol. Discovered 40 or more years ago, each of these drugs must be administered for six to nine months, often under the direct observation of a health care provider. A shorter TB treatment could improve patient adherence to treatment, lower the rates of treatment failure and relapse, and ultimately reduce the emergence of drug-resistant strains that are more deadly, as well as more costly and burdensome to treat.

Developed and marketed since 1999 by Bayer HealthCare, a unit of Leverkusen, Germany-based Bayer, moxifloxacin has been shown in animal studies to be effective against the organism that causes TB. Preclinical studies commissioned by the TB Alliance in 2002-03 and conducted by investigators at The Johns Hopkins University have found, for example, that substituting moxifloxacin for isoniazid in a mouse model system decreased the amount of time needed to eradicate TB infection by two months. A moxifloxacin-containing regimen has the potential to reduce TB treatment time from six or more months to four.

Finding Common Ground

It is uncommon for major drug companies to provide best-selling patented drugs for use against diseases of the poor. Many fear the loss of brand equity in serving poor countries due to possible gray market sales, overuse and misuse, and the possible loss of sales in their primary target markets — wealthy residents of North America, Europe and Japan.

With this challenge as a backdrop, the TB Alliance had to develop a flexible and adaptable strategy at the onset to make the case for moxifloxacin as an affordable TB treatment with a company like Bayer. How does a not-for-profit organization establish a win-win situation for a profit-oriented pharmaceutical company that has an existing commercially available drug that is successful in the global market?

“It seems pretty clear that to manage this and other challenges that arise throughout a project of this magnitude, you first must establish a foundation of trust, mutual respect and commitment to the project for all the parties involved,” says Dr. Mel Spigelman, president and chief executive officer of the TB Alliance, a not-forprofit, product development partnership. “In early negotiations it was integral for each organization to take time to understand the needs and potential reservations of the other as well as to the end user; this process takes time and may be incremental. Today, our organizations work well together and listen to each other because the knowledge, judgment and expertise of each organization were clearly communicated in the negotiating process.”

The TB Alliance and Bayer agreement to develop moxifloxacin for TB brings together some of the world’s leading institutions that already had some knowledge of the drugs’ potential and had an interest in doing independent research. These institutions include the U.S. Centers for Disease Control and Prevention’s TB Trials Consortium, The Johns Hopkins University Center for Tuberculosis Research, the Centre of Medical Microbiology of the Royal Free & University College Medical School at University College London, and the British Medical Research Council Clinical Trials Unit.

Under this historical agreement, the collaborative effort is clearly defined:

• Bayer provides drug development know-how, supplies moxifloxacin (and matching placebo) and will serve as the regulatory sponsor for any U.S. and global registrations.
• University College London serves as the sponsor for the Phase III TB trial, called REMoxTB, and is the home institution of this trial’s chief investigator who provides therapeutic area clinical and laboratory expertise.
• The British Medical Research Council provides clinical trial expertise, particularly as it relates to studies conducted in Africa, and develops and manages the REMoxTB trial database.
• The TB Alliance serves as the lead coordinator of the moxifloxacin clinical development program and hires and oversees contract research organizations to carry out a number of key functions, including packaging, stability testing, releasing and distributing good manufacturing practice-compliant study drug and ensuring good clinical practice-compliance at study sites through site monitoring and auditing. It also ensures compatibility of the clinical and safety databases of the different trials, and coordinates final combined data analysis and writing of the integrated clinical study report. The TB Alliance is also addressing the issue of global clinical trial capacity by the TB Alliance clinical trial site assessment project. Sites selected to participate in the REMoxTB study receive training from the TB Alliance and its partners in conducting registration standard TB drug trials.
• Centers for Disease Control and Prevention’s TB Trials Consortium sponsored two global Phase II trials that evaluated moxifloxacin in nearly 800 combined subjects.
• The Johns Hopkins University Center performed much of the research throughout the development of moxifloxacin, including acting as sponsor for a Phase II trial conducted in Brazil.

“The success of this project depends on a combination of experienced, knowledgeable veterans who obviously know what they are doing and can think out of the box,” says Spigelman. “This leads to trust and confidence, which are the key underlying elements whether there is a profit or not.”

Public-Private Partnership Breaking New Ground

It was important for both organizations to mutually commit to the goals of the partnership, as well as to acknowledge and respect concerns specific to each organization’s business model. Once an understanding was cemented, the parties quickly aligned under an agreement that established the most significant clinical development program for the treatment of active TB since the late 1960s. “This clinical trial program is unique in its dimension for TB development,” says Dr. Martin Springsklee, vice president of global medical affairs for Bayer HealthCare. “It is the first of its kind in TB—to evaluate an existing compound for a new use for neglected disease and gain regulatory approval.”

With partners and sites on five continents, the members of the partnership recognized the project requires effective, communication-based industry and regulatory standards, an especially daunting challenge given the different languages and cultures represented across the vast geographical scope of the clinical trial sites. The partners tackled this issue by forming an array of working groups, operational as well as strategic oversight committees, and developing a local network of contacts that identify and reach key decision-makers and appropriate individuals in each location.

Few clinical trial sites have the capacity and experience to conduct large-scale pivotal registration trials of TB drug candidates, a long standing roadblock to TB drug development. To help remedy this situation for the future and identify potential sites suitable for moxifloxacin pivotal registration trials, the TB Alliance initiated a clinical trial site assessment project to evaluate potential sites. Presently, 93 sites have been assessed, and a number of these sites have been selected for participation in the ongoing Phase III REMoxTB trial. These assessments are available publicly, via a database, and are an important contribution to the scientific and clinical infrastructure needed to support current and future clinical TB research.

As no drugs for TB have been registered according to modern regulatory standards, little regulatory guidance exists to facilitate the approval of new TB regimens by global regulatory and standard-setting authorities. Working together with industry and advocacy partners, the TB Alliance initiated a dialogue with the U.S. Food and Drug Administration, European Medicines Agency, the WHO and a number of high burden countries, through its Open Forum series, to address key issues in the critical path to TB drug registration. Bilateral discussions specific to moxifloxacin are also under way with regulatory agencies.

“The standards that will stem from these activities will be influential because there are no completed registration programs for TB drugs in the modern regulatory environment,” says Dr. Ann Ginsberg, head of clinical development at the TB Alliance. “We’re charting new territory; it’s a learning curve for everyone because the moxifloxacin study is designed to simultaneously establish pivotal data while building capacity.”

In preparing for the launch of a moxifloxacin-containing regimen, initial market access research identified that universal adoption will be a much more difficult and protracted process than originally envisioned due to a lack of established global- and country-level processes for adopting and implementing new TB regimens. To solve this problem, the TB Alliance initiated a “Country Introduction Study” to understand the issues a country might face when adopting, introducing and making available a new TB regimen, once a new TB drug is recommended by global technical agencies. The results will help establish a regulatory strategy for moxifloxacin registration and identify countries that might be engaged to actively introduce a moxifloxacin-based TB treatment regimen.

The TB Alliance and Bayer also have developed an adaptable forecast model to estimate future demand for moxifloxacin for TB treatment and prepare for manufacturing if the drug is registered and adopted for first-line therapy of TB.

“This program is much broader than just about developing moxifloxacin as a potential TB treatment,” says Bayer’s Springsklee. “It will also pave the way for building clinical trial capacity and expertise in TB endemic countries.”

Progress Being Made

Moxifloxacin is in clinical trials to evaluate its potential for treatment-shortening for TB. The Bayer-TB Alliance clinical development program includes three completed Phase II trials and an ongoing pivotal REMoxTB trial. Upon completion, these trials will have enrolled more than 3,000 TB patients. These completed Phase II trials were at sites in Africa, Europe and the Americas, including 10 in the United States. Two drug regimens are being evaluated: the first substitutes moxifloxacin for ethambutol, and the second substitutes moxifloxacin for isoniazid in the standard four-drug treatment regimen. REMoxTB will determine whether these new, four-month regimens are not inferior to standard six-month therapy in terms of failure and relapse, as well as safety.

REMoxTB patient enrollment began in January 2008. A total of 20 to 30 sites, including ones in Asia, Africa and Latin America, are being recruited into the study to reach enrollment targets. Assembling this network of sites has spurred an assessment of the readiness and capabilities of TB clinical trial sites worldwide; a total of 195 sites contacted, and 93 sites in 42 countries have been assessed as of August 2009. Thirty-four REMoxTB protocolspecific assessments have been conducted in addition to these baseline assessments in 19 countries. Assessments related to capacity to support MDR-TB trials have also been conducted in eight countries as part of the overall site assessment project.

Public health experts await the registration of a shorter moxifloxacin-based TB regimen and the subsequent expansion of the underlying knowledge base, capacities and standards necessary to accelerate clinical testing, registration and introduction of additional new regimens. Ultimately, a new regimen will lessen the burden of TB for patients and health systems alike and save lives.

“It is interesting. When you shed past dogmas and look objectively at what we’ve collectively been doing for almost the past decade, it makes all the sense in the world,” says Spigelman of the TB Alliance. “Doing something novel takes time for people to accept.”

By David Perilstein